Contents I

MEDICAL RADIOLOGY
Diagnostic Imaging
Editors:
A. L. Baert, Leuven
M. Knauth, Göttingen
K. Sartor, Heidelberg
 Contents III

M. F. Reiser · G. van Kaick

C. Fink · S. O. Schoenberg (Eds.)

Screening and Preventive

Diagnosis with
Radiological Imaging
With Contributions by

S. H. Aguiar · S. J. Allison · G. Antoch · S. M. Ascher · A. Baur-Melnyk · C. R. Becker

N. Becker · F. Berger · U. Beuers · H. Boehm · J. Bogner · G. Brix · M. Cham · S. Delorme
G. U. Denk · O. Dietrich · R. Eibel · M. Essig · Z. A. Fayad · D. Filipas · C. Fink
M. Fischereder · A. Graser · J. Griebel · V. Heinemann · K. Hellerhoff · C. I. Henschke
P. Herzog · U. Hoffmann · H. Kramer · S. Ladd · D. Nowak · S. Pahernik · C. Perlet
S. A. Polin · F. Raue · M. F. Reiser · S. Reiter-Theil · J. H. F. Rudd · T. Schlossbauer
S. O. Schoenberg · J. Schröder · R. Schulz-Wendtland · R. Stahl · N. Stingelin Giles
G. Stolz · J. W. Thüroff · G. van Kaick · N. Weiss · D. Weitzel · D. Y. Yankelevitz

Foreword by
A. L. Baert

With 123 Figures in 226 Separate Illustrations, 70 in Color and 49 Tables

123
IV Contents

Maximilian F. Reiser, MD Christian Fink, MD

Professor and Chairman Associate Professor
Department of Clinical Radiology Section Chief Cardiothoracic Imaging
University Hospitals – Grosshadern and Innenstadt Department of Clinical Radiology
Ludwig-Maximilians-University of Munich University Hospital Mannheim
Marchioninistrasse 15 Medical Faculty Mannheim
81377 Munich University of Heidelberg
Germany Theodor-Kutzer-Ufer 1–3
68167 Mannheim
Gerhard van Kaick, MD Germany
Professor Emeritus
German Cancer Research Center (DKFZ) Stefan O. Schoenberg, MD
Im Neuenheimer Feld 280 Professor and Chairman
69120 Heidelberg Department of Clinical Radiology
Germany University Hospital Mannheim
Medical Faculty Mannheim
University of Heidelberg
Theodor-Kutzer-Ufer 1–3
68167 Mannheim
Germany

Medical Radiology · Diagnostic Imaging and Radiation Oncology

Series Editors:
A. L. Baert · L. W. Brady · H.-P. Heilmann · M. Knauth · M. Molls · C. Nieder · K. Sartor
Continuation of Handbuch der medizinischen Radiologie
Encyclopedia of Medical Radiology

Library of Congress Control Number: 2006927816

ISBN 978-3-540-23553-8 Springer Berlin Heidelberg New York

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 Contents V

Foreword

In modern society ever more attention is focused on preventive medicine and ever
more resources are allocated to this rapidly growing field of medical activity.
Image-based early detection and correct diagnosis of a whole spectrum of diseases
is the key component of many programmes of population screening.
This book is the most comprehensive up-to-date work on the many, and sometimes
complex, aspects of preventive diagnosis with radiological imaging.
It not only covers the important fundamentals of mass screening and preventive
diagnosis, but also deals systematically and in depth with most clinical areas where
radiological screening has proven its value.
I am very much indebted to the editors of this volume, M. F. Reiser, G. van Kaick,
C. Fink and S. O. Schoenberg – who enthusiastically undertook this difficult task – for
their dedication and tireless efforts to finalize this project successfully in such a rela-
tively short period of time.
I would like to congratulate the editors and contributing authors, both from Europe
and overseas and all carefully chosen for their exceptional expertise in the field, on the
outstanding quality of the different chapters and the wide range of topics covered in
this book.
I strongly recommend this volume to all clinicians involved in population screening
and preventive diagnosis with radiological imaging. It will without doubt support and
guide them in their routine clinical activities.
I am confident that this volume will stimulate great interest within the medical com-
munity and that it will meet with the same success as the other volumes in this series.

Leuven Albert L. Baert

 Contents VII

Introduction

Modern, non-invasive imaging technologies have developed rapidly and now enable
us to image extended anatomical areas or even the entire body. Outside any screening
programs, ultrasound, e.g., has contributed to early detection of renal cell carcinomas
– simply by being performed for which reason whatsoever. Today, more than 50% of
renal cell carcinomas are detected incidentally, and most frequently in a curable stage.
The range of diseases which can possibly be identified by imaging is wide: Cancer,
atherosclerosis, aneurysms, osteoporosis, brain atrophy, and more.
When whole-body CT as a screening method is offered to the so-called “Worried
Wealthy”, like in the United States, there is legitimate criticism, because its benefit is
unproven, and because ionizing radiation and possibly contrast media are used.
With magnetic resonance imaging, no risks are imposed by ionizing radiation, but all
other concerns remain and must be weighted against the expected benefit: Costs, con-
cerns, time, and the inherent risks of further diagnostic procedures for confirmation of
unclear imaging findings. There are additional ethical issues, e.g., whether insurance
companies must be notified of significant screening findings, or how to deal with signs
of intractable disease, like, e.g., brain atrophy as a possible herald of dementia.
Studies of asymptomatic persons, particularly using MRI, will play a gaining role
for various reasons:

Awareness for health and fitness is increasing, and people may be worried for their
health, even without obvious reason.

Entrepreneurs, physicians and non-physicians who are convinced having detected a
new field of engagement will offer this method to the above-mentioned persons.

Industrial companies developing and producing medical devices suitable for screen-
ing will have legitimate financial interests in that they are used. For ahead planning
of their developments, they also need qualified and realistic advice, which fields may
in future warrant new or dedicated imaging devices.

For radiological prevention procedures, the same requirements apply as in non-

radiological screening:

High sensitivity

High specificity

Non-invasiveness

Balanced cost-benefit ratio

Long preclinical phase in which the disease can be detected

Possible therapeutic options.
VIII Introduction

Today, as we are experiencing a plethora of imaging procedures offered to the healthy,

and the least among them evidence-based or at least scientifically accompanied, a sober
and academic analysis is overdue. “Sine ira et studio”, the possibilities, limitations and
risks of radiological secondary screening need to be analysed and weighted against
each other – in the interest of all three above groups.
The questions to be answered are:

Which examination technique is best for which organ, and for which disease?

Should whole-body examinations or high-detail techniques be used?

Should screening be offered to all or rather to high-risk candidates – keeping in mind
the consequences for an optimal cost benefit ratio?

Who is to pay? What are the consequences for health insurers?

Which doctor should receive which results, and what are the clinical consequences?

Once early signs are present, can the progression to overt disease be effectively pre-
vented, and how many years of survival or at least wellbeing can be achieved?

Which are the consequences for the one with a pathological result: Stress, grief, reac-
tions by family, friends, physicians, and – very important – employers?

To assess the benefits of screening is difficult, and hardly ever possible based on
individual fates. Too much are, e.g., survival or time to progression flawed by effects
like the “Lead time bias” or the “Length time bias”. It requires epidemiological meth-
ods to approach this problem, and it may take decades to achieve results.
Today, when high-level health service becomes increasingly unaffordable to the
community, who will pay how much for mass screening and related procedures, are
the expenditures balanced by benefits? If benefits are immaterial, how much are they
worth? Projections for proven methods like the “Papanicolaou-Test” starting with an
age of 20 years calculate 99.000 dollars per life saved. With annual mammography
for early detection of breast cancer between the 55 and 64 years we have to calculate
132.000 dollars, and for colorectal cancer up to 92.000 dollars for each saved person
(Friedenberg, 2002). Although these figures are only rough estimates, they demon-
strate that mass screening has its price and critical projection and calculation of costs
are essential, particularly with limited resources. This unconsidered, the intention of
secondary prevention must not be forgotten: To save lifes, spare harm and grief, and to
avoid costly treatment of advanced disease and disability.
The participation in screening is highly variable – high, e.g., in the Netherlands, but
only between 15 % (men) and 30 % (women) in Germany. Very probably, the participa-
tion will increase if screening is offered to risk groups, and if the persons at risk become
aware of this.
Reading imaging studies in screening requires a profound “change of mind”: Unlike
radiological studies which are clinically indicated, the vast majority of screening stud-
ies are normal, and almost all participants do not have a disease. The first command-
ment “not to harm” means to spare the healthy unnecessary distress or even harmful
diagnostic tests. This requires special training, rigid quality assurance, and regular
auditing. Better no screening than bad screening.
 Introduction IX

Without doubt, the “king`s road” of preventive medicine would be primary preven-
tion. If causes of diseases are known – which is the case in only few types of cancer and
vascular diseases – eliminating the cause or possibly antagonizing its harmful effects
(chemo-prevention) might result in true primary prevention. In most instances, how-
ever, the causes are poorly understood, multiple, or impossible (genetic disposition) or
difficult to influence. Who ever tried to “change his lifestyle” can tell how easily this
is said, and how difficult to achieve. So, for most diseases, we are left with secondary
prevention.
Therefore, shall we do nothing because we can not achieve everything? To answer
this, we need large and solid, controlled trials, even if they are difficult and expen-
sive.
So, screening is an entirely unknown terrain. No patients, but clients, no personal-
ized medicine, but standard procedures, and a different attitude of all involved per-
sons. Finally, it must be stressed that secondary radiological prevention does not mean
to open “new markets”. It aims at improving treatment results by early detection of
diseases, and thereby help to a longer life in acceptable health.

Munich Maximilian F. Reiser

Heidelberg Gerhard van Kaick
Mannheim Christian Fink
Mannheim Stefan O. Schoenberg

Friedenberg, R.M. The 21st Century: The age of screening. Radiology 2002; 223: 1–4.
 Contents XI

Contents

Part 1: Fundamentals and Prerequisites

1 Epidemiology and Statistics

Nikolaus Becker. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2 Relevant Diseases and Therapeutic Options

2.1 Oncological Diseases

Volker Heinemann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.2 Vascular Diseases Relevant to Screening

Norbert Weiss and Ulrich Hoffmann . . . . . . . . . . . . . . . . . . . . . . 23

3 Pathology

3.1 General Oncological Aspects of Screening

Stefan Delorme and Gerhard van Kaick . . . . . . . . . . . . . . . . . . . . 39

3.2 Screening for Vascular Pathology

James H. F. Rudd, Silvia H. Aguiar, and Zahi A. Fayad . . . . . . . . . . . . . 45

4 Screening and Preventive Diagnosis with Radiological Imaging

Diagnostic Algorithms for Whole-Body Exams
Harald Kramer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

5 Personnel and Structural Prerequisites for Screening-Programs

Stefan O. Schoenberg and Maximilian F. Reiser. . . . . . . . . . . . . . . . . . . 63

6 Technical Prerequisites

6.1 Whole-Body MRI

Olaf Dietrich and Stefan O. Schoenberg. . . . . . . . . . . . . . . . . . . . 77

6.2 CT
Chistoph Becker, Anno Graser, and Peter Herzog . . . . . . . . . . . . . . 89

6.3 Ultrasound
Stefan Delorme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

6.4 Mammography
Rüdiger Schulz-Wendtland . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

6.5 PET-CT
Gerald Antoch and Robert Stahl . . . . . . . . . . . . . . . . . . . . . . . . 113
XII Contents

7 Risks of Screening and Preventive Diagnosis

Jürgen Griebel, Gunnar Brix, and Harald Kramer . . . . . . . . . . . . . . . . 127

8 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging

Stella Reiter-Theil and Nicola Stingelin Giles . . . . . . . . . . . . . . . . . . 137

Part 2: Organ-Related Examinations

Screening in Unselected Populations

9 Cardiovascular Diseases
9.1 MRI
Susanne Ladd and Harald Kramer . . . . . . . . . . . . . . . . . . . . . . . . 147
9.2 CT
Cristoph R. Becker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.3 Duplex Ultrasound of the Carotid Arteries:
Practical Aspects and Results of Screening for Carotid Disease
Norbert Weiss and Ulrich Hoffmann . . . . . . . . . . . . . . . . . . . . . . 165

10 Oncological Diseases
10.1 Breast Cancer
Karin Hellerhoff, Claudia Perlet, and Thomas Schlossbauer . . . . . . 183
10.2 Renal Cancer - Ultrasound
Dragana Filipas, Sascha Pahernik, and Joachim W. Thüroff . . . . . . . . 193
10.3 Colorectal Cancer
Anno Graser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

11 Congenital Pediatric Diseases

11.1 Pre- and Postnatal Kidney Screening
Gabriela Stolz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
11.2 Sonographic Screening of the Infant Hip
Dieter Weitzel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

12 Magnetic Resonance Imaging in Prevention of Alzheimer’s Disease

Marco Essig and Johannes Schröder. . . . . . . . . . . . . . . . . . . . . . . . . . 233

13 Osteoporosis
Andrea Baur-Melnyk and Holger Boehm . . . . . . . . . . . . . . . . . . . . . . . 249
 Contents XIII

Preventive Diagnosis for Risk Groups

14 Exogenous Exposure: Occupation and Environment

14.1 Asbestos
Roger Eibel and Dennis Nowak . . . . . . . . . . . . . . . . . . . . . . . . . . 261
14.2 Heavy Smokers
14.2.1 CT Screening for Lung Cancer for High-Risk People
Claudia I. Henschke, Matthew D. Cham,
and David F. Yankelevitz . . . . . . . . . . . . . . . . . . . . . . . . . . 275
14.2.2 Characterization of Lung Nodules Using Radiological Imaging
Christian Fink and Frank Berger . . . . . . . . . . . . . . . . . . . . 285
14.3 Screening for Endometrial Cancer in Asymptomatic Patients
Receiving Tamoxifen Therapy
Sandra A. Polin, Sandra J. Allison, and Susan M. Ascher . . . . . . . . . . 293

15 Genetic Disposition
15.1 Breast Cancer – Screening in Women with an Inherited Risk
Thomas Schlossbauer, Karin Hellerhoff, and Claudia Perlet. . . . . . 311
15.2 Practical Aspects and Results of Screening for Medullary Thyroid Carcinoma
Friedhelm Raue and Stefan Delorme . . . . . . . . . . . . . . . . . . . . . . 323

16 Predisposing Diseases
16.1 Chronic Hepatitis and Liver Cirrhosis
Gerald U. Denk and Ulrich Beuers . . . . . . . . . . . . . . . . . . . . . . . . 329
16.2 Autoimmune Disease, AIDS and Transplanted Patients
Johannes R. Bogner and Michael Fischereder . . . . . . . . . . . . . . . . 335

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

 Epidemiology and Statistics 1

Part 1:
Fundamentals and Prerequisites
 Epidemiology and Statistics 3

Epidemiology and Statistics 1

Nikolaus Becker

CONTENTS 1.1
Introduction

1.1 Introduction 3 The concept of screening is that detection of early

disease may permit treatment at a more tractable
1.2 Screening as Periodical Application of
Dedicated Tests in a Basically Unaffected stage and thus improve prospects for survival and
Population 4 prevention of death from the disease (Morrison
1992). In technical terms, it is the periodical rou-
1.3 Inevitability of Side Effects of Screening 4 tine examination of the general population or large
subgroups of it for early asymptomatic disease by
1.4 Inappropriateness of Clinical Parameters for
Proof of Effectiveness of a Screening application of dedicated screening tests (UICC 1978;
Modality 5 Miller 1985).
The principle is so suggestive and early practi-
1.5 Appropriate Epidemiological Study cal examples were so promising that the concept
Designs 6
appeared undisputable for a long time. Successful
1.6 Overdiagnosis 6 prevention of childhood disease by postnatal screen-
ing, or the 80%–90% prevention of cervical cancer
1.7 Sensitivity, Specificity and Predictive Value 7 by regular screening with the Papanicolao test each
3–5 years appeared convincing by itself and gave
1.8 Combination of Tests 8
rise to the suggestion to extend the approach suc-
1.9 Combination of Outcomes 9 cessfully to other diseases as well getting a powerful
tool either for disease prevention or for prevention
1.10 Conclusions and Discussion 10 of a lethal course of disease.
References 11
However, more in-depth analysis of the intrinsic
mechanisms of systematic screening and experi-
ences with less effective screening approaches indi-
cate that – against popular belief – screening as a
strategy of “secondary” disease prevention is not so
straightforward and requires specific constraints
in terms of scientific proof of effectiveness before
introduction in routine health care and regular
quality control in routine operation. Each is – as to
be shown – a matter of epidemiological methodol-
ogy.
In the following, the basic methodological issues
N. Becker, PhD
of systematic screening and the related problems
Professor, Division of Cancer Epidemiology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 will be outlined, and full-body screening discussed
Heidelberg, Germany in the light of these principles.
4 N. Becker
1.2
Screening as Periodical Application of
Dedicated Tests in a Basically Unaffected
Population
The definition of screening given above implies that
screening takes place in a population which does not
carry the disease of interest in its overwhelming major-
ity, and most of it will never get the disease during
lifetime. For example, in mammography screening,
the detection rate within one screening round is about
3–6 cases per 1000 screened subjects; the lifetime risk
of getting breast cancer is around 10%. This means
that in about 99.5% of women no breast cancer will
be found per screening round, and in about 90% of
women a breast cancer will never be diagnosed. For
other cancer sites for which screening appears effec-
tive, conditions are not substantially different.
Thus, the screening physician leaves the area of
diagnostics and treatment of disease and gets in
touch with qualitatively different problems than in
disease-related care by application of a diagnostic test
to a chiefly unaffected clientele (not patients!). A key
issue of that difference is the ethical assessment of
potential side effects of the respective screening test.
In disease care, the side effects of the diagnostic tests
are counterbalanced by the progress of the disease
to be diagnosed if the patient refused their applica-
tion. The patient will most likely have personal ben-
efit by application of diagnostic tests and takes thus
potential side effects into account. Within screen-
ing, potential side effects of the screening tests are
not counterbalanced by progress of disease for most
screenees, since currently they do not carry the dis-
ease and most of them will never carry the disease.
Thus, the ethically crucial difference between diag-
nostics of disease and screening for disease is that all
screenees are target for potential side effects, while
the benefit is confined to the comparatively small
group of factual disease carriers which are found by
screening and prevented from death from the disease.
This setting implicates especially high requirements
on the safety and other relevant properties of the test.
It excludes in any way an approach to screening which
promotes the free application of a novel test based only
on some early promising findings without proper sci-
entific proof of effectiveness and assessment of poten-
tial side effects in terms of a benefit – side effect ratio
prior to broad practical application.
Initially it appears suggestive not allowing for
any side effects of screening tests.
1.3
Inevitability of Side Effects of Screening
Unfortunately, side effects are an intrinsic and
inevitable property of screening. Some of them are
test-related and some are related to the crucial role
which specificity plays in screening.
Examples for test-specific side effects are the
exposure to X-ray with mammography screening or
complications with colonoscopy. In the individual
setting of X-ray exposure within diagnostic mam-
mography, it is reasonable to tell the patient that
the administered dose is on a level which makes
personal harm for her very unlikely. However, in a
screening population of millions of women, a small
rate of, say, 0.004% of induced cancers (see, e.g.,
Jung 2001) implies dozens of cancer cases induced
by screening. In screening with faecal occult blood
test (FOBT), experience shows that about 1% of
the tests are positive among which a considerable
portion requires further diagnostic assessment by
colonoscopy. Serious complications such as perfo-
ration or death through colonoscopy are very rare,
and it is again reasonable to tell the patient in an
individual diagnostic setting that it is very unlikely
(but not impossible) for him to be harmed by its
administration. In the screening setting with appli-
cation of the FOBT to dozens of millions of subjects
(if compliance is as high as desired by programme
authorities), hundreds of thousands of assessment
colonoscopies have to be carried out, and the small
individual risk of complications extends to dozens
of perforations and several deaths by screening on
the population level. Unlike mammography screen-
ing, where cancer cases due to the cumulative pop-
ulation dose of radiation is a statistical quantity,
deaths by FOBT screening are personally identifi-
able subjects who lose their lives because they par-
ticipated in the programme and might even have
turned out to have been unaffected by colorectal
cancer.
Inherent side effects of the principle of screening
are false-positive results which increase participants’
anxiety and lead to the need for further diagnostic
investigations which may themselves generate side-
effects (e.g., additional radiation doses in the case
of radiological assessment, colonoscopy after FOBT,
see above) and additional expense. There is inevita-
bly collateral damage from screening since none of
the screening tests so far known has a 100% specifi-
city (see below).

A further screening-related side-effect is over-
diagnosis and overtreatment (for definition see
below). These turn participants – who would never
have got cancer without screening – into cancer
patients and possibly lead to unnecessary treatment
with further – treatment-related – side-effects.
These issues underline the fact that screening
is ethically only justifiable if evidence is available
that those risks are counterbalanced by a screen-
ing-related benefit which is larger by magnitudes
than the risks. Thus, it is ethically mandatory that
scientific evidence about a clearly positive benefit/
risk ratio is demonstrated before a novel screening
modality is put into application, and that the ben-
efit/risk ratio remains positive throughout when it
has been put into practice in the frame of a screen-
ing programme. Assurance of programme quality is
thus not optional but condition sine qua non for its
ethical justification.
1.4
Inappropriateness of Clinical Parameters
for Proof of Effectiveness of a Screening
Modality
Unfortunately, the clinical parameters survival
and stage distribution, which are so impressively
affected by screening and comparatively easily to
Phase of detectability
Onset of
Carcinogenesis
A B
Fig. 1.1. Schematic illustration of
the biological course of disease with
a preclinical, screening-detectable
phase and a symptomatic, clinical
phase including the representation of Preclinical asymptomatic
ineffective and effective screening phase
Epidemiology and Statistics 5
quantify, are unsuited for proof of effectiveness due
to uncontrollable screening-related bias.
Survival time is necessarily prolonged since
screening tends to advance the time of diagnosis.
Thus, observation time from diagnosis to endpoint
of interest, occurrence of the disease or death from
the disease, is prolonged to the “left” (see Fig. 1.1),
while the intention of screening is to achieve pro-
longed survival “to the right” due to earlier start of
– and thus more effective – treatment. This implies
that effective screening would prolong observation
time in both directions. Longer survival can, how-
ever, not be distinguished from longer observation
time just by advanced diagnosis (ineffective screen-
ing). Only quantification of the outcome of interest
(incidence of the target disease or mortality from the
target disease) on the population level, i.e. by appro-
priate epidemiological methods, can overcome this
obstacle. This is one reason why epidemiology plays
a crucial role in screening.
Similarly, stage distribution is also uncontrol-
lably biased by screening. Slower growing tumours
are within the preclinically detectable period for a
longer time span and more likely to be detected by
screening in this earlier stage than faster growing
tumours which are more likely to become clini-
cally symptomatic within the interval between two
screening rounds than the slower growing cancers
(see Fig. 1.2). Thus, the slower growing, less aggres-
sive tumours occur as early stage tumours with
a higher proportion among the screen-detected
Death if no Death with
or ineffective screening effective
First clinical symptoms screening
by screening Onset of symptomatic
disease
Time
C D E
Biological course of disease
Clinical course without screening
Course with ineffective screening
Course with effective
screening
„lead time“
True prolongation of
lifetime with effective
screening
Clinical phase
6 N. Becker
Time
SCREENING
Fig. 1.2. Representation of length-biased sampling. Hori-
zontal lines represent cases of variable duration. Those with
longer duration are more likely to be prevalent at the time a
screen takes place. Source: Walter and Day (1983), Fig. 1.2
cancers, while the faster growing, more aggressive
tumours, occur as advanced-stage tumours with a
high proportion among the clinically detected can-
cers. Since the former are more likely to have the
better prognosis and the latter the worse, the diag-
nostic and clinical profi le of the two sets of cancers
is rather different simply due to the screening inter-
vention and even if the purpose of screening, effec-
tive therapeutic intervention, would completely fail.
Thus, the effectiveness of screening in improving
the prognosis of cancer patients cannot be proven
by considering the quantity “stage distribution”.
Again, examination of stage shift under screening
within the entire target population of screening is
required to demonstrate effectiveness. Thus control
of this second bias also leads to the need of an epide-
miological approach.
The implication of these considerations is that
the ongoing quality assurance of running screening
programmes must be carried out using an epidemio-
logical approach. Thus, epidemiological parameters
play a crucial role for quality assurance of screening
programmes (see, e.g., Perry et al. 2006).
1.5
Appropriate Epidemiological Study
Designs
The ideal approach is the prospective randomized
screening study. Despite some similarities to ran-
domised clinical trials, screening studies show
substantial differences: they are based on unaf-
fected, i.e. “healthy”, volunteers for many tests;
they cannot be blind and they have frequently
a long duration. “Contamination” in the control
group (the volunteers assigned to the control
group undergo the screening test on their own
expense) has to be taken into account, and sample
sizes must be specified in accordance with sta-
tistical methods dedicated to this type of study.
Examples of screening modalities which have been
evaluated in this way are mammography screen-
ing, colorectal screening with the faecal occult
blood test (FOBT) and neuroblastoma screening
(see below).
A weaker but sometimes used approach is a non-
randomised prospective design which has either
an interventional component (“quasi-experimental
study”) or is purely observational. The British mam-
mography study (Moss et al. 1999) and the Austrian
Prostate screening study with PSA (Bartsch et al.
2001) were designed in this way.
Yet stronger limitations apply to case-control
studies in which, among subjects having the disease
of interest and an appropriately selected compari-
son group of disease-free individuals, the history
of participation at screening examinations is deter-
mined and the relative risk of not having complied
with screening offers calculated. Self-selection of
participants, the need to compare dead cases with
dead controls if mortality is the endpoint of interest,
are factors which seriously bias the outcome of stud-
ies with this design.
The weakest approach is to carry out geographi-
cal comparisons (“ecological correlation”) between
regions for which data or indicators for high or low
prevalence of screening exist. Nevertheless, this
approach provided convincing evidence in the case
of cervical cancer screening, since the effect is so
substantial (IARC 2005).
Details on study design, sample size calcula-
tion and methods of evaluation can be found in
Morrison 1992 and Prorok 1995.
1.6
Overdiagnosis
Overdiagnosis is defi ned as identification of dis-
ease in subjects which would never have got the

disease in the absence of screening (Morrison
1992). Two types of overdiagnosis can be distin-
guished. The fi rst derives from disease which is
asymptomatically present and even progressive,
but would nevertheless not have reached a clini-
cal stage during lifetime. The second derives from
alterations which are not progressive, would never
have developed to clinical disease or would even
have regressed. While the fi rst type of overdiag-
nosis appears to some extent inevitable and has
to be taken into account, if the concept of early
detection has been accepted at all, the second
type represents a serious side-effect of screening
which creates harm to the affected subjects. They
are burdened with anxiety and further diagnostic
procedures which may cause further harm with-
out really helping the respective individual. In the
end, the person may be driven into treatment of
an actually medically irrelevant disease, so-called
“overtreatment”.
By definition, this type of disease, sometimes
called “pseudo-disease” (Morrison 1992), and
its proportion among screen-detected cases
cannot be determined clinically, but only epi-
demiologically by an increase and persistence
of screening-related incidence above the level
without screening. Overdiagnosis lets key quan-
tities of screening appear in a positive light (high
detection rate, high proportion of early-state dis-
ease, decreased morbidity) without contributing
to a real decline of target morbidity or mortal-
ity rates. Randomised trials on effectiveness of
screening for neuroblastoma turned out to pro-
duce substantial overdiagnosis without really
decreasing mortality and led to the recommen-
dation not to screen for this disease (Schilling
et al. 2002). A further example is prostate cancer
screening with PSA by which apparently a portion
of the many dormant cancers among middle-aged
and old men is brought to the surface and creates
much uncertainty on how to cope (for details see
Auvinen et al. 2002).
Modern radiology or molecular biology tech-
niques enable the detection of smaller and
smaller tumours. Being helpful in clinical diag-
nostics, efficient tools of this type may sub-
stantially enforce the problem of overdiagnosis,
especially if it turns out that they allow detection
of less aggressive subclinical disease, while the
detection of more aggressive forms remains unaf-
fected.
Epidemiology and Statistics 7
1.7
Sensitivity, Specificity and Predictive Value
As outlined above, it is an ethical requirement that
as few screening tests as possible should end in false-
positive results, i.e. positive test results among truly
unaffected screenees. In other words, the specificity
of the screening test (probability that unaffected
subjects are classified truly as “unaffected”) must
be high. For reasons which can best be recognized
by considering the “positive predictive value” to be
introduced below, the specificity must be particu-
larly high in screening and ranges in established
screening modalities within 95%–99%.
The corresponding problem, to avoid false-nega-
tive results, i.e. negative test results among actually
affected screenees which will then get the disease in
the interval after this screening and before the next
screening date (“interval cancer”), is encountered
by the criteria of the high sensitivity of a test (prob-
ability that affected subjects are classified truly as
“affected” by the test). Usually, the sensitivity of
screening tests ranges between 60% and 90%.
A third basic quantity having a very straight-
forward meaning is the “positive predictive value”
(PPV). It is defined as the proportion of truly affected
subjects among the screening positives. Impor-
tantly, although this quantity looks so elementary
its formal mathematical derivation shows that it
depends not only upon sensitivity and specificity
but also upon the prevalence of the target disease.
The precise formula is (Abel 1993)
rSe
PVp = (1)
rSe + (1 − r ) (1 − Sp )
This dependency has substantial consequences for
screening since, in most diseases for which screen-
ing tests are available, the point prevalence at a given
time is comparatively low, e.g. for so far unrecog-
nised colorectal cancer or breast cancer it is in the
region of 1%. This implies that, for the achievable
magnitudes of sensitivity and specificity mentioned
above, the PPV is rather low and ranges between 10%
and 15% even for mammography as an established
screening modality (see Table 1.1). The formula or
the table which is derived from it demonstrates why
the specificity of the test is the central quantity in
screening: the PPV and thus the proportion of sub-
jects to be invited for further diagnostic assessment
are crucially dependent upon specificity, much more
8 N. Becker

Table 1.1. Examples of the positive predictive value (PPV) an established diagnostic test is inadequate. A test
in dependence upon sensitivity, specificity and prevalence which performs well in a clinical setting must not do
of the disease of interest
so under screening conditions. Thus, a comparison
Sensitivity Specificity Predictive value (%) with
with known diagnostic tests can at most serve as a
prevalence of the disease first “knock out” step to exclude tests with a poor
of interest of performance even in a clinical setting.
The appropriate setting for the examination of
0.1% 1%
a screening test is a population group of symptom-
0.5 0.95 1.0 9.2 free subjects which may at most be pre-selected in
0.5 0.975 2.0 16.8 terms of increased risk of getting the respective
0.5 0.99 4.8 33.6 disease, not having it. The test had to be compared
0.75 0.95 1.5 13.2 with a gold standard, or if this is not available, to be
0.75 0.975 2.9 23.3 investigated within a prospective design as outlined
0.75 0.99 7.0 43.1 above. The follow-up serves for the identification
0.9 0.95 1.8 15.4
of those cases which were test-negative but become
symptomatic relatively shortly after testing, i.e. are
0.9 0.975 3.5 26.7
likely to be false-negatives.
0.9 0.99 8.3 41.6

than upon sensitivity. It is thus inappropriate to refer

to a specificity of 97% or 98% as “almost 100%” as is
sometimes seen in clinical publications.
An example is transvaginal sonography for early
detection of ovarian cancer. Studies demonstrated a
high sensitivity of about 81% and a high specificity
of 98.9%. Since however the prevalence of ovarian
cancer is low, the positive predictive value ranged
only around 9.4%. Because further diagnostics after
a positive test result requires surgery, this value
means 11 surgical interventions to verify one cancer
diagnosis. This appears unacceptable for broad
application in mass screening (Paley 2001).
Another example is HIV testing. In the early years
of HIV testing a test was proposed with a specificity of
about 98%. This test was rejected as unsuitable because
of its specificity was too low. The currently used test
has a specificity of 99.99%. This means that one out
of 10,000 tests is false-positive. Because, however,
e.g., in the German heterosexual male population the
prevalence is also 0.01%, i.e. one out of 10,000 males
is HIV positive, the positive predictive value is in this
population only 50%: among 10,000 tests, one is on
the average HIV true positive and one is false-positive
(Hoffrage et al. 2000).
The specific purpose of a screening test, to detect
early disease in a preclinical state, determines the
setting in which sensitivity and specificity of a
novel test has to be examined. Since it is not a test
for the clinical diagnosis of a symptomatic disease,
its examination within series of clinically diseased
subjects or a comparison with the sensitivity of
1.8
Combination of Tests
It has been proposed that a test with superior sensi-
tivity and specificity may be developed by combina-
tion of several individual tests with moderate sen-
sitivity and specificity. To determine the properties
of combined tests, it shall first be assumed that two
binary tests T1 and T2 are to be used simultaneously
as a combined test (see, for example, Abel 1993).
Then, sensitivity and specificity depend upon the
interpretation rule which has to be fi xed in advance
of application. Two options exist. Either the com-
bined test is defined positive if either of the compo-
nent tests is positive – this rule is frequently called
“believe the positive” (BTP) rule. Or the combined
outcome is defined positive only if both component
tests are positive which is equivalent to the defini-
tion of negativity of the combined test if one of the
component tests is negative. This option is called the
“believe the negative” (BTN) rule.
It is intuitively evident that the BTP rule implies
an increased sensitivity of the combined test com-
pared to the component tests and the BTN rule an
increased specificity. Thus, the problem focuses on
the combined specificity in the BTP case and the
combined sensitivity in the BTN case.
The mathematical form of these two quantities
depends upon a basic internal statistical relation-
ship between components of combined test, namely
whether they are mutually statistically independ-

ent or dependent. Statistical dependence must be
assumed if, for example, two different imaging
procedures react on the same morphological or
biochemical characteristics of the respective target
structure. Thus, basically, independence may not be
assumed a priori, but must be verified empirically.
On the other hand, unconditional independence of
the component tests can never be expected because
they are related by the respective early signs of the
disease to be detected. Otherwise, one or both of
the component tests are likely to be uninformative.
Thus, optimal information is obtained from the
component tests if they are independent conditional
on the disease status. This means that – provided
the disease status is positive – the probability that
the combined test is positive is the product of the
probabilities of the component tests being positive,
and – provided the disease status is negative – again
the probability that the combined test is positive is
the product of the probabilities of the component
tests being positive.
Assuming that in this sense the component tests
T1 and T2 are conditionally independent, the sensi-
tivity (Se) and specificity (Sp) of the combined test
under the BTP or BTN rule result from the compo-
nent sensitivities Se1 and Se2 and specificities Sp1
and Sp2 according to the simple equations
SeBTN = Se1uSe2
SpBTN = 1–(1–Sp1) u(1–Sp2)
SeBTP = 1–(1–Se1) u(1–Se2)
SpBTP = Sp1 uSp2 (2)
The structure of the formulas shows that it is a
straightforward matter to extend them to a combina-
tion of more than two component tests. The positive
predictive value may be obtained from Equation (1)
using the combined sensitivity and specificity under
the BTP or BTN rule, respectively.
The conclusion of this result is that under the BTN
rule the specificity increases at the cost of decreas-
ing sensitivity, and under the BTP rule the sensitiv-
ity increases at the cost of decreasing specificity. For
example, assuming for the component sensitivities
Se1 = Se2 = 0.8, the combined sensitivity under BTP
gives SeBTP = 1–(1–Se1) u(1–Se2) = 1–0.04 = 0.96, i.e.
a substantial increase in sensitivity. On the other
hand, assuming the corresponding specificities are
Sp1 = Sp2 = 0.9, the corresponding combined specifi-
city is SpBTP = Sp1 uSp2 = 0.9u0.9 = 0.81. Thus, a mod-
erate specificity of component tests may inevitably
lead to an unacceptably low specificity of a combined
Epidemiology and Statistics 9
test. It is straightforward to extend the example to a
combination of more than two component tests: the
tendencies just seen will be enforced in the benefi-
cial or detrimental direction, respectively, by adding
further component tests.
The above observation that, for example, under
the BTP rule the combined sensitivity will be higher
and the combined specificity will be lower than the
respective component quantities is generally valid
independent of whether the tests are conditional
independent or correlated. However, if they are cor-
related the type of correlation affects the degree by
which, for example, the sensitivity may be increased:
the combination of positively correlated tests is less
beneficial than the combination of negatively cor-
related tests to increase the combined sensitivity
under the BTP rule (for details see, e.g., Lin 1999).
In the present consideration, it was assumed that
the component tests were used simultaneously, i.e.
in parallel. On the other hand, a test combination
can also be used sequentially. Nevertheless, the two
interpretation rules persist as the only available
options, and one can show that sensitivity and spe-
cificity remain the same under either mode of appli-
cation (Cebul et al. 1982).
A further assumption was that the component
tests were binary, leading to a binary combined test.
However, biomarker-based tests (e.g. serological
tests) may alternatively be used quantitatively. Then
the combination rules are less straightforward, and
strategies for optimisation can be developed taking
priorities regarding levels of sensitivity or specifi-
city into account. See for examples and further ref-
erences McIntosh and Pepe (2002).
Overall, the potential to create superior tests by
combination is structurally limited by the statistical
rules which govern the combination of the probabil-
istic quantities sensitivity and specificity.
1.9
Combination of Outcomes
An issue which is complementary to the combina-
tion of two or more tests for the more efficient detec-
tion of a specific disease is to apply a specific test to
a scan for two or more diseases. An example of the
latter is full-body screening.
Some of the notions of the previous paragraph
also apply to this setting. Obviously, the test outcome
10 N. Becker
will be considered positive if a least one disease was
detected. Thus, the probability of a truly positive out-
come Ppos corresponds in a natural way to the BTP
interpretation rule in the above paragraph, imply-
ing that the total specificity also behaves according
to the corresponding formula. Denoting by Se1, Se2,
Sp1 and Sp2 the specific sensitivities and specificities
for disease 1 and disease 2, the respective formulas
can be rewritten as
Ppos = 1–(1–Se1) u(1–Se2)
SpTotal = Sp1 uSp2
Thus outcome combination increases the prob-
ability of obtaining any positive outcome and
decreases the probability of classifying screening
participants which are unaffected by any disease
of interest truly as screening negative. Obviously,
in the present setting, correspondence to the BTN
interpretation rule does not exist, nor to a sequential
application of tests.
A precondition for using the above combination
rules is again independence, in the present instance
of the diseases taken into consideration. In the
present setting even unconditional independence
may be achievable, though different diseases may be
related by common risk factors.
1.10
Conclusions and Discussion
Side effects are an intrinsic property of screening.
It is not intrinsically for screening that it is benefi-
cial for screening participants. Thus, it is ethically
mandatory to demonstrate (a) before introduction
into routine operation that a screening modality is
effective in terms of reduction of mortality or mor-
bidity, respectively, and (b) that effectiveness can
also be maintained in the long run during routine
operation (“process quality”). The latter implies a
commitment to ongoing quality assurance.
Clinical quantities which are changed under
screening are inappropriate for proving effectiveness
and assurance of process quality. Well-designed epi-
demiological studies and the quantification of dedi-
cated epidemiological effect measures are required
to demonstrate effectiveness and monitor persistent
quality.
The focus of studies and quality assurance must
be the entire screening chain including potentially
needed diagnostic steps for further assessment
of positive findings during screening, taking into
account potential harm by further diagnostic inter-
ventions.
Strategies to increase efficiency by combination of
two or more tests for detecting the disease of interest
or by scanning for several diseases by a single test
are only able to achieve a better performance on one
hand at the cost of worse performance on the other.
These methodological issues provide the frame-
work for approaching full-body screening. Since it
has its particular scope and its specific benefits and
risks, full-body screening has to undergo – for the
ethical reasons outlined above – the same proof of
effectiveness as any other screening approach. The
statistical considerations of the previous paragraph
show that a combined scan for several diseases does
not just make the early detection of disease more effi-
cient, but may also increase the risk of side-effects to
a detrimental level.
Thus, following the principles outlined above,
full-body screening may currently not be offered to
the population for screening or early detection in
subjects “on demand” outside of well-designed and
externally reviewed epidemiological studies which
must themselves be in accordance with ethical prin-
ciples.
The scope of studies would be to quantify the
probability of positive and false positive fi ndings;
the amount of further diagnostic action; side-effects
including exposure to radiation by the primary scan
(in the case of full-body CT screening) or subsequent
diagnostics; the effectiveness to achieve the desired
goals – reduction of mortality or morbidity from the
target diseases, respectively.
Proper quantification of these parameters can
only be achieved if the target diseases of the screen-
ing are accurately defined and a precise procedural
strategy determined which signs of illness will be
followed by which diagnostic workup. On this basis,
effectiveness and side effects of full-body screening
has also to be weighed against established dedicated
screening modalities for specific target diseases
(e.g. biannual mammography screening for breast
cancer).

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 Relevant Diseases and Therapeutic Options: Oncological Diseases 13

Relevant Diseases and Therapeutic Options 2

2.1 Oncological Diseases
Volker Heinemann

CONTENTS

2.1.1 Screening in Oncological Diseases 13 2.1.4 Defi nition of Risk Groups with Potential
2.1.1.1 Defi nition of Screening 13 Benefit from Screening 18
2.1.1.1.1 Screening May Be Harmful 14 2.1.4.1 Familial Adenomatosis Coli (FAP) 18
2.1.1.2 Bias of Screening 14 2.1.4.2 HNPCC 18
2.1.1.2.1 Lead Time Bias 14 2.1.4.3 Hereditary Breast- and Ovarian
2.1.1.2.2 Length Time Bias 14 Cancer 19
2.1.1.2.3 Selection Bias 14 2.1.4.4 Examples of Hereditary Cancer
2.1.1.2.4 Overdiagnosis Bias 14 Predisposition Syndromes 19
2.1.1.2.5 Evaluation of Screening Test 15
2.1.5 Impact of Screening on Therapy 19
2.1.2 Screening Recommendations in 2.1.5.1 Detection of Resectable Disease 19
Oncological Diseases 15 2.1.5.2 Detection of an Early Stage of
2.1.2.1 Colorectal Cancer 15 Disseminated Disease 20
2.1.2.1.1 Screening for Fecal Occult Blood
(FOBT) 15 References 20
2.1.2.1.2 Screening Sigmoidoscopy 15
2.1.2.1.3 Screening Colonoscopy 16
2.1.2.1.4 Virtual Colonoscopy and
CT Colonography 16
2.1.2.1.5 Screening in Average Risk
Individuals 16
2.1.2.1.6 Screening in High Risk Individuals 16
2.1.2.2 Breast Cancer 16
2.1.2.2.1 Mammography in Normal Individuals 2.1.1
Aged t50 Years 16
2.1.2.2.2 Mammography in Asymptomatic
Screening in Oncological Diseases
Individuals Aged 40–49 Years 16
2.1.2.2.3 Mammography in a Genetically Defi ned While there is a general assumption that screening
Risk Group 16 should be a helpful instrument to decrease cancer
2.1.2.3 Cervical Cancer 17 associated mortality, many issues remain unre-
2.1.3 Tumor Entities Without a Screening solved. Therefore, only few disease entities can be
Recommendation 17 defined where screening is supported by prospec-
2.1.3.1 Prostate Cancer 17 tively gained clinical evidence. Specific attention
2.1.3.2 Lung Cancer 17 should be paid that screening does not entail unnec-
2.1.3.3 Ovarian Cancer 18
2.1.3.4 Skin Cancer 18
essary diagnostic procedures and treatment.
2.1.3.5 Adenocarcinoma of the Esophagus 18

V. Heinemann, MD
Professor, Department of Internal Medicine III, University
Hospitals – Grosshadern, Ludwig-Maximilians-University
of Munich, Marchioninistrasse 15, 81377 Munich, Germany
2.1.1.1
Definition of Screening
Cancer screening is performed in asymptomatic
individuals to search for neoplasias that require
14 V. Heinemann
further evaluation. The main purpose of screening
is to detect cancers at an early stage when a curative
approach is still possible and the risk of metastatic
spread is low. It is assumed that the reduced occur-
rence of advanced disease, which for most patients
implies a lethal outcome, may subsequently lead to
a reduction of cancer-associated mortality.
2.1.1.1.1
Screening May Be Harmful
Screening may also be harmful (Walter and
Covinsky 2001). It may be associated with compli-
cations induced by the screening test itself or by the
subsequent diagnostic workup. For example, a false-
positive fecal occult blood test (FOBT) may expose
the patient to the anxieties and injuries associated
with colonoscopy. Treatment of screen-detected
prostate cancer may lead to urinary incontinence
and impotence, while the great majority of patients
would have otherwise suffered from indolent dis-
ease only (Harris and Lohr 2002).
In some settings, the early establishment of cancer
diagnosis only appears to prolong survival after
diagnosis. In reality, this may only be a “lead-time
effect” which specifically occurs when treatment has
little impact on survival. In these patients screen-
ing does not prolong survival, it only prolongs the
time span between diagnosis of cancer and death.
In other words, screening may cause harm in that it
reduces the duration of life in apparent health.
Harm can also be induced when otherwise harm-
less diseases are diagnosed and patients subse-
quently undergo unnecessary and toxic treatment.
“Overdiagnosis of pseudodisease” is a problem
which should therefore be taken seriously when
screening strategies are designed. In addition, the
psychological stress should not be underestimated
when patients undergo cancer screening tests
(Brawley and Kramer 2005).
Last but not least, it should be kept in mind that
screening may cause psychological distress. Anxiet-
ies are induced not only by the test itself, but more
specifically by false-positive results and the subse-
quent diagnostic procedures.
Settings where screening may be harmful:
앬 Complications induced by the screening test
앬 Diagnostic procedures and treatment of false-
positive test results
앬 Detection and treatment of disease which never
would have produced symptoms
앬 Psychological distress
2.1.1.2
Bias of Screening
The results of cancer screening may be confounded
by several biases, among which the lead time bias,
the length time bias, the selection bias, and the over-
diagnosis bias may be the most important. A critical
understanding of possibly underlying biases is there-
fore essential when screening results are evaluated.
2.1.1.2.1
Lead Time Bias
Lead time bias occurs when the early diagnosis of
cancer only causes a prolonged survival with diag-
nosed cancer, but since effective treatment is not
available, the overall duration of life is not affected.
From this it becomes evident that the early diag-
nosis of cancer must be related to a clearly defi ned
and effective treatment intervention resulting in a
clinically substantial survival benefit. Otherwise,
screening remains useless (Hakama et al. 1995).
2.1.1.2.2
Length Time Bias
Length time bias is observed when screening causes
the detection of slowly growing tumors which other-
wise would remain asymptomatic for prolonged time.
More aggressive and faster growing tumors tend to
become symptomatic during screening intervals. As
a consequence, screen-detected tumors may tend to
have a better prognosis (Hakama et al. 1995).
2.1.1.2.3
Selection Bias
Selection bias occurs when the individuals volun-
teering for screening constitute a subpopulation
characterised by a common motivation to undergo
screening. In this context it may be expected that
specifically the better educated and frequently also
healthier individuals have a greater motivation to
participate in screening interventions (Bourne et
al. 1994).
2.1.1.2.4
Overdiagnosis Bias
Overdiagnosis bias is expected when screen-detected
disease is indolent and causes no or only a low rate
of mortality.
 Relevant Diseases and Therapeutic Options: Oncological Diseases
2.1.1.2.5
Evaluation of Screening Test
A screening test should be highly specific, safe and
cost-effective. According to Ashar et al. (2005)
the following questions can be asked to evaluate a
screening test:
앬 Does the disease cause sufficient morbidity and
mortality?
앬 Is the disease prevalent in the target population?
앬 Is the disease treatable in an asymptomatic stage?
앬 Is the screening test accurate, safe and inexpen-
sive?
앬 Would the patient be willing and able to undergo
follow-up and treatment?
앬 Has the screening program been shown to reduce
morbidity and mortality?
앬 Does the outcome measure avoid lead-time and
length-time bias?
2.1.2
Screening Recommendations in
Oncological Diseases
Screening for cancer requires high specificity,
whereas sensitivity of the test is of less importance.
There is good evidence that in a “normal risk popu-
lation” screening for breast, colorectal, and cervi-
cal cancer reduces cancer mortality. Screening in
other cancers such as prostate or ovarian cancer
is, however, not supported by randomised trials. In
contrast, the benefit from surveillance in popula-
tions with an elevated cancer risk is subject to a
more controversial debate (Brawley and Kramer
2005).
2.1.2.1
Colorectal Cancer
Colorectal cancer is the third most common cancer
and the fourth most common cause of cancer deaths
worldwide. Whereas most colorectal cancers are
sporadic, approximately 20% are associated with
a familial risk, and 5%–10% arise within defined
hereditary cancer syndromes (Lynch and de la
Chapelle 2003; Weitz et al. 2005), and 1%–2% are
associated with inflammatory bowel disease such as
Crohn’s colitis or ulcerative colitis.
15
Colorectal cancer appears to provide an ideal set-
ting for screening (Labianca et al. 2005):
앬 High incidence and prevalence of colorectal
cancer
앬 Long time interval (ca. 10 years) between the
development of cancer from premalignant lesions
such as adenomatous polyps
앬 The premalignant lesions are easy to remove by
endoscopic interventions
앬 Improved prognosis when (pre-)malignant
lesions are removed at an earlier stage
In fact, screening is effective to reduce the mor-
tality from CRC. Established screening procedures
include testing for fecal occult blood (FOBT), colo-
noscopy, and rectosigmoidoscopy. The value of
digital rectal examination or barium enema is less
clear.
2.1.2.1.1
Screening for Fecal Occult Blood (FOBT)
Randomised trials have indicated that screening for
FOBT performed in normal individuals at the age
of 50 to 80 years results in a decrease of mortality
by 13% to 33% (Ault and Mandel 2000; McLeod
2001; Pignone et al. 2002). A meta-analysis showed
a reduction in CRC mortality of 16% (Towler et
al. 2004). The mortality reduction was 23% when
adjusted for attendance to screening. Patients with
a positive FOBT have a 20%–30% probability to
have adenomatous polyps, whereas the probability
of colorectal cancer is only 10% (Ransohoff and
Lang 1997). Clearly, the sensitivity of FOBT is lim-
ited (30%–50%), but it is expected to increase when
used annually as recommended.
An increased specificity is expected from immu-
nological FOBT designed to detect human hemo-
globin only. Also fecal DNA tests show better per-
formance characteristics than FOBT, results from
randomised comparative studies are, however, not
yet available.
2.1.2.1.2
Screening Sigmoidoscopy
In patients over the age of 50 years, screening
sigmoidoscopy was shown to decrease mortality
in two case-control studies (Ault and Mandel
2000). The advantage of flexible sigmoidoscopy is
direct visualization of the lesion, its disadvantage
is that more proximally located lesions are not
detected.
16 V. Heinemann
2.1.2.1.3
Screening Colonoscopy
Colonoscopy may be regarded as the gold standard
of screening. However, also this procedure misses up
to 6% of polyps greater than 10 mm in size and up
to 13% of polyps between 6 mm and 9 mm (Hixson
et al. 1990; Rex et al. 1997).
2.1.2.1.4
Virtual Colonoscopy and CT Colonography
Virtual colonoscopy using CT colonography has a
substantial clinical potential. It has the advantage
to be fast and minimally invasive and therefore
does not require sedation. Radiation exposure can
be greatly reduced with modern CT technology.
Bowel preparation is, however, comparable to that
needed for the endoscopic procedures. Moreover,
it needs to be taken into account that colonoscopy
has to be performed for any abnormal fi ndings.
Virtual colonoscopy has reached impressive results
in a highly trained setting. However, it may loose
its accuracy in the setting of broader application.
Smaller lesions (< 10 mm), flat polyps and lesions
at hidden locations may escape detection by vir-
tual colonoscopy. Until the issues of reproducibil-
ity and cost-effectiveness have been solved, virtual
colonoscopy is not recommended as a standard of
screening.
2.1.2.1.5
Screening in Average Risk Individuals
Individuals at an average risk are recommended
to perform annual FOBT tests starting at the
age of 50 years. A f lexible rectosigmoidoscopy
should be added every 5 years, alternatively a
total colonoscopy every 10 years (Hawk and
Levin 2005).
2.1.2.1.6
Screening in High Risk Individuals
Screening colonoscopy starting in young adults
is recommended in individuals with a familial or
genetically defined high risk to develop colorectal
cancer as well as in patients with chronic inflam-
matory bowel disease. The benefit of screening in
this high-risk population still needs to be demon-
strated.
2.1.2.2
Breast Cancer
Screening in breast cancer involves manual self-
examination, clinical breast examination or mam-
mography. Magnetic resonance imaging of the
breast may be used when mammography provides
uncertain results. While manual self-examination
may raise the awareness of the population at risk, a
clear benefit of this screening modality has not been
shown with regard to a reduction of breast cancer
related mortality (Thomas et al. 2002).
2.1.2.2.1
Mammography in
Normal Individuals Aged t50 Years
A reduction of mortality in normal individuals has
been demonstrated for screening mammography.
Several trials performed in women t50 years of age
indicate that mammography alone or in combination
with clinical examinations of the breast may reduce
breast cancer related mortality by 20%–30%.
2.1.2.2.2
Mammography in
Asymptomatic Individuals Aged 40–49 Years
By contrast, the benefit of screening mammography
performed in women aged 40–49 is much less clear.
The greater breast density observed in younger women
as well as the impact of periodic hormonal changes on
breast density decrease the sensitivity of mammogra-
phy (Brisson et al. 2000). As a consequence, annual
screening in this younger age population resulted in
a false-positive detection rate of nearly 50% causing
anxiety, as well as unnecessary biopsies and surgi-
cal interventions. Screening of women under the age
of 50 years, who are at normal risk, is therefore not
recommended (Elmore et al. 1998).
2.1.2.2.3
Mammography in a Genetically Defined Risk Group
In women with a genetically determined higher
risk of breast cancer, an earlier commencement of
screening is thought to be useful. Women with a
BRCA1- or BRCA2-gene mutation typically develop
breast cancer at a younger age when mammography
is notably less sensitive due to the greater density of
the breast. This deficiency in diagnostic sensitivity
 Relevant Diseases and Therapeutic Options: Oncological Diseases
can only in part be overcome by MRI screening,
which, however, bears the advantage that ioniz-
ing radiation can be avoided. Since patients with
an impaired BRCA1 pathway may be specifically
sensitive to DNA damage, a more cautious use of
diagnostic radiation exposure has been recom-
mended.
2.1.2.3
Cervical Cancer
Screening for cervical cancer involves cervical cytol-
ogy and testing for the human papilloma virus.
While several cohort- and case-control studies indi-
cated the benefit from the cervical cytology screen-
ing established as the Papanicolaou (Pap) smear, a
reduction of mortality has not been proven in ran-
domized trials.
Regular cervical cytology screening is recom-
mended within 3 years of the onset of sexual activity,
but no later than by the age of 21 years. According to
the ACS guidelines, cervical screening by Pap smear
should be performed at yearly intervals or every
2 years with liquid-based Pap tests (Saslow et al.
2002). After three subsequently performed normal
tests, intervals may be extended to 2–3 years. It may
be safe to stop screening in women above the age of
65 once repeatedly negative Pap smears indicate a
low risk.
It can be anticipated that the necessity of screen-
ing for this tumor entity will be abrogated in a fore-
seeable future once vaccination against the human
papilloma virus has become a standard.
2.1.3
Tumor Entities Without a
Screening Recommendation
2.1.3.1
Prostate Cancer
Despite the lack of positive data from prospective
randomised trials screening for prostate cancer is
widely used. The applied screening modalities in
prostate cancer are digital rectal examination and
the analysis of prostate-specific antigen (PSA) in
serum. Specifically in prostate cancer, the problem
of overdiagnosed indolent disease is important.
17
The prevalence of disease is much greater than the
actual risk to die from it, and indolent disease is
expected in 50%–88% of detected cancers. Accord-
ingly, it has been questioned whether screening
truly has an impact on mortality (Klotz 2005; Lu
et al. 2002).
In the Prostate Cancer Prevention Trial, seven
years of screening resulted in the detection of
prostate cancer in more than 12% of a normal
risk population. When after the end of this 7-year
follow-up a biopsy was performed in individuals
with normal screening tests, an additional rate of
15% prostate cancers was detected. This is con-
trasted by the observation that the expected prob-
ability to die from prostate cancer is less than 3.5%
in males aged t60 years (Thompson et al. 2003).
Moreover, this trial indicates that screening alone
missed approximately half of the actual prostate
cancers.
Based on the available evidence, recommenda-
tions for prostate cancer screening remain con-
troversial. Clearly, the challenge consists in the
separation of good risk from bad risk patients. The
perspective is to use PSA doubling time as a prag-
matic tool to stratify patients according to the risk
of tumor progression and to apply either watchful
waiting or radical therapy (Klotz 2005).
2.1.3.2
Lung Cancer
Several randomised trials have shown that screen-
ing for lung cancer using chest X-ray and sputum
cytology is ineffective with regard to lung cancer-
related mortality (Marcus et al. 2000; Marcus
2001). New diagnostic modalities such as spiral CT
and positron emission tomography (PET) are pres-
ently under investigation. In fact, CT scanning was
found to be 3–4 times more sensitive than chest
radiographs (Henschke et al. 1999; Sobue et al.
2002). While sensitivity for tumor detection has
greatly increased, the true impact of these proce-
dures on mortality in specified risk groups remains
to be clarified (Manser et al. 2003; Mulshine 2005;
Pastorino et al. 2003). A major concern regarding
CT-based screening for lung cancer consists in the
high rate of false-positive results (5%–50%) which
may require unnecessary lung biopsies (Sobue et
al. 2002).
A large randomised trial, the National Lung
Screening Trial, is recruiting 50,000 high-risk
18 V. Heinemann
patients (current or former smokers) and compares
spiral-CT scanning to chest X-ray performed every
4 months. Until the results of this and other trials
are available, screening for lung cancer can not be
recommended.
2.1.3.3
Ovarian Cancer
Modalities of ovarian cancer screening are trans-
vaginal ultrasound, measurement of CA125 serum
levels, and manual examination. Specifically the
use of tumor markers within screening strategies
requires that cut-off values are defined which
allow for an optimal specificity without too much
loss in sensitivity. While several clinical trials
are under way to clarify the benefit from ovarian
cancer screening, no data are available at present
time. Screening for ovarian cancer is therefore not
recommended for normal risk individuals (NIH
Consensus Conference 1995).
2.1.3.4
Skin Cancer
No randomised prospective trials are available which
support the benefit of screening in skin cancer. It
may be speculated that primary prevention strate-
gies may be more effective to reduce mortality asso-
ciated with this disease entity.
2.1.3.5
Adenocarcinoma of the Esophagus
Chronic gastroesophageal reflux disease (GERD)
is most likely the cause for the development
of Barrett’s esophagus, a change from normal
squamous esophageal epithelium to metaplastic
columnar cells. While it appears plausible that
the sequence of GERD to Barrett’s esophagus to
adenocarcinoma could be followed by screening
of a high-risk population (defined by GERD), the
present data do not support this approach. As
a consequence the American Gastroenterologi-
cal Association (AGA) did not recommend rou-
tine screening programs for Barret’s esophagus
(Dellon and Shaheen 2005).
2.1.4
Definition of Risk Groups with Potential
Benefit from Screening
It is estimated that 5%–10% of cancers are associ-
ated with inherited genetic mutations which predis-
pose carriers to an elevated risk of cancer develop-
ment. Once familial clusters of certain cancers and
the associated gene mutations have been detected,
family members with an increased cancer risk can be
identified. It is a general, though unproven, assump-
tion that screening may play an important role in
the reduction of mortality in this high-risk popula-
tion. In the following paragraphs, three examples
of hereditary cancer predisposition syndromes are
illustrated, namely familial adenomatosis coli, the
hereditary non-polyposis colorectal cancer syn-
drome, and the BRCA1- and BRCA2-mutations in
breast- and ovarian cancer.
2.1.4.1
Familial Adenomatosis Coli (FAP)
FAP arises from germline mutations of the APC
gene. The risk of colon cancer in the affected popu-
lation is nearly 100% with a median age of 39 years
at first diagnosis. FAP testing is recommended at the
age of 10–12 years for members of high-risk families.
Once the diagnosis of FAP is established, prophy-
lactic colectomy is performed before the age of 20.
Notwithstanding this intervention, patients remain
at an elevated lifelong risk for the development of
duodenal and rectal polyps and cancers as well as for
several other malignancies. Accordingly, patients
require lifelong surveillance for GI cancers as well
as for malignancies outside of the digestive tract.
2.1.4.2
HNPCC
The hereditary non-polyposis colorectal cancer
(HNPCC) syndrome is an autosomal-dominant
syndrome caused by germline mutations of genes
involved in DNA mismatch repair. The HNPCC syn-
drome is expected to be responsible for 3%–4% of
colorectal cancers (Lackner and Hoefler 2005). On
a molecular basis, defects in one of the DNA repair
 Relevant Diseases and Therapeutic Options: Oncological Diseases
genes, namely hMLH1 or hMSH2, have been identi-
fied. These defects are associated with microsatellite
instability (MSI) defined as an elevated frequency
of mutations occurring in microsatellites. In conse-
quence, HNPCC is a predisposition for the accelerated
development not only of colon cancer, but also of other
cancers such as brain, stomach, small bowel, pan-
creas, biliary tract, renal, ureter, and ovary (Duval
and Hamelin 2002). The lifetime risk of colon cancer
in HNPCC patients is between 70% and 90%, whereas
the endometrial cancer risk is 30%–60%.
The recommended screening for HNPCC family
members is colonoscopy performed at 1- (2-) year
intervals starting at the age of 20–25 years or at an
age 10 years younger than the earliest case in the
afflicted family (Garber and Offit 2005; Winawer
et al. 2003). In a controlled trial performed over
15 years, surveillance by colonoscopy and polyp-
ectomy at 3-year intervals resulted in a reduction
of CRC by 62% and a 65% reduction of mortality
(Jarvinen et al. 2000). Prophylactic colectomy in
HNPCC gene carriers remains a controversial issue
(Rodriguez-Bigas 1996).
Apart from colonoscopy, screening in HNPCC
patients should also be devoted to the detection of
extracolonic tumors and therefore should involve
abdominal ultrasound and urine cytology as well as
gynecological examinations in female patients.
2.1.4.3
Hereditary Breast- and Ovarian Cancer
In breast cancer, 5%–10% of cases are associated with a
hereditary predisposition. Specifically mutations of the
BRCA1- and BRCA2-genes have a strong penetrance.
The probability of a gene mutation increases with breast
cancer occurring at an early age, clustering of breast-
and ovarian cancers (80% BRCA1), and male breast
cancer (66% BRCA2) (Garber and Offit 2005). Breast
cancers with BRCA1 mutations are frequently identi-
fied as basal type cancers characterised by high-grade
tumors, poor differentiation, and negative estrogen-,
progesterone-, and HER2-receptors triple-negative
breast cancer. BRCA2-associated cancers, by con-
trast, rather resemble sporadic breast cancers and do
not have a distinct phenotype. The lifetime risk for
breast cancer associated with BRCA1 mutations is in
the range of 50%–80%, whereas for BRCA2 mutations
the risk is somewhat lower with a range of 40%–70%.
The lifetime ovarian cancer risk is greater in BRCA1
mutation carriers (40%–50%) compared to individuals
19
with BRCA2 mutations (20%) (Narod and Offit 2005;
Risch et al. 2001).
Intensified breast cancer screening in genetically
defined high-risk patients is suggestive, but its ben-
efit remains to be proven. In addition to self-exami-
nation, clinical examination, and mammography,
the inclusion of MRI into the routine screening of
women with BRCA mutations is supported by recent
data (Robson and Offit 2004). In women with a
family history of ovarian cancer, the combination of
ultrasound and CA-125 screening was recommended
by the American College of Physicians (American
CoP). Screening is performed twice a year with an
onset at an early age. In individuals with the highest
genetic risk of breast and ovarian cancer, prophylac-
tic surgery is a valid option and may outweigh the
benefit from intensified screening in selected cases.
2.1.4.4
Examples of Hereditary Cancer Predisposition
Syndromes
Details of hereditary syndromes and associated
genes are shown in Table 2.1.1.
Table 2.1.1. Details of hereditary syndromes and associated
genes
Hereditary syndromes Genes
Hereditary breast and ovarian cancer BRCA1, BRCA2
syndrome
Hereditary non-polyposis colorectal MLH1, MSH2
cancer (HNPCC) syndrome
Familial adenomatous polyposis (FAP) APC
2.1.5
Impact of Screening on Therapy
2.1.5.1
Detection of Resectable Disease
Screening can be beneficial when diagnosis of
cancer is made possible at an early time point when
metastatic spread has not yet taken place and when
curative interventions are still possible. Screening
can also detect an early stage of metastatic disease.
In rare cases of oligometastatic disease, surgical
resection or comparable modalities such as radio-
20 V. Heinemann
frequency ablation or radiation therapy are still
options which can either be curative or can result
in prolonged disease-free intervals.
2.1.5.2
Detection of an Early Stage of
Disseminated Disease
In some patients screening may detect an early stage
of disseminated metastatic disease. In this case, early
diagnosis may help to prevent symptomatic disease,
such as pathological bone fractures or respiratory
distress. Greatest benefit can be achieved in sub-
groups of patients in whom well tolerated systemic
treatment may cause long-term control of disease.
Targeted therapy including endocrine or antiangio-
genic treatment hold promise to combine antitumor
activity with a good quality of life. In these patients
the benefit from early detection of metastatic disease
may exceed the lead-time bias.
It should be pointed out that a positive effect of
screening can only be expected when subsequent
diagnostic steps are clearly defined and when the
associated therapeutic options are highly effective.
In the absence of this interaction between screen-
related diagnosis and therapeutic measures, screen-
ing strategies have no impact on mortality.
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 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 23

Relevant Diseases and Therapeutic Options 2

2.2 Vascular Diseases Relevant to Screening
Norbert Weiss and Ulrich Hoffmann

CONTENTS 2.2.1
Introduction

2.2.1 Introduction 23 A hundred years ago, cardiovascular disease (CVD)

accounted for less than 10% of all deaths worldwide.
2.2.2 Vascular Risk Factors Relevant to
Screening 23 Nowadays nearly 50% of all deaths in developed and
2.2.2.1 The Evolution of Atherosclerotic Vascular around 25% of deaths in developing countries are
Lesions 24 due to CVD (WHO 1999). Within the next 20 years,
2.2.2.2 Hyperlipidemia 25 CVD will surpass infectious diseases as the world’s
2.2.2.3 Hypertension 25
number one cause of death and disability.
2.2.2.4 Insulin Resistance and Diabetes
Mellitus 25 Despite this global increase in CVD mortality
2.2.2.5 Smoking 27 during the last century, countries like the United
2.2.2.6 Hyperhomocysteinemia 27 States experienced a decline in CVD mortality rates
2.2.2.7 Lipoprotein(a) 28 since the beginning of the mid-1960s. Since then
2.2.2.8 Markers of Inflammation 28
there has been substantial reductions in mortal-
2.2.3 Risk Groups with Potential Benefit for ity from stroke and coronary heart disease (CHD)
Screening and Impact of Screening on (CDC 1999). Age-adjusted death rates from CHD
Therapy 30 have fallen approximately 2.5% per year, and stroke
2.2.3.1 Patients at Risk of Coronary Heart
rates have fallen 3% per year (Jemal et al. 2005)
Disease 31
2.2.3.2 Patients at Risk of Abdominal Aortic (Fig. 2.2.1).
Aneurysms 31 Two main factors have contributed to the decline
2.2.3.3 Patients at Risk of Peripheral Arterial in CVD mortality rates: therapeutic advances for
Occlusive Disease 32 treatment of established CVD (Hennekens et al.
2.2.3.4 Patients at Risk of Cerebrovascular
Disease 33
1996) and preventive measures targeted at those
with established disease (secondary prevention) or
References 33 those at risk for it (primary prevention) (Hunink et
al. 1997). Each of these factors may have contributed
equally to the reduction in CVD mortality rates.

N. Weiss, MD
PD, Department of Vascular Medicine, Medical Policlinic,
2.2.2
University Hospitals Munich, Ludwig-Maximilians- Vascular Risk Factors Relevant to Screening
University of Munich, Pettenkoferstrasse 8a, 80336 Munich,
Germany A risk factor is a characteristic or feature of an
U. Hoffmann, MD individual or population that is present prior to the
Professor and Division Head Vascular Medicine, Depart-
ment of Internal Medicine, University Hospital, Ludwig-
development of a disease and is associated with an
Maximilians-University of Munich, Pettenkoferstrasse 8a, increased risk of developing future disease. To be
80336 Munich, Germany considered causal, the risk factor in question must
24 N. Weiss and U. Hoffmann

550 rotic risk factors hyperlipidemia, hypertension,

500 Heart Disease insulin resistance and diabetes mellitus, and smok-
450 ing. However, the cardiovascular risk is not fully
Rate per 100,000 Population

400
explained by these above-mentioned risk factors.
For example, in the United States nearly half of all
350
cases of myocardial infarction occur in individuals
300 without overt hyperlipidemia (Rubins et al. 1995).
250 Therefore, this chapter also reviews a series of novel
Cancer
200 atherosclerotic risk factors, including homocysteine
150 and lipoprotein(a). In addition, recent developments
Stroke
100 indicate that indices of fibrinolytic function and
50 markers of vascular inflammation may have addi-
0
tional impact on the individual’s risk of developing
1970 1974 1978 1982 1986 1990 1994 1998 2002 atherosclerotic CVD.
Year of Death

Fig. 2.2.1. Trends in age-standardized death rates for lead- 2.2.2.1

ing causes of death in the United States, 1970–2002 [from
Jemal et al. (2005)]
The Evolution of Atherosclerotic Vascular
Lesions

predate the onset of disease and must have biologi-
cal plausibility. In the case of CVD, risk factors may
be inherited (e.g. family history, gender, and age), a
certain behavior (e.g. smoking), or a clinical or labo-
ratory measurement (e.g. blood pressure or choles-
terol level). Most risk factors used in daily practice
have demonstrated a graded-response effect. Their
evidence has been substantiated by a large series
of prospective studies in broad population groups.
Several cardiovascular risk factors are modifiable,
and intervention trials have demonstrated that low-
ering these factors reduces vascular risk.
The following chapter reviews the epidemiologi-
cal evidence underlying the established atheroscle-
The evolution of atherosclerotic vascular lesions
involves several highly interrelated processes
(Fig. 2.2.2). These include exposure to cardiovas-
cular risk factors like hyperlipidemia resulting in
endothelial dysfunction. This results in recruit-
ment and accumulation of circulating inflammatory
cells (i.e. monocytes and T-lymphocytes) within the
vessel wall. Monocytes accumulate cholesterol and
become foam cells. Smooth muscle cell proliferation
and foam cell accumulation results in growth of
the plaque. Altered matrix metabolism, remodeling,
and further inflammatory responses contribute to
the propagation of vascular lesions. Platelet acti-
vation and thrombosis mediate complications of

Fig. 2.2.2. The 7 stages of development of an atherosclerotic plaque. First LDL moves into the subendothelium and is oxi-
dized by macrophage and SMCs (1 and 2). Release of growth factors and cytokines attracts additional monocytes (3 and 4).
Foam cell accumulation and SMC proliferation result in growth of the plaque (6, 7, and 8) [from Faxon et al. (2004)]
 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening
atherosclerosis. A detailed description of the vascu-
lar biology of atherosclerosis is beyond the scope of
this chapter, but has been reviewed in detail recently
(Faxon et al. 2004).
2.2.2.2
Hyperlipidemia
Extensive epidemiologic data correlate elevations of
total cholesterol (TC) or LDL-cholesterol (LDL-C)
with increased CHD incidence. These data are
derived both from between-population and within-
population studies. In addition, large cohort studies
showed remarkable consistency. A review of inter-
national studies found a 10% difference in TC to
be associated with an approximate 38% difference
in CHD mortality rate in men aged 55 to 64 years
(Law et al. 1994). Clinical trials using lipid-modi-
fying drugs have unequivocally demonstrated that
lowering LDL-C yields significant reduction in both
morbidity and mortality from CHD in patients with
or without established CHD, including patients with
only average cholesterol values for Westernized
societies. Moreover, LDL-C reduction as secondary
prevention significantly increases survival rates
(Tables 2.2.1 and 2.2.2).
2.2.2.3
Hypertension
Elevated levels of blood pressure consistently cor-
relate with elevated risks of stroke and myocardial
infarction. An early meta-analysis evaluated over
5500 cardiovascular events. Every 7 mm Hg eleva-
tion of diastolic blood pressure was associated with
a 27% increase risk of CHD and a 42% increase in
risk of ischemic stroke (MacMahon et al. 1990).
A more recent meta-analysis including 1 million
adults above 40 years of age with no previous his-
tory of CVD confi rmed these data. Each 20 mm Hg
increase in systolic blood pressure above 115 mm
Hg and each 10 mm Hg increase in diastolic blood
pressure above 75 mm Hg was associated with a
more than twofold increase in stroke death rate,
and with a twofold increase in cardiovascular
death rates (Lewington et al. 2002).
Even isolated systolic hypertension has been
shown to increase the risk for non-fatal myocardial
infarction and cardiovascular death in population
studies like the Multiple Risk Factor Intervention
25
Trial or the Physicians’ Health Study (Neaton and
Wentworth 1992; O’Donnell et al. 1997). The
recently published report of the Prospective Collab-
orative Study Group pooled 61 observational studies
in more than 1 million volunteers with a collective
experience of more than 12 million person-years. It
showed that the systolic blood pressure level at base-
line was a significantly more informative reading
than diastolic blood pressure for predicting strokes
and CHD (Black 2004).
To underline the causality of hypertension as a
cardiovascular risk factor, pharmacological reduc-
tion in diastolic blood pressure of 5–6 mm Hg
appeared to reduce the risk of vascular mortality by
21%, the risk of CHD by 14%, and the risk of stroke
by 40% (Collins et al. 1990). Treating isolated systo-
lic hypertension has also been shown to be efficient,
at least in the elder population (Staessen et al. 1999;
Sutton-Tyrrell et al. 2003).
2.2.2.4
Insulin Resistance and Diabetes Mellitus
CHD accounts for three fourths of all deaths among
diabetic patients (Gu et al. 1998). Diabetic patients
not only have a dramatically increased risk to
develop CVD but also have a substantially elevated
risk of secondary complications after vascular inter-
ventional procedures (Stein et al. 1995; Thourani
et al. 1999). Thus, diabetes ranks among the major
cardiovascular risk factors. Insulin resistance, even
before the manifestation of frank diabetes, promotes
atherosclerotic vascular disease and has been identi-
fied as an independent risk factor for CVD (Despres
et al. 1996; St-Pierre et al. 2005). The latter find-
ing has emphasized the importance of the insulin
resistance syndrome, which is characterized by
the combination of glucose intolerance and hyper-
insulinemia, hypertriglyceridemia, and low HDL
levels, as well as the predominance of small dense
LDL particles (Lewinter 2005).
Although randomized trials, like the Diabetes
Control and Complications Trial and the UK Pro-
spective Diabetes Study (UKPDS), provided evi-
dence that intensive glycemic control obtained with
either intensive insulin or oral therapy effectively
slowed the onset and progression of diabetic retin-
opathy, nephropathy, and neuropathy in patients
with type 1 and type 2 diabetes, these studies did not
find a significant (Anonymous 1993) or only a mar-
ginal (Anonymous 1998) benefit on coronary event
 26

Table 2.2.1. Summary of major statin clinical event trials in primary prevention

Trial and Agent Follow-up, Subjects Baseline Changes in Primary end point Event rate Other clinical events
years (placebo/verum) LDL-C Lipids
(mg/dl) Statin Placebo RRR ARR NNT
WOSCOPS 4.9 3293/3302 192 LDL-C p 26% Nonfatal MI or CHD 5.5% 7.9% 31% 2.4% 42 No excess non-CVD death
pravastatin 40 mg/d HDL-C n 5% death Total mortality p 22%
TG p 12% CABG or PTCA p 37%
N. Weiss and U. Hoffmann

AFCAPS/TexCAPS 5.2 3301/3304 150 LDL-C p 25% Nonfatal or fatal 3.5% 5.5% 37% 2.0% 50 No excess in total mortality
lovastatin HDL-C n 6% MI, unstable an- CABG or PTCA p 33%
20–40 mg/d TG p 15% gina, sudden cardiac
death
ASCOT-LLA 3.3 5137/5168 133 LDL-C p 33% Nonfatal MI and 1.9% 3% 36% 1.1% 91 All-cause mortality p 13%
atorvastatin 10 mg/d HDL-C l CHD death Fatal and non-fatal stroke p 27%
TG p 22% Total CV events and procedures
p 21%

Table 2.2.2. Summary of major statin clinical event trials in secondary prevention

Trial and Agent Follow-up, Subjects Baseline Changes in Primary end point Event rate Other clinical events
years (placebo/verum) LDL-C Lipids
(mg/dl) Statin Placebo RRR ARR NNT

4s 5.4 2223/2221 188 LDL-C p 35% All-cause mortality 8.2% 11.5% 30% 3.3% 30 CABG or PTCA p 37%
simvastatin 20– HDL-C n 8%
40 mg/d 2223/2221 TG p 10% Nonfatal MI, CHD Post-hoc: Stroke or TIA p 30%
death, resuscit-ated 19.4% 28% 34% 8.6% 12
cardiac arrest
CARE 5.0 2078/2081 139 LDL-C p 32% Nonfatal or CHD 10.2% 13.2% 24% 3.0% 33 No excess non-CVD death
pravastatin HDL-C n 5% death CABG or PTCA p 27%
40 mg/d TG p 14% Stroke p 31%
LIPID 6.1 4502/4512 150 LDL-C p 25% Nonfatal MI and 12.3% 15.9% 24% 3.6% 28 Total mortality p 22%
pravastatin 40 mg/d HDL-C n 5% CHD death CABG or PTCA p 20%
TG p 11% Stroke p 19%
HPS 5 10,267/10,269 131 LDL-C p 29% All-cause mortality 12.9% 14.7% 13% 1.8% 56 Revasularization procedures p 24
simvastatin 40 mg/d HDL-C n 3% Stroke p 25%
10,267/10,269 TG p 14% Fatal or nonfatal
vascular events 19.8% 25.2% 24% 5.4% 19
 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening
rates. Therefore, aggressive control of additional
cardiovascular risk factors together with life style
modifications including absence of smoking, regu-
lar exercise, diet, and avoidance of obesity remain
the primary strategies to reduce the cardiovascular
risk in diabetics (Patel et al. 2005).
2.2.2.5
Smoking
Since the first reports in the early 1950s of a strong
positive association between cigarette smoking and
CHD a series of prospective studies have consist-
ently and clearly confirmed these observations.
Smokers of 20 or more cigarettes per day compared
with nonsmokers have a two- to threefold increase
in total CHD. Moreover there is a dose-dependent
effect of smoking on CHD which starts to increase
with as few as one to four cigarettes daily (Willett
et al. 1987; Chen and Boreham 2002). Even pas-
sive exposure to smoke has now been recognized
to increase coronary risk (Kawachi et al. 1997;
Pitsavos et al. 2002).
In accordance with these findings, quitting smok-
ing compared to continuous smoking has been found
to result in a 36% reduction in mortality in patients
with CHD (Critchley and Capewell 2004). In a
primary prevention setting, smoking cessation alone
reduces the risk of a first heart attack by nearly 65%
(Manson et al. 1992). Stopping smoking therefore
constitutes the single most important intervention
in preventive cardiovascular medicine.
2.2.2.6
Hyperhomocysteinemia
Homocysteine is a sulfhydryl-containing amino acid
that is derived from the demethylation of dietary
methionine. Early clinical studies in children with
rare inborn errors of homocysteine metabolism,
that lead to markedly elevated plasma homocysteine
levels up to 30 times the normal range, suggested
that severe hyperhomocysteinemia is associated
with the development of premature atherosclero-
sis and thromboembolism, besides other clinical
abnormalities (McCully 1969; Mudd et al. 1995).
Untreated patients suffer one thromboembolic event
per 25 patient-years (Mudd et al. 1985). Treatment
of hyperhomocysteinemia in these patients leads to
a significant, more than 90% reduction in throm-
27
boembolic events as shown in a multicenter obser-
vational study (Yap et al. 2001). In contrast to severe
hyperhomocysteinemia, mild elevation of plasma
homocysteine (> 12 µmol/L) is commonly found in
general populations, primarily due to insufficient
dietary intake of folic acid (Weiss et al. 2004).
During the last 20 years, a great number of retro-
spective case-control studies and prospective nested
case-control studies nearly uniformally established
the link between mild hyperhomocysteinemia and
atherothrombotic vascular diseases in the general
population. Mild hyperhomocysteinemia appears
to be an independent risk factor for CHD, cerebrov-
ascular disease, and peripheral arterial occlusive
disease, as the relationship persists after statistical
adjustment for conventional risk factors. A meta-
analysis by Boushey et al. 1995 using data from
27 studies published before 1995 indicated that a
5 µmol/L increase in plasma homocysteine above
median levels of 10 µmol/L is associated with a
significant and graded increase in the risk of CHD
(odds ratio 1.6 [95% confidence interval: 1.4 to 1.7]),
cerebrovascular disease (odds ratio 1.5 [1.3 to 1.9]),
and peripheral vascular disease (odds ratio 6.8 [2.9
to 15.8]). Comparing elevated homocysteine levels to
other established vascular risk factors, the authors
calculated that a 5 µmol/L increase in plasma homo-
cysteine levels is equivalent to a 0.5 mmol/L (20 mg/
dL) increase in plasma cholesterol levels in increas-
ing the risk for myocardial infarction. From data
of a recent case-control study conducted in nine
European centers it was estimated that the cardio-
vascular risk associated with elevated homocysteine
levels (> 12 µmol/L) is comparable to the risk associ-
ated with hyperlipidemia or smoking, but somewhat
lower than that of hypertension (Graham et al.
1997). From these studies it has been estimated that
10% of the population’s CHD risk appears attribut-
able to plasma homocysteine levels (Boushey et al.
1995).
Prospective cohort studies, however, have yielded
some inconclusive results in linking homocysteine
to vascular disease. Most of the prospective stud-
ies have provided evidence for mild hyperho-
mocysteinemia as a major risk factor for athero-
thrombotic vascular disease after adjustment for
conventional risk factors (Stampfer et al. 1992;
Arnesen et al. 1995; Perry et al. 1995; Petri et
al. 1996; Nygard et al. 1997; A’Brook et al. 1998;
Moustapha et al. 1998; Wald et al. 1998; Bostom et
al. 1999; Bots et al. 1999; Kark et al. 1999; Ridker et
al. 1999; Whincup et al. 1999), although some stud-
28 N. Weiss and U. Hoffmann
ies have not (Alfthan et al. 1994; Verhoef et al.
1994; Evans et al. 1997; Folsom et al. 1998; Kuller
and Evans 1998; Ubbink et al. 1998). These conflict-
ing results might be partly explained by the differ-
ent ethnic background and lifestyle of the specific
study’s participants and by the sample size. Lifestyle
issues appear to be especially important as a source
of potential bias owing to multivitamin use by study
subjects. For example, the Atherosclerosis Risk in
Community Trial, the largest prospective trial with a
negative outcome, did not provide detailed informa-
tion about vitamin supplementation as a potential
confounding variable (Folsom et al. 1998; Kuller
and Evans 1998; Ubbink et al. 1998).
Several meta-analyses of the retrospective case-
control and of the prospective population based
studies showed similar, consistent results favoring
hyperhomocysteinemia as a vascular risk factor
(Boushey et al. 1995; Danesh and Lewington 1998;
Wald et al. 1998; Moller et al. 2000; Ueland et al.
2000; Schnyder et al. 2001). These combined data
indicate that mild hyperhomocysteinemia above
12 µmol/L increases the risk for CHD by 1.5 and for
stroke by 1.4 (Fig. 2.2.3) (Bautista et al. 2002). The
debate about hyperhomocysteinemia as a cardiovas-
cular risk factor will continue, as long as results of
large scaled intervention studies aimed at reducing
cardiovascular events by homocysteine lowering
treatment, are still pending.
2.2.2.7
Lipoprotein(a)
Lipoprotein (a) [Lp(a)] consists of an LDL particle
with its apo B-100 component linked by a disulfide
Coronary Heart Disease 1.33 (1.21 − 1.47)
and Stroke
(15 studies)
1.49 (1.31 − 1.70)
Coronary Heart Disease
(9 studies)
1.37 (0.99 − 1.91)
Stroke
(3 studies)
0.8 1.0 1.2 1.4
Relative Risk (x ± 95% - Cl)
bridge to apo(a), a protein of variable length
with a high sequence homology to plasminogen
(Berglund and Ramakrishnan 2004). Plasma
Lp(a) concentrations are mainly genetically deter-
mined, as they vary inversely with the apo(a) iso-
form size (Rader et al. 1994). In addition, they may
vary even within isoform size based on differential
levels of production (Rader et al. 1994).
The normal function of Lp(a) is unknown. Due
to the close homology between Lp(a) and plasmino-
gen it has been suggested that this lipoprotein may
inhibit endogenous fibrinolysis by competing with
plasminogen for binding on the endothelial surface
(Hajjar et al. 1989).
Prospective studies that examined the associa-
tion between Lp(a) and cardiovascular risk, have
not always found consistent evidence of associa-
tion. Some of them supported a positive association
between either plasma apo(a) or Lp(a) mass and vas-
cular risk (Schaefer et al. 1994; Wald et al. 1994;
Cremer et al. 1997; Wild et al. 1997), whereas others
did not (Jauhiainen et al. 1991; Ridker et al. 1993,
1995; Cantin et al. 1998). In conclusion, present
prospective studies do not establish the importance
of Lp(a) as a risk factor for future cardiovascular
events. It remains open whether any increased risk
is restricted to those with the highest levels of Lp(a)
or whether there is an interaction with other cardio-
vascular risk factors.
2.2.2.8
Markers of Inflammation
As outlined above, inflammation characterizes all
phases of atherosclerosis (Faxon et al. 2004). Based
Fig. 2.2.3. Average relative risk esti-
mated with fi xed effect models from
prospective cohort studies of plasma
homocysteine and risk of cardiovas-
1.6 1.8 2.0 cular disease [adapted from Bautista
et al. (2002)]
 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 29

on this pathophysiological concept it is not surpris-
ing, that several markers of low-grade systemic
inflammation have shown to be useful for cardiovas-
cular risk prediction. These markers include unspe-
cific acute-phase reactants, such as high-sensitive
C-reactive protein (hsCRP) and serum amyloid
A (Libby and Ridker 2004), adhesion molecules,
such as VCAM-1, ICAM-1 or P-selectin (Lutters
et al. 2004) which mediate monocyte attachment
to the vascular endothelium, and cytokines such as
Interleukin-6 and tumor necrosis factor D (Ridker
et al. 2000b; Steffens and Mach 2004). Among
these markers, hsCRP has created most interest and
will possibly prove to be the clinically most useful
marker. It is easy and inexpensive to measure with
commercial assays, and levels in a given individual
are quite stable over long periods as long as hsCRP is
not measured within 2–3 weeks of an acute inflam-
matory stimulus like an intercurrent infection. This
marker showed a consistent and strong association
with cardiovascular risk in several risk groups.
These groups included currently healthy men and
women (Ridker et al. 1997, 1998a, 2000a; Rohde
et al. 1999), elderly (Tracy et al. 1997), high-risk
smokers (Kuller et al. 1996), hyperlipidemic sub-
jects (Ridker et al. 2001), diabetics (Coppola et
al. 2006), patients with stable and unstable angina
pectoris (Liuzzo et al. 1994; Haverkate et al. 1997;
Morrow et al. 1998; Rebuzzi et al. 1998; Sabatine
et al. 2002), and in patients that had already suf-
fered a myocardial infarction (Ridker et al. 1998c;
Hoffmann et al. 2005). In these studies, individuals
with hsCRPS levels in the upper quartile had relative
risks of future vascular events three to four times
higher than individuals with lower levels (Fig. 2.2.4).
The effects were independent of all other traditional
cardiovascular risk factors (Fig. 2.2.5).
Moreover, plasma levels of hsCRP add additional
information to the predictive value of plasma lipid
measurements (Ridker et al. 1998b). Patients with
elevated levels of hsCRP are more likely to benefit
from lipid-lowering therapy even when their choles-
terol levels are only slightly elevated (Ridker et al.
2001; Anonymous 2005b; Kinjo et al. 2005).

Kuller MRFIT 19961996 CHD Death

Ridker PHS 1997 MI
Ridker PHS 1997 Stroke
Tracy CHS/RHPP 1997 CHD
Ridker PHS 1998, 2001 PAD
Ridker PHS 1998, 2000, 2001 CVD
Koenig MONICA 1999 CHD
Roivainen HELSINKI 2000 CHD
Mendall CAERPHILLY 2000 CHD
Danesh BRHS 2000 CHD
Gussekloo LEIDEN 2001 Fatal Stroke
Lowe SPEEDWELL 2001 CHD
Packard WOSCOPS 2001 CV Events*
Ridker AFCAPS 2001 CV Events*
Rost FHS 2001 Stroke
Pradhan WHI 2002 MI, CVD Death
Albert PHS 2002 Sudden Death
Sakkinen HHS 2002 MI
0 1.0 2.0 3.0 4.0 5.0 6.0
Relative Risk (upper vs lower quartile)

Fig. 2.2.4. Prospective studies relating baseline CRP levels to the risk of fi rst cardiovascu-
lar events. CHD indicates coronary heart disease; MI, myocardial infarction; PAD, pulmo-
nary artery disease; CV, cardiovascular; MRFIT, Multiple Risk Factor Intervention Trial;
PHS, Physicians’ Health Study; CHS, Cardiovascular Health Study; RHPP, Rural Health
Promotion Project; WHS, Women’s Health Study; MONICA, MONItoring trends and de-
terminants In CArdiovascular disease; HELSINKI, Helsinki Heart Study; CAERPHILLY,
Caerphilly Heart Study; BRHS, British Regional Heart Study; LEIDEN, Leiden Heart Study;
SPEEDWELL, Speedwell Heart Study; WOSCOPS, West of Scotland Coronary Prevention
Study; AFCAPS, Air Force Coronary Atherosclerosis Prevention Study; FHS, Framingham
Heart Study; WHI, Women’s Health Initiative; and HHS, Honolulu Heart Study [from
Ridker (2003)]
30 N. Weiss and U. Hoffmann
Lipoprotein(a)
Homocysteine
Interleukin - 6
TC
LDL - C
sICAM - 1
Serum amyloid A
Apolipoprotein B
TC - HDL - C ratio
hs - CRP
hs - CRP + TC - HDL - C ratio
0 1.0 2.0
Relative Risk of Future Cardiovascular Events
2.2.3
Risk Groups with Potential Benefit for
Screening and Impact of Screening on
Therapy
CVD is the leading cause of death in the developed
world (Pasternak et al. 2003) and may become the
leading cause of death in the entire world (Murray
and Lopez 1997). However, many patients with
prognostically significant atherosclerotic vascular
disease are asymptomatic (Pasternak et al. 2003).
Manifestations of CVD are of clinical importance
in regard to their quantitative impact on mortality
and morbidity in a population, and in regard to an
important impact on the quality of life of affected
subjects includes CHD, peripheral arterial occlusive
disease, cerebrovascular disease, and abdominal
aortic aneurysms.
Consequently, there is enormous interest in
developing screening techniques by which relevant
but asymptomatic disease can be detected at an
early stage (Greenland et al. 2001). This strategy
is first aimed at identifying high-risk patients with-
out established CVD which need aggressive medical
therapies for primary prevention. Furthermore, this
strategy is aimed at identifying patients with exist-
ing, although clinically asymptomatic disease, that
may profit from therapeutic intervention beyond risk
factor management, to prevent progression of the
disease or to prevent acute clinical consequences.
In addition, cardiovascular screening may be
of importance in patients who already suffer from
Fig. 2.2.5. Clinical application of C-re-
active protein for cardiovascular dis-
ease detection and prevention [from
Ridker (2003)]
4.0 6.0
established CVD. This secondary prevention strat-
egy is directed to determine the prognosis for future
cardiovascular events in the same vascular bed or
the development of vascular complications in other
territories.
In an asymptomatic patient the initial assessment
is aimed to obtain an estimate of his risk for devel-
oping the disease (Smith et al. 2000; Greenland et
al. 2001). Risk estimates are essentially of two types
– absolute risk and relative risk. Absolute risk is
the probability to determine the disease in a finite
period, whereas relative risk is the ratio of absolute
risk for a patient over a standard risk. The latter can
be either the average risk or the low risk associated
with an absence of risk factors.
To determine the risk, the clinical end point must
be specified. In the case of CHD, clinical end points
are well defined. Traditionally, total coronary heart
disease endpoints, including stable angina pectoris,
major coronary events (unstable angina and myo-
cardial infarction), and coronary death, have been
used. In the case of peripheral arterial occlusive
disease, relevant end points are less well defined but
may include limb survival, need for revasculariza-
tion procedures due to critical ischemia or disabling
claudication, or additional cardiovascular events,
including death. In the case of cerebrovascular dis-
ease, the most relevant end point is the combination
of non-disabling or disabling stroke, and death. The
clinical end point of abdominal aortic aneurysmatic
disease which needs to be avoided is the catastrophic
event of rupture. An additional end point may be
 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening
symptoms of aneurysmatic disease including local
pain or peripheral embolization.
Risk stratification of asymptomatic persons fur-
thermore includes a quantitation of the probability
of developing future events in a definite period of
time. In the case of CHD, and for clinical applica-
bility, the absolute risk of a person is categorized
into three categories. Persons in a high risk group
are estimated to have a > 20% risk in 10 years to
develop CHD endpoints, an intermediate risk indi-
cates a 10%–20% risk in 10 years, and persons in the
low risk group are estimated to have < 10% risk in
10 years. This risk estimate is based on the Framing-
ham risk score (Anonymous 2001). The risk factor
management and further screening strategies for
risk assessment should be adjusted by the severity of
the risk. This concept has been adopted in the guide-
line of the National Cholesterol Education Program
in the United States, the joint European Societies,
and other organizations. For other manifestations of
atherosclerotic vascular disease, risk estimates have
not been defined that clearly. However, as peripheral
arterial occlusive disease, cerebrovascular disease
and abdominal aortic aneurysms are occurring in
individuals with a risk profi le comparable to patients
at risk for CHD, similar algorithms may be used.
2.2.3.1
Patients at Risk of Coronary Heart Disease
Initial risk estimation of CHD in asymptomatic
patients is performed in an office-based risk assess-
ment (Smith et al. 2000; Greenland et al. 2001).
It first uses the determination of proven causative
cardiovascular risk factors, including cigarette
smoking, elevated blood pressure, elevated serum
cholesterol (or LDL cholesterol), low HDL choles-
terol, and diabetes mellitus. Conditional risk fac-
tors, including triglycerides, small LDL particles,
Lp(a), homocysteine, hsCRP, and coagulation fac-
tors may or may not be included in the estimate. The
latter factors are considered conditional risk factors,
when serum levels are abnormally high. Based on
the above mentioned parameters, individual per-
sons may be classified into one of the three risk
categories.
In a primary prevention setting, patients at a
low risk for developing CHD (no major coronary
risk factor) do not need specific intervention and
no further testing besides reevaluation in about
5 years. High risk patients, which are those with
31
established CVD, with type 2 diabetes or multiple
other CHD risk factors, are candidates for intensive
risk factor intervention. Non-invasive testing is not
required to determine risk factor treatment goals.
Intermediate risk patients are persons that have
at least one major risk factor outside the desirable
range or a positive family history of CHD. These
groups of patients may benefit from non-invasive
testing for further risk assessment to determine
risk factor treatment goals. These tests may include
tests for silent or inducible ischemia (exercise
ECG testing, exercise and pharmacological stress
echocardiography, exercise and pharmacological
myocardial perfusion imaging, ambulatory ECG
monitoring, positron emission tomography), and
noninvasive tests of atherosclerotic burden (systolic
ankle/brachial pressure index, B-mode ultrasound
to measure carotid artery intima-media thickness,
coronary calcium score measurement by electron
beam tomography, MRI imaging techniques of
atherosclerotic disease, endothelial function stud-
ies or measurement of hsCRP) (Smith et al. 2000).
Identification of atherosclerotic vascular disease in
these patients would qualify them for more aggres-
sive risk factor modification.
2.2.3.2
Patients at Risk of Abdominal Aortic Aneurysms
Abdominal aortic aneurysms (Sakalihasan et al.
2005) cause 1.3% of all deaths among men aged 65–
85 years in developed countries. These aneurysms
are typically asymptomatic until the catastrophic
event of a rupture. Repair of large (> 5.5 cm in diam-
eter) or symptomatic aneurysms by open surgery
or endovascular repair is recommended, whereas
repair of small abdominal aortic aneurysms does
not provide a significant benefit. The incidence of
abdominal aortic aneurysms has increased during
the past two decades. This may be due to the aging
of the population, the rise in the number of smok-
ers, and the introduction of screening programs and
improved diagnostic tools.
There are many causes of aneurysmal dilatation.
Few abdominal aortic aneurysms are due to specific
causes like trauma, infection (i.e. salmonellosis, sta-
phylococcal infection, brucellosis) (Benenson et al.
2001), inflammatory diseases (Behcet and Takayasu
disease) (Matsumura et al. 1991; Erentug et al.
2003), and connective tissue disorders (Marfan syn-
drome, Ehlers-Danlos type IV) (Towbin et al. 1999).
32 N. Weiss and U. Hoffmann
Most aneurysms are associated with atherosclerotic
damage of the aortic wall and are thereby a conse-
quence of atherosclerosis (Johnston et al. 1991).
The main risk factors for the development of
abdominal aortic aneurysms include tobacco smok-
ing, hypertension, chronic obstructive pulmonary
disease, hyperlipidemia, male gender, age, and
family history of the disorder. Smokers have a more
than four times higher risk of developing abdominal
aortic aneurysms compared to people who have never
smoked. Smoking confers the single most important
risk factor for this disorder. First-degree relatives
of patients with abdominal aortic aneurysms have
a 15%–19% risk of the disease compared with only
1%–3% in unrelated patients (Sakalihasan et al.
2005).
Screening abdominal ultrasonography in asymp-
tomatic individuals is an accurate test, with 95% sen-
sitivity and near 100% specificity for the detection of
abdominal aortic aneurysms (Fleming et al. 2005).
Death from AAA rupture after negative results on
a single ultrasound scan at age 65 years is rare, and
thereby virtually excludes the risk for future AAA
rupture or death.
A recent study evaluated the incidence of abdom-
inal aneurysms in a population of patients with
symptomatic CHD (Hanly et al. 2005). A total of 47
aneurysms were detected in 415 patients (9.9%). All
aneurysms were detected in patients over 60 years of
age (detection rate 11.7%). This study thereby sup-
ports the concept of screening a higher risk popula-
tion of patients over 60 years of age with CVD for
abdominal aortic aneurysms primarily by ultra-
sound.
The effectiveness and cost-effectiveness of
screening for abdominal aortic aneurysms in the
general population is based on results from four
randomized controlled trials (Scott et al. 1995,
2002; Ashton et al. 2002; Lindholt et al. 2002;
Vardulaki et al. 2002; Norman et al. 2003). A cost-
effectiveness analysis using a Markov model showed
that ultrasound screening of white men beginning
at age 65 is both effective and cost-effective in pre-
venting abdominal aortic aneurysms related death.
Such screening would have a small but real impact
over a 20-year period for these men (Silverstein et
al. 2005). The Society of Vascular Surgery and the
Society for Vascular Medicine and Biology there-
fore recommends screening for abdominal aortic
aneurysms in all men aged 60–85 years (Kent et
al. 2004). The U.S. Preventive Services Task Force
restricts their recommendation for screening by
ultrasonography to men aged 65–75 years who have
ever smoked (Anonymous 2005a)
For patients with a known abdominal aortic
aneurysm which is often detected incidentally, evi-
dence recommends periodic ultrasound surveil-
lance for those with small abdominal aortic aneu-
rysms (3.0–3.9 cm in diameter) and elective surgical
repair for those with large abdominal aortic aneu-
rysms (t5.5 cm). Two recent randomized controlled
trials have shown that early surgical repair confers
no survival benefit compared with periodic surveil-
lance for patients with intermediate-sized abdomi-
nal aortic aneurysms (4.0–5.5 cm in diameter).
Therefore, those patients can also be monitored
(Anonymous 2002; Lederle et al. 2002; Powell
and Greenhalgh 2003). Some centers choose to
increase the frequency of monitoring to every 3–
6 months when the aneurysm size reaches 5.0 cm.
In symptomatic patients factors to consider
include the high risk of life-threatening condi-
tions, the potential increased risk of death or poor
outcome with delay in diagnosis, the limitations of
ultrasound in identifying whether symptoms are due
to known or suspected abdominal aortic aneurysm
and the timely availability of computed tomogra-
phy or other imaging tests. If available, computed
tomography is preferred in patients with recent or
severe symptoms, since it is better at detecting retro-
peritoneal hemorrhage and other complications and
in providing preoperative definition of the anatomy
(Silverstein et al. 2005).
2.2.3.3
Patients at Risk of Peripheral Arterial Occlusive
Disease
Patients’ history of intermittent claudication or even
more sophisticated questionnaires on symptoms of
peripheral arterial occlusive disease like the WHO/
Rose questionnaire are limited by their low sensitiv-
ity (< 30%) to detect angiography-positive peripheral
arterial occlusive disease. Screening for peripheral
arterial occlusive disease therefore should include
palpation of lower extremity pulses and measurement
of the systolic ankle-brachial pressure index and/or
the toe-brachial pressure index. An ankle-brachial
pressure index below 0.9 has been shown to be more
than 95% sensitive and nearly 100% specific for the
detection of relevant peripheral arterial occlusive dis-
ease (Dormandy and Rutherford 2000). In patients
with falsely high ankle pressures due to mediasclero-
 Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening
sis, measurement of the toe-brachial pressure index
may be used (Williams et al. 2005).
Several studies have shown that the ankle-bra-
chial pressure index is a robust and independent
predictor of all-cause mortality in both men and
women (Vogt et al. 1993; Hooi et al. 2004; Lange
et al. 2005). Therefore, this measurement, a simple,
objective, non-invasive technique which can be used
in the physician’s office, may be useful for early
identification of patients at high risk for morbidity
and mortality, mainly due to CVD. These patients
should be treated intensively to lower or eliminate
their cardiovascular risk factors.
Besides its usefulness as a screening tool for
detection of asymptomatic atherosclerosis, identi-
fication of asymptomatic peripheral arterial occlu-
sive disease and especially early revascularization of
symptomatic patients has not been shown to result
in a reduction of amputation rates or in increased
survival (Dormandy and Rutherford 2000).
2.2.3.4
Patients at Risk of Cerebrovascular Disease
Atherosclerotic disease accounts for approximately
25% of ischemic strokes. Atherosclerotic stroke is
caused mainly by embolic events from the carotid
artery bifurcation or the aortic arch, although intra-
cranial thrombosis may occur. Primary prevention
of stroke is critical for patients with risk factors for
atherosclerosis or manifestation of atherosclerosis in
other vascular territories. Stroke can be prevented in
patients with established atherosclerotic disease by
identification of patients with carotid artery stenosis
by non-invasive testing and subsequent revascular-
ization of high-grade carotid stenosis (Weinberger
2005). The rationale of screening for carotid stenosis
is discussed elsewhere in more detail (see chapter 9.3
Duplex Ultrasound of the Carotid Arteries: Practi-
cal Aspects and Results of Screening for Carotid
Disease).
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 Pathology: General Oncological Aspects of Screening 39

Pathology 3
3.1 General Oncological Aspects of Screening
Stefan Delorme and Gerhard van Kaick

CONTENTS The term “screening” denotes a systematic exam-

ination of a hitherto healthy population, or at least a
large number of persons, with the intent to fi lter out
3.1.1 Important Types of Cancer 39
those, in whom a treatment is necessary, or, more
3.1.2 Natural History 40 often, further diagnostic tests are needed for clari-
fication. With the tools available today, screening
3.1.3 Tumor Growth Rate 41 will never be done for an entire population, but in
a cohort which is defined by e.g. age, gender, or the
3.1.4 Treatment Options 42
presence of certain risk factors. Whenever screening
3.1.5 Acceptance and Safety of for cancer is attempted, a number or requirements
Screening Procedures 42 must be fulfi lled:
References 43

The cancer screened for must be an important
health problem.

The natural history of the target lesions should
The intent of screening is to reduce mortality by be known.
detecting a cancer in its curable stage – i.e., before
The disease should have an asymptomatic, pre-
it has become locally invasive, and, more impor- clinical phase in which it is detectable by diag-
tant, before lymphatic or hematogeneous spread nostic tests.
has occurred. Metastases may develop at any stage
An effective treatment for the lesions must be
of a tumor, even when it is still occult, but the prob- available.
ability of spread increases as the tumor grows, for
The screening test should be acceptable and safe.
very simple reasons (Table 3.1.1). First, the more
time elapses, and the more cells a tumor contains,
the higher is statistically the chance that metasta- Table 3.1.1. Clinical appearance of metastasis as a function
sis occurs. Second, due to their genetic instabil- of tumor size
ity, tumor cells tend to de-differentiate with time,
Diameter Eventual metastasis Number of
and become more aggressive. Third, angiogenesis (cm) (%) cases
occurs during tumor growth and is a prerequi-
1–2.5 27 317
site for invasion and metastatic spread. Note that,
although rarely, even large tumors may not have 2.5–3.5 42 496
caused distant metastases. 3.5–4.5 57 544
4.5–5.5 67 422
5.5–6.5 73 329
S. Delorme, MD 6.5–7.5 84 192
Professor, Department of Radiology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 7.5–8.5 81 136
69120 Heidelberg, Germany > 8.5 92 212
G. van Kaick, MD
Professor Emeritus, German Cancer Research Center (DKFZ), According to Koscielny et al. (1984), modified according
Im Neuenheimer Feld 280, 69120 Heidelberg, Germany to Hellman (1994)
40 S. Delorme and G. van Kaick
3.1.1
Important Types of Cancer
In industrialized countries, 25% of the population
die of cancer. Of all patients who suffer from ma-
lignant diseases, approximately 40% are cured, or
survive at least the first 5 years. Therefore, the in-
cidence of cancer is considerably higher than the
mortality from malignant diseases. Unfortunately,
although deaths from cancer are registered centrally
via the death records, first diagnoses are not. In
Germany, cancer registries are being built up, but
so far only the Saarland has a fully established one
(www.krebsregister.saarland.de/datenbank/index.
php), and so have some former East German states.
The frequencies at which certain types of cancer
occur are different for industrialized and develop-
ing countries. Whether they constitute an “impor-
tant health problem”, however, depends not only on
their incidence but also on their prognosis, and pos-
sibly socio-economic sequelae. Clinically, the most
important ones in western countries are cancers of
the lung, large bowel and rectum, breast, prostate,
as well as pancreas, whereas in the far east and in
third world countries, oral, lung, stomach, breast,
esophagus, cervical and liver cancer predominate
(Bosch and Coleman 1994). The reasons are, e.g.,
differences in nutrition, smoking habits, exposition
to carcinogens, or chronic infections with oncogenic
Cancer initiating agents and
processes
(e.g. chemical carcinogens,
mediation, chronic inflammation)
(epi)genetic change
Normal cell
• Transient cell cycle
Extensive DNA damage can
arrest
lead to constant inhibitation of
• DNA repair
• Replication with no • Transcription
DNA sequence changes • Replication
• Chromosome regregation
Apoptosis
viruses. Therefore, the targets for screening vary for
different parts of the world.
The most important, and intractable risk factor is
age. The incidence rises significantly and continu-
ously from the fourth decade on. Therefore, screen-
ing will mostly be offered to those who are aged
between 40 and 70. Older persons more often die of
cardiovascular diseases, and slow-growing cancer is
more frequent than in younger individuals.
3.1.2
Natural History
Malignant tumors develop in several steps which
may take years to decades (Fig. 3.1.1). The first step is
termed initiation, and was formerly viewed as a sin-
gle event, e.g., the exposure to chemicals, radiation,
or oncogenic viruses, which induced a mutation,
which then, after further promoting steps would re-
sult in malignant transformation. One must realize,
however, that cells are constantly exposed to numer-
ous factors which might possibly cause malignant
transformation, and that they have highly efficient
defense mechanisms, like transient cell cycle arrest,
DNA repair, or – in case of severe damage – apop-
tosis. Only if these mechanisms fail, which may be
due to some overweight or addition of damaging
• Activation of proto-oncogenes
• Inactivation of tumor suppressor
genes
• Inactivation of genomic stability
genes (e.g. DNA repair genes
• Changes in DNA methylation
patterns
(epi)genetic change
Cancer,
metastasis
Initated cell Malignant cell
The cells develop characteristics
such as
• Defects in cell cycle and growth
control
• Increasing genetic instability
• Defects in programmed cell Fig. 3.1.1. Steps of carcino-
death (apoptosis) genesis, according to
• Simulation of angiogenesis Schmezer (2006), with
• Gain of immortality
permission

factors, or maybe chance, may such “initiation” be
completed.
Promotion is the influence of additional factors
on initiated cells, which enhance further carcino-
genesis. By nature, promoting factors are non-ge-
netic damages, and they are reversible. The most
important promoter is chronic inflammation, but a
variety of other factors is known. Note that some ini-
tiating carcinogens also have promoting properties.
After further steps termed conversion and propa-
gation, progression is the last pre-clinical phase,
in which invasion, angiogenesis, lymphatic as well
as hematogenous spread may, but need not, occur.
A sensible screening method should be capable of
detecting a tumor in this phase. When a tumor has
reached a clinically detectable size, 25–30 doublings
have already occurred (Fig. 3.1.2).
Most of what is known about the natural history
of cancer results from animal experiments. In hu-
mans, there are only few instances where persons
could be followed after a certain event which might
contribute to the development of cancer, mostly ex-
posure to radiation (nuclear bombing of Hiroshima
and Nagasaki, Thorotrast exposure, fallout from
the Chernobyl catastrophe). Exposure to chemicals
or viral oncogens is by nature chronic and not a sin-
gle event. Therefore, the latency period between ex-
posure and the development of cancer is more easy
to estimate after radiation exposure than it is after
contact with chemical of biological agents.
The most important factors to know are how many
persons exposed ultimately develop cancer, and af-
ter which latency period. After the nuclear raids on
Hiroshima and Nagasaki, where the survivors were
hit by a single flash of gamma quants and neutrons,
an excess of solid tumors (over those expected in a
non-exposed population) occurred no earlier than
after 15 years, whereas the incidence of acute my-
eloid leukemias began to rise after 3 years already.
In exact figures, there were 335 excess deaths from
solid tumors and 85 from leukemia which occurred
between 1950 and 1990. Whereas the excess in inci-
dence of leukemias was limited in time, and lasted
no longer than 15 years, the risk for solid tumors re-
mained elevated life-long (Pierce et al. 1996).
After incorporation of radioactive nuclides and
chronic internal irradiation (Thorotrast adminis-
tration for diagnostic angiographies), the latency
periods are comparable: 15 years for liver cancer
(with relentlessly increasing incidence), and 5 years
for leukemias (van Kaick et al. 1999). Although the
increase in risk is striking, it must be noted that the
Pathology: General Oncological Aspects of Screening 41
Fig. 3.1.2. Time line of the development of cancer
(Bryan 1994)
majority (80%) of Thorotrast-exposed persons did
not develop liver cancer.
A puzzling fact with the Chernobyl catastrophe is
that there was a striking rise in incidence of thyroid
carcinomas in children, which occurred as early as
4 years after the event (Ivanov et al. 2006). The rea-
sons for this are still unclear –genetic instability of
the growing, juvenile tissue may have caused the ra-
diation effect to become manifest so early.
How much smoking contributes to the develop-
ment of lung cancer and other malignancies is well
enough known in public. It is impressive to see how
steep the incidence of lung cancer (an exceedingly
rare entity until 1900) rose 30 years after the in-
crease in consumption of industrially manufactured
cigarettes, and also how the incidence in women be-
gan to increase in the 1960s, again 30 years after,
around 1930, cigarette smoking had become popu-
lar in women (Weiss 1997). It is proven that both
the number of cigarettes smoked daily and the years
of smoking are the most important risk factors, but
also the age at beginning to smoke is of consider-
able importance. Smoking also shortens the latency
period of lung cancer when additional risk fac-
tors are present: In non-smoking uranium miners,
the latency period until lung cancer occurred was
25 years, but in smoking miners it was only 19 years
(Archer et al. 2004).
The role of viral infections for the development of
cancer was for long denied and it has only been ac-
42 S. Delorme and G. van Kaick
cepted and investigated since the 1970s (Bannasch
and Schröder 2002; zur Hausen 2006). Today,
viral carcinogenesis is proven for the Epstein-Barr
virus (Burkitt’s lymphoma and nasopharyngeal
carcinoma), Hepatitis B and C virus (hepatocellu-
lar carcinoma), and, most recently, subtypes of the
human papilloma virus (HPV). With hepatitis and
papilloma virus, the latency period is in the range of
decades. Hepatitis B and HPV are the rare instances
where a primary prevention is possible since actively
immunizing agents have been clinically approved
and are commercially available.
Persons with a genetic predisposition for cancer
constitute a major challenge for screening. Genetic,
predisposing changes are known, e.g., for cancer of
the breast, colon, thyroid (medullary carcinoma), and
for retinoblastoma. The individual risk is enormous,
being approximately 70% for carriers of a BRCA-1
mutation (breast cancer), or almost 100% for patients
with hereditary adenomatosis of the colon (colorec-
tal cancer). The vast majority of all cancer patients,
however, has sporadic, and not hereditary cancer.
Furthermore, whenever the individual risk is as high,
it may be preferable to surgically remove the organ at
risk instead of screening for the cancer. So, carriers
of mutations of the RET-proto-oncogene are offered
thyroidectomy, patients with adenomatosis undergo
total proctocolectomy; also subcutaneous mastec-
tomy is an option for carriers of a BRCA mutation.
Screening patients with genetic risk is methodi-
cally difficult. First, the responsible mutations
not only cause cancer but also potentiate harm-
ful effects e.g., of radiation, because DNA repair
mechanisms are deficient. Obviously, X-ray mam-
mography for women with BRCA mutations must
therefore be used with care. Second, screening
has to begin at young age because the cancer of-
ten arises early. Third, genetically induced cancers
may be more aggressive and have higher growth
rates than sporadic ones, as has been shown for
BRCA-associated breast cancer, and this may war-
rant adjustment of screening intervals (Tilanus-
Linthorst et al. 2005).
Patients who have been treated successfully for
cancer before constitute a risk group of its own,
not only because late recurrences are a remaining
threat. Chemo- and radiotherapy are by nature mu-
tagenic and may therefore cause secondary malig-
nancies (Dores et al. 2002; Matesich and Shapiro
2003). The excess rate is estimated to be around 15%,
and the latency period to be similar to that with the
above injuries, i.e., longer than 10 years.
3.1.3
Tumor Growth Rate
Outside animal experiments, the growth rate of a tu-
mor can not be measured before it has been detected
clinically or by imaging. The main determinants of
the growth rate are the length of the cell cycle, the
rate of cell death, and the relation between resting
and proliferating cells. Shortening of the cycle, a
decrease in the death rate, and a shift from G0 to
G1 will accelerate tumor growth.
There are empirical mean values which have been
published for various solid tumors: short doubling
times are, e.g., reported for small cell lung cancer,
Burkitt’s lymphoma, or Ewing sarcoma, whereas slow
growth is seen in some renal cell or colorectal carcino-
mas. As a rule, the doubling time of solid, malignant
tumors rarely exceeds 600 days. However, some facts
must be born in mind (Table 3.1.2). Within one tumor
type, the range of tumor volume doubling times is con-
siderable, reflecting variations in aggressiveness of the
given cancer. When screening is performed with the
usual intervals (1 or 2 years), only those patients with
relatively slow-growing tumors (tumor volume dou-
bling time > 300 days) will benefit, whereas rapidly
growing tumors will frequently be detected clinically
(interval carcinomas). Not unlikely however, such tu-
mors might be those which also metastasize early, and
the prognosis might therefore be dismal, even if shorter
screening intervals were used, and the tumor were de-
tected earlier. Therefore, we doubt whether shorten-
ing the screening interval will always be beneficial.
Often, unclear findings are followed up after a short
interval, e.g., 3 or 6 months. It is important to consider
that even malignant tumors may have unusually long
doubling times, and a lesion which appears not to have
grown may still be malignant (Jennings et al. 2006).
Therefore, such control examinations must be judged
with great caution – seemingly constant findings may
be falsely reassuring. Consider also that the diameter
only changes by the cubic root of the change in vol-
ume. So, when a sphere increases from 2 to 2.6 cm in
diameter, it has already doubled its volume.
3.1.4
Treatment Options
It does not make sense to screen for a tumor which is
intractable from its very beginning. For carcinomas

of the breast, prostate, colon, lung (except for small
cell lung cancer), kidney, liver, cervix uteri, and oth-
ers, primary surgery is possible, and the long-term
outcome is clearly dependent on the tumor stage
or size at the time of diagnosis. Comorbidity may
preclude surgery, even in the early stages, such as
lung emphysema or liver cirrhosis, but minimally
invasive methods may offer similar outcome as sur-
gery (e.g., stereotactic radiotherapy for lung cancer,
or ethanol injection or radiofrequency ablation for
hepatocellular carcinoma).
Mortality is not everything. Even where the ben-
efit of early detection for long-term outcome is un-
clear, the patient may benefit personally by being
spared mutilating surgery or morbidity from local
tumor invasion. This is particularly clear where
small, organ-conserving procedures are available,
such as in the breast, lung, cervix, or colorectum.
3.1.5
Acceptance and Safety of
Screening Procedures
Very obviously, the risks of any screening proce-
dure must be within an acceptable range, and the
procedure itself must be tolerated by the screening
participants and not be associated with major dis-
comfort. The medical risk of screening procedures
are radiation-induced carcinogenesis, toxicity of
contrast media and allergic reactions, hazards
caused by ferromagnetic objects inside MR scan-
ners, and, fi nally, complications of endoscopy.
Radiation exposure due to screening mammog-
raphy is controversially discussed. Clearly there
are no empirical data, and all calculations are ex-
trapolated from those made on occasion of high-
Table 3.1.2. Volume doubling times of some selected solid tumors
Primary tumor n Tumor volume
doubling time
Renal cell carcinoma 56 603 (mean)
Hepatocellular carcinoma 11 127 (median)
Lung carcinoma 149 161 (mean)
Lung carcinoma 11 117
Benign lung nodules 52 947
n/a = not available
Pathology: General Oncological Aspects of Screening 43
dose exposures (Jung 2001). The large screening
studies in the Netherlands and in Sweden have
meanwhile clearly shown that the mortality due to
breast cancer has decreased in the screened popu-
lation. So, however high the risks may have been,
they are more than outweighed by the benefits of
screening.
Iodine-containing contrast agents are currently
not used for any screening purpose, and will prob-
ably rarely be so. Gadolinium chelates in MR im-
aging and angiography are necessary for screen-
ing for vascular diseases, MR mammography for
high-risk groups, and perhaps, in future, for pa-
tients at risk for hepatocellular carcinoma. Their
risk for serious adverse events is notoriously small.
Very recently, they are discussed as cause for ne-
phrogenic systemic fibrosis, and their use in pa-
tients with impaired renal function is prohibited
for Gadodiamide and discouraged for other agents
(Michaely et al. 2007).
It has been proven that colonoscopy is efficient
in detecting colorectal cancer early, and that it also
is a mean to remove adenomas, which are the most
important precancerous lesions. However, the rate
of fatal perforations is around 1 in 80.000 (see also
the contribution by Becker). Furthermore, in or-
der to be tolerated, it has to be performed under
analgesia and sedation (with their own potential
hazards), and it requires bowel cleansing, which is
anything but comfortable for the patient.
The risks of screening are not only associated
with the test itself, but also with all further proce-
dures which are necessary in case of unclear results
(Friedenberg 2002). These range from ultrasound
or punch biopsies for suspicious lesions at mam-
mography to colonoscopy for fecal blood, coniza-
tion for suspicious pap smears, or bronchscopy,
thoracoscopy, or even open chest surgery for lung
nodules, with increasing probability of fatal com-
Range or standard Source
deviation (SD)
510 (SD) Ozono et al. (2004)
18–541 (range) Taouli et al. (2005)
117 (SD) Jennings et al. (2006)
37–646 (range) Revel et al. (2006)
n/a Revel et al. (2006)
44 S. Delorme and G. van Kaick
plications. This shows how important the specificity
of the screening test is, and how important the skill
of the readers and quality assurance measures. For
good reason, the qualifying criteria for readers in
mammography screening programs are extremely
rigorous.
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Pathology
3.2 Screening for Vascular Pathology
James H. F. Rudd, Silvia H. Aguiar, and Zahi A. Fayad
CONTENTS
3.2.1 Epidemiology of Atherosclerosis 45
3.2.2 Pathology of Atherosclerosis 45
3.2.3 Screening and Therapeutic Implications 48
3.2.4 Risk Assessment in Asymptomatic Women 49
References 50
3.2.1
Epidemiology of Atherosclerosis
Atherosclerosis and its complications are the lead-
ing cause of mortality and morbidity in the devel-
oped world. The situation is becoming increasingly
concerning in the developing world, with athero-
sclerotic cardiovascular disease set to replace infec-
tion as the leading cause of death early this century
(Reddy and Yusuf 1998).
The number of deaths per 100,000 attributable
to cardiovascular disease peaked in the Western
world in 1964. Around this time, the Framingham
study identified a number of modifiable risk fac-
tors for cardiovascular disease, including cigarette
J. H. F. Rudd, MD, PhD
S. H. Aguiar, MD
Z. A. Fayad, PhD, FAHA
Mount Sinai School of Medicine, One Gustave L. Levy Place,
Imaging Science Laboratories, Box 1234, New York, NY
10029, USA
Imaging Science Laboratories, Departments of Radiology
and Medicine (Cardiology), The Zena and Michael A. Wiener
Cardiovascular Institute, The Marie-Josée and Henry R.
Kravis Cardiovascular Health Center, Mount Sinai School
of Medicine, New York, NY, USA
Pathology: Screening for Vascular Pathology 45
3
smoking, hypertension, and hypercholesterolemia
(Wong et al. 1991).
Over the last quarter century there has been a
gradual decline in death rates (NHLBI 1998). The
age-adjusted coronary heart disease (CHD) mortal-
ity in the United States has dropped by more than
40% and cerebrovascular disease mortality by over
50%, with the greatest reductions seen among whites
and males.
There are several reasons for this. Public health
promotion campaigns aimed at reducing the preva-
lence of Framingham risk factors have been particu-
larly successful. Indeed, there has been a substantial
change in risk factor prevalence over the last 30 years.
The war is not won, however, and the decline in the
death rate from atherosclerosis slowed in the 1990s.
This is likely due to an epidemic of both obesity
and non-insulin dependent diabetes, as well as an
increased prevalence of cigarette smoking particu-
larly among young women (Cooper R et al. 2000).
Female death rates from cardiovascular disease over-
took male in 1984, and have shown a smaller decline
over the last 30 years (McGovern et al. 1996).
Fortunately, evidence has emerged over the last
decade that the progression of atherosclerosis can
be slowed and in some cases reversed with lifestyle
and drug interventions. However, identifying those
with or at-risk of atherosclerosis is not a trivial task,
and such screening will be the focus of this chapter
(Fig. 3.2.1). First, there follows a description of the
natural history of atherosclerosis.
3.2.2
Pathology of Atherosclerosis
Atherosclerosis is characterized by the gradual
accumulation of lipid, inflammatory cells and con-
46 J. H. F. Rudd, S. H. Aguiar, and Z. A. Fayad
Hypertension
Low HDL
Family history
Smoking
Risk Score
Fig. 3.2.1. Screening for atherosclerosis: the use of a combination of risk factor scoring with imaging. From left to right
– measurement of carotid IMT, plaque burden assessed using MRI and coronary calcium quantification by multislice CT
nective tissue within the arterial wall. It is a chronic,
progressive disease with a long asymptomatic phase
(Fuster et al. 2005a,b). The fi rst pathological abnor-
mality is the fatty streak, caused by an aggregation
of lipid and macrophages in the subendothelial
space. Fatty streaks may be seen in the aorta from
the second decade of life (Ross 1999; Tzou et al.
2005), and develop primarily in regions of endothe-
lial dysfunction. Endothelial cells in these regions,
often occurring in branch or bifurcation points of
the arterial tree (VanderLaan et al. 2004), have
decreased production of nitric oxide as a result of
their experiencing low wall shear stress (Ku et al.
1985). In contrast, chronic exposure to high shear
stress causes the cells to show an atheroprotective
phenotype (Traub and Berk 1998).
The major atherogenic risk factors such as
smoking, elevated low density lipoprotein (LDL)
levels, hypertension, and diabetes mellitus have
all been shown to impair endothelial function
(Cunningham and Gotlieb 2005). Normal
endothelium has anti-thrombotic, anti-inflam-
matory and vasomodulatory functions as a result
Age
Diabetes
Metabolic syndrome
Elevated LDL
of secretion of prostacyclin and nitric oxide (NO),
which inhibit platelet activation and promote
vasodilatation. In addition NO ameliorates expres-
sion of the endothelial adhesion molecules respon-
sible for inflammatory cell recruitment. Both the
barrier function and secretory capacity of the
endothelium become disrupted in atherosclerosis.
This manifests as an increase in permeability to
blood-derived lipids and inflammatory cells.
Once oxidized, LDL is retained within the sub-
endothelial space and attracts monocytes by trig-
gering the release of monocyte chemoattractant pro-
tein-1 (MCP-1) from endothelial cells (Cushing et
al. 1990). The newly expressed endothelial adhesion
molecules, including vascular cell adhesion mole-
cule-1, intercellular adhesion molecule-1, E-selectin,
and P-selectin, facilitate the internalization of more
monocytes into the sub-endothelium. Once there,
monocytes transform into macrophages, and bind
and internalize oxLDL via their scavenger recep-
tors (Hamilton et al. 1999; Ross 1999). OxLDL also
induces the production of macrophage colony-stim-
ulating factor (M-CSF) by vascular cells and mac-

rophages, which inhibits macrophage apoptosis and
sustains proliferation (Hamilton et al. 1999). Even-
tually, the subendothelial accumulation of modified
LDL and macrophage-derived foam cells leads to the
formation of the atheromatous lipid core.
Given favourable conditions (ongoing presence of
atherogenic risk factors), the lipid core may develop
over time into a mature atherosclerotic plaque. It
becomes bounded on its luminal side by an endothe-
lialized fibrous cap consisting of vascular smooth
muscle cells (VSMC) and connective tissue, in par-
ticular collagen. VSMCs migrate from the medial
layer of the artery and synthesize extracellular
matrix components such as elastin and collagen to
form the fibrous cap. The fibrous cap also contains
inflammatory cells, predominantly macrophages,
but sometimes T-lymphocytes and mast cells. As
the plaque enlarges, the affected artery grows out-
wards (by expansion of the external elastic lamina)
so that lumen diameter and therefore blood flow
is initially preserved [a process known as positive
remodeling (Glagov et al. 1987)]. As wall stress
increases with outward remodeling, eventually fur-
ther expansion becomes impossible and the plaque
starts to encroach into the lumen of the vessel. This
may cause symptoms by compromising blood flow.
Mature plaques may also become calcified, a process
that preferentially affects the intima of the artery.
Very advanced plaques will also often be perforated
by new blood vessels under the influence of ang-
iogenic factors, a process called ‘neovascularisation’.
However, these new vessels are structurally fragile,
and have a tendency to undergo spontaneous haem-
orrhage which can destabilize the plaque(Fuster
et al. 2005b) leading to clinical syndromes such as
heart attack.
Atherosclerotic plaques may remain quiescent for
decades. However, when they initiate clot formation
in the vessel lumen they can become life-threaten-
ing. This may occur either as a result of fibrous cap
rupture, with consequent exposure of the thrombo-
genic extracellular matrix of the cap and the tissue
factor (TF)-rich lipid core to circulating blood. Less
commonly, there can be erosion of the endothelial
cell layer overlying the fibrous cap, again potentially
leading to intravascular thrombosis. Endothelial
erosion accounts for around 30% of plaque rupture
events overall and seems more common in women
for unknown reasons (Farb et al. 1996). Both forms
of plaque disruption invariably lead to local platelet
accumulation and activation at the site of rupture
ulceration with subsequent thrombus formation.
Pathology: Screening for Vascular Pathology 47
This may trigger the clotting cascade, with throm-
bus formation and, if extensive, complete vessel
occlusion.
Symptoms are not inevitable after plaque cap
disruption however. Up to 70% of plaques causing
significant arterial stenosis contain histological evi-
dence of previous subclinical plaque rupture with
subsequent repair (Davies 1995). This is particu-
larly likely to occur if high blood flow through the
vessel prevents the accumulation of a large occlu-
sive thrombus. Additionally, the body’s natural
fibrinolytic pathways can deal with some thrombi,
allowing subsequent healing of the cap and overly-
ing endothelium. This process of repeated rupture
and repair may allow plaques to grow in a step-wise
fashion.
Atherosclerosis is a dynamic process in which
the balance between the destructive influence of
inflammatory cells and the reactive, stabilizing
effects of VSMCs determines outcome. The balance
can be tipped toward plaque rupture by factors such
as an atherogenic lipoprotein profi le, high levels of
lipid oxidation, local free radical generation, and
individual genetic variability. Alternatively, the
balance can be pushed toward plaque stability by a
reduction in plaque inflammation or an increase in
VSMC-driven repair. Lipid reduction, by whatever
means, reduces clinical events. Evidence that this
may be due to a plaque-stabilizing effect comes from
animal studies that showed that statins reduced
inflammatory cell and increased VSMC content of
plaques (Shiomi et al. 1995; Williams et al. 1998),
changes that would be expected to enhance stabil-
ity. Dietary lipid lowering in rabbits also reduced
the number of microvessels in the aortic intima,
suggesting another mechanism of favorably alter-
ing the biology of plaques (Aikawa et al. 1998).
It has become clear that the cellular and extracel-
lular composition of the plaque is the primary deter-
minant of plaque stability. Lesions with a large lipid
core, thin fibrous cap, a preponderance of inflam-
matory cells and few VSMCs are at the highest risk
of rupture. Inflammatory cells, particularly mac-
rophages, produce metalloproteinases which break
down the matrix proteins in the fibrous cap. In addi-
tion, they secrete inflammatory cytokines, in partic-
ular interferon J (IFN-J), which inhibit VSMC pro-
liferation and collagen synthesis. Other cytokines
secreted by inflammatory cells such as interleukin
1E, tumour necrosis factor-D and IFN-J are cyto-
toxic to VSMCs. Activated macrophages can also
induce VSMC death by direct cell-cell contact (Boyle
48 J. H. F. Rudd, S. H. Aguiar, and Z. A. Fayad
2005). Furthermore, VSMCs in the fibrous cap have
a reduced proliferative capacity and a propensity to
apoptosis. Consequently, the inflammatory process
within the lesions tends towards destruction of the
fibrous cap and subsequent thrombosis, and there is
a dynamic balance within the plaque between mac-
rophages, which promote erosion and rupture of the
fibrous cap, and VSMCs which nourish and repair
it. These processes are independent of plaque size.
Consequently, small asymptomatic and angiograph-
ically invisible plaques can rupture to precipitate a
fatal clinical event, whilst some large plaques which
obstruct flow to produce symptoms such as angina,
may be stable and not life threatening. There is an
urgent need to discriminate “stable” from poten-
tially “unstable” lesions in clinical practice.
3.2.3
Screening and Therapeutic Implications
Screening of patients at risk of vascular disease
(primary prevention) is desirable for a number of
reasons. Pre-symptomatic identification of high-
risk patients enables the prescription of lifestyle
changes or drug treatment aimed at either halt-
ing or even reversing the disease. Statin drugs are
very useful in this regard and have been shown to
reduce both death rates and cardiovascular out-
comes in asymptomatic high-risk patients (LIPID
Study Group 1998; Shepherd et al. 1995). Recently,
developments in imaging technology, computer
software and the discovery of an array of cellular
and molecular imaging targets has accelerated the
effort toward the identification of high-risk athero-
sclerotic disease.
The initial recommendation for screening of
asymptomatic patients is for the calculation of an
office-based risk score. This score is a multivariable
statistical model that takes into account the pres-
ence or absence of several risk factors including age,
sex, diabetes, hypertension and lipid abnormalities.
The commonest risk scoring system in the US uses
data from the Framingham study, and is endorsed
by the National Cholesterol Education Program
(NCEP) (NCEP Expert Panel 2002). Slight modi-
fications were made to this score to reflect the find-
ings of recent large clinical trials (Grundy et al.
2004). Similar scoring systems are used in Europe
(Conroy et al. 2003).
Risk scoring will provide a patient with an esti-
mated risk of a clinical event over the following
10 years (usually heart attack, stroke or a diagno-
sis of angina). Subjects can be stratified into three
groups: low-risk (10-year risk of less than 10%);
intermediate risk (10-year risk between 10% and
20%) and high-risk (10-year risk greater than 20%).
The 10-year risk is then used to set lipid level tar-
gets for treatment with statin drugs, and to recom-
mend further evaluation with imaging if necessary
(Grundy et al. 2004; Nasir et al. 2005a,b; NCEP
Expert Panel 2002).
Low-risk patients can be reassured and given
appropriate lifestyle advice. At the other end of
the spectrum, high-risk individuals will undergo
aggressive (probably invasive) investigation and
will receive intensive drug and lifestyle manage-
ment, without the need for further non-invasive
testing.
The most difficult group to advise are those that
fall into the intermediate Framingham risk score cat-
egory, estimated to represent about 40% of the adult
US population (Greenland et al. 2001). Within this
group, the risk score model is poor at discriminat-
ing those who will actually suffer a hard event. The
addition of non-invasive imaging to the office-based
score is most appropriate in this setting.
Although risk scoring is a simple way of cat-
egorizing a patient’s 10 year potential for vascular
events, the ability of the score to accurately predict
events on an individual basis has been questioned
(Cooper JA et al. 2005; D’Agostino Sr et al. 2001).
This has led to the increasing emphasis on the
detection of subclinical atherosclerosis using imag-
ing technology.
Several supplemental investigations have been
considered, including carotid intima-media thick-
ness (IMT) and black-blood MR imaging (mark-
ers of carotid atherosclerosis), the ankle-brachial
pressure index (a surrogate marker of periph-
eral vascular disease) and direct assessment of
coronary calcium deposits using either electron
beam or multislice computed tomography (CT)
(Greenland et al. 2004) – Fig. 3.2.1. The result of
non-invasive testing can help to refi ne the inter-
mediate Framingham risk score, either moving the
patient up or down one risk category. Positive test-
ing would place the subject in the high risk Fram-
ingham group, with further appropriate investiga-
tion required. However a negative non-invasive test,
such a zero calcium score, would give reassurance
to both patient and doctor. The choice of which test
 Pathology: Screening for Vascular Pathology 49

to use is still a matter of conjecture. There is good

evidence for both calcium scoring (Bellasi and
Raggi 2005) and carotid IMT measurement (Tzou
et al. 2005). In addition, novel modalities such as
FDG PET/CT imaging (Fig. 3.2.2) and black blood
MRI (Fig. 3.2.3) are currently being evaluated in
this regard in a long-term prospective outcomes
study known as REDEEM, a sub-study of the mulit-
centre FREEDOM trial.

Multi Slice Black Blood Imaging

Rapid Extended Coverage (REX) Turbo Spin Echo Technique

Fig. 3.2.3. Transaxial CT (top) and co-registered CT/FDG

PET image (bottom) of a diabetic patient with a high Fra-
mingham risk score (25%). The section is at the level of the
aortic arch. In the bottom image, the orange areas overlaid
onto the CT image represent areas of active inflammation
within atherosclerotic plaques

3.2.4
Risk Assessment in Asymptomatic Women

Cardiovascular diseases are the main cause of death

b in women in most of the developed countries. How-
ever the disease behaves differently in women. Com-
Fig. 3.2.2a,b. Proton density-weighted MR images of the
pared to men, women have more atypical heart dis-
aorta, from root to abdominal segment: (a) a double oblique
view (‘candycane’); (b) an axial section with overlying wall ease symptoms, less angiographically-demonstrated
contours used for plaque area calculations. Both views confirm obstructive disease (Bugiardini and Bairey Merz
eccentric wall thickening consistent with atherosclerosis 2005) and poorer outcomes (Hochman et al. 1997).
50 J. H. F. Rudd, S. H. Aguiar, and Z. A. Fayad
Many of the established non-invasive tests used
in men perform less well in women, with poorer
predictive values (both positive and negative). The
National Heart, Lung and Blood Institute (NHLBI)-
sponsored project Women’s Ischemia Syndrome
Evaluation (WISE) is an ongoing prospective, multi-
center observational study of diagnostic modalities
for reliable cardiovascular assessment of ischemic
heart disease in women, and will hopefully provide
better guidelines for non-invasive assessment in this
patient group (Lerman and Sopko 2006; Pepine
2006).
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 Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams
Screening and Preventive Diagnosis
with Radiological Imaging
Diagnostic Algorithms for Whole-Body Exams
Harald Kramer
CONTENTS
4.1 Introduction 53
4.2 Computed Tomography (CT) 53
4.3 Magnetic Resonance Imaging (MRI) 56
4.4 Considerations for Cardiovascular
Whole-Body MRI Protocols 56
4.5 Cardiovascular Whole-Body MRI in
High-Prevalence Risk Groups 59
4.6 Oncologic Whole-Body MRI 59
4.7 Conclusion 61
References 61
4.1
Introduction
Nowadays various diseases, such as atherosclerosis,
malignant tumors, inflammatory joint disorders and
diabetes are understood as systemic in their nature
(Baur et al. 2002; Diehm et al. 2004; Fenchel et
al. 2006; Goyen et al. 2002, 2003; Kafetzakis et al.
2005; Kramer et al. 2005; Weckbach 2006). The
conventional approach of diagnostic imaging, how-
ever, is focused on the examination of a particular
organ and body part in which clinical symptoms are
present. In the past, radiological modalities also were
technically restricted, allowing only to image a cir-
cumscribed part of the body. Established diagnostic
algorithms reflect these limitations, and frequently
a combination of different imaging modalities is
H. Kramer, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
53
4
recommended for the work-up of patients suffering
from diseases potentially involving multiple organs
and body parts, respectively. This stepwise multimo-
dality approach is time consuming and associated
with high costs. Moreover, it may be stressful for
the patient. Disease manifestations asymptomatic at
the time point of the initial diagnostic work-up may
remain undetected, so that the treatment may not
be adequate (Fig. 4.1) (Goyen et al. 2002; Barkhau-
sen 2006; Baumgartner et al. 2005; Ho et al. 1999;
Matsubara et al. 1990; Rubin 1997).
It would be desirable to have imaging modalities
on hand capable of covering the whole body or large
body parts within one examination and without com-
promises in image quality and diagnostic accuracy.
Recent technical developments in MRI and CT pro-
vide opportunities to achieve these requirements. In-
troduction of multidetector CT (MDCT) technology
and multi-channel MR systems as well as new data-
acquisition techniques, e.g. parallel acquisition tech-
niques (PAT) in MRI, nowadays make these modali-
ties much more versatile and comprehensive (Leiner
et al. 2005; Ruehm et al. 2001; Wilson et al. 2004).
4.2
Computed Tomography (CT)
The increased examination speed makes MDCT
most useful for imaging of acutely ill and severely
traumatized patients. Virtually the whole body can
be imaged with high image quality within less than
one minute. For example, in multiple trauma, inju-
ries of the brain, spine, skeletal system, parenchy-
mal organs as well as the vascular system can be
assessed with a comprehensive CT protocol (Fig. 4.2)
(Matsubara et al. 2990). This whole-body approach
is also used for tumor staging and follow-up of pa-
54 H. Kramer

tients with known malignancy. For the purpose of
screening, however, such a whole-body CT approach
is limited by the high radiation exposure and poten-
tial risk of radiation-related cancer mortality. For
example the estimated dose to the lung or stomach
from a single whole-body CT exam is 14–21 mGy,
which corresponds to a regional dose that may be
associated with an increased risk of cancer mortality
[Brenner Radiology 2004 Sep;232(3):735–738]. Thus,
the value of whole-body CT for screening purposes
in asymptomatic individuals is limited.
PET/CT allows one to co-register and fuse PET
and CT data, thus combining the functional infor-
mation of PET with the high spatial resolution of CT
(Fig. 4.3). Various studies indicate that fused PET
and CT image data provides an added value over that
of the separate methods and results in an improved
diagnostic accuracy in the diagnosis of oncologic
diseases compared to PET and CT alone. Again, the
high radiation dose of PET/CT limits the practical
value of this imaging test for the purpose of screen-
ing, but has its value in the field of surveillance.

a b

Fig. 4.1. a Example of an MRA exam of the lower body part including the abdominal aorta and renal arteries, iliac arteries and
vessels of the lower extremity. b Example of a CTA exam of the same anatomic area. View from anterior and posterior
 Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 55

Fig. 4.2. CTA in a patient with acute

onset of dyspnea. Axial and coronal
slices show extensive central pulmo-
nary embolism on both sides

Fig. 4.3. Fused images of PET and CT with physiological FDG uptake
in the brain and kidney and excretion of FDG into the renal pelvis and
the bladder. In this patient suffering from colon cancer, multiple areas
of increased FDG- uptake in the liver indicate metastatic spread
56 H. Kramer
4.3
Magnetic Resonance Imaging (MRI)
For a long time MRI has been restricted to imag-
ing of a defi ned body part and also suffered from
long data-acquisition times. Recent developments
in hard- and software contributed to overcome
these restrictions. With the implementation of
multi-channel MR technology with multiple re-
ceiver coils it is now possible to image the entire
body within one comprehensive whole-body MRI
exam (see also chapter 6.1 Dietrich O, Schoenberg
SO. Technical prerequisites). For this approach,
the patient is covered with multiple receiver coils
(Fig. 4.4). Due to a large range of table movement
all anatomic areas can be positioned in the iso-
center of the magnet one after the other without
repositioning the patient. With parallel acquisi-
tion techniques (PAT) the acquisition time of MRI
can be greatly reduced without compromise in
image quality. On the other hand, image quality
is superior, when the same acquisition times are
employed (Kramer et al. 2005). This flexibility of-
fers several new opportunities when dealing with
systemic disease. Typical indications for whole-
body MRI are the assessment of cardiovascular
and malignant disease.
Fig. 4.4a,b. Matrix coil system with multi element coils. Before the exam all required coils are positioned on the patient
and are electronically selected during the exam
4.4
Considerations for Cardiovascular Whole-
Body MRI Protocols
Cardiovascular whole-body MRI can be performed
as a clinical exam in patients suffering from ath-
erosclerosis or as a check-up exam in asymptom-
atic individuals with a defi ned risk-profi le. A dedi-
cated cardiovascular whole-body MRI consists of
a complete cardiac exam and a whole-body MR
angiography (MRA). A state-of-the-art compre-
hensive cardiac exam includes functional imaging
of the left ventricle, myocardial perfusion imag-
ing as well as a delayed contrast-enhanced scan to
detect infarcted myocardium (Fig. 4.5). Adequate
temporal resolution is a mandatory requirement
for functional cardiac imaging because a too low
temporal resolution (> 50 ms) leads to an overesti-
mation of the endsystolic volume and an underesti-
mation of the ejection fraction (Wintersperger et
al. 2003). Perfusion imaging of the left ventricular
myocardium can be performed at rest and at phar-
macologically induced stress. At rest only coronary
artery stenoses of more than 90% are detectable,
while pharmacologically-induced stress enables to
diagnose even lower grade stenoses that are hemo-
dynamically significant. When adenosine is used
 Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 57

for pharmacologically-induced stress, a low rate
of severe complications of less than 2% is found.
When performing whole-body MRI as a check-up
exam the question nevertheless arises if it is legally
justifiable to induce stress by administering ade-
nosine in asymptomatic individuals because of the
potentially related risks. Participants of preventive
exams have to be informed about the possibility of
side effects and have to give informed consent. For
the selection of individuals to be subjected to stress
perfusion imaging, assessment of coronary calcifi-
cations and traditional risk factors may be useful
to identify those subgroups with an intermediate
risk of a major cardiac event (see also Chap. 5.1
Schoenberg SO, Reiser MF. Personnel and struc-
tural prerequisites for screening-programs).
Whole-body MRA has to be performed employ-
ing standards of good clinical practice. It is not ac-
ceptable to reduce acquisition time at the expense
of spatial resolution, when this is associated with
a decrease in diagnostic accuracy. In contrast en-
hanced MRA data acquisition has to be confi ned
to the fi rst pass of the contrast material bolus pas-
sage and venous contamination has to be excluded.
With isotropic high spatial resolution, multi-planar
reformations of 3D datasets can be performed. This
substantially improves the diagnostic accuracy in
the assessment of stenoses because measurement
of the degree of area stenosis is much more accu-
rate than only measuring the diameter stenosis
(Fig. 4.6).
The combination of all these different exams
requires a complex imaging protocol as well as a
tailored contrast agent injection scheme. Perfusion
imaging of the left ventricular myocardium has to
be performed as the fi rst contrast-enhanced exam
because prior contrast agent application would
confound the results of the semi-quantitative per-
fusion analysis. In subsequent MRA examinations,
a subtraction mask is acquired which allows to
eliminate tissue enhancement due to prior contrast
injection. To avoid false negative results of delayed
contrast enhancement imaging in infracted myo-
cardium, this exam is performed approximately
15 min after the previous contrast agent applica-
tion. To reduce the standby time between the differ-
ent contrast agent applications contrast-enhanced
scans of the brain, thorax and abdomen can be per-
formed (Table 4.1). A complete cardiovascular MRI
protocol including a comprehensive cardiac exam,
whole-body MRA as well as scans of the brain,
thorax and abdomen results in an in-room time of
about 60 min (Goyen et al. 2002, 2003; Kramer et
al. 2005; Herborn et al. 2004).

a b

Fig. 4.5a,b. Functional imaging of the left ventricular myocardium (a) as well as delayed contrast enhancement imaging
(b). Due to the implementation of parallel imaging techniques at high field strength (3 Tesla) spatial and temporal resolution
can be maintained at a high level while acquisition time is reduced to a single breath-hold
58 H. Kramer

Fig. 4.6. MR Angiography of the abdominal aorta and the renal arteries with an isotropic spatial
resolution of 1 × 1 × 1mm3 allowing for multiplanar reformations. This is very important for accu-
rate assessment of vessel stenosis by determining area stenosis in addition to diameter stenosis

Table 4.1. Protocol of a cardiovascular whole-body MRI exam. Dedicated whole-body MR systems allow for pre and post
CA imaging of the entire body without repositioning of the patient. The time interval between the contrast agent (CA) ap-
plication and the recommended delay for imaging of myocardial infarction by delayed contrast enhancement (DCE) is used
for post CA imaging of the chest and abdomen

Min heart MRA chest abdomen brain

20 T1, T2 pre CA
diffusion; TOF
40 function, perfusion carotids, calves
60 DCE abd. aorta, thighs VIBE post CA VIBE, FLASH
post CA
 Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams
4.5
Cardiovascular Whole-Body MRI in High-
Prevalence Risk Groups
Diabetes is one of the major causes for morbidity
and mortality in the world. Prevention, diagnosis
and therapy of diabetic long-term complications
are extremely important. Due to the combination
of systemic manifestations such as diffuse mi-
cro- and macroangiopathy and silent myocardial
infarction as well as local disease such as osteo-
myelitis or neuropathic foot, diabetes offers great
diagnostic challenges. Accelerated atherosclerosis
of the whole arterial vasculature, including the
coronary arteries the neck and lower leg arteries
is a frequent consequence of longstanding diabe-
tes. Therefore, patients with diabetes are at a high
risk of experiencing myocardial infarction, stroke
and critical limb ischemia. The combination of
microvessel disease and neuropathy may result in
ulceration of the skin and cellulites and osteomy-
elitis of the feet.
Preventive imaging has to include the potential
manifestations of diabetes in the whole body. Whole
body MRI has already been used as a comprehensive
non-invasive examination of patients with diabetes
mellitus and a large proportion of asymptomatic
disease manifestations could be detected. The pro-
tocol for a whole-body MRI included the cardiovas-
cular system in the same way as described earlier
in this chapter. In order to detect neuropathic and
inflammatory disease manifestations in the feet, na-
tive and contrast enhanced T1-weighted spin echo
sequences and STIR (short tau inversion recovery)
images of the lower leg and feet were acquired. For
the assessment of cerebral micro-vascular lesions,
T2* and diffusion imaging was additionally per-
formed (Weckbach 2006).
Other potential applications of whole-body MRA
for screening of risk groups with high disease preva-
lence include diseases such as vasculitis or congeni-
tal vascular diseases such as Marfan’s or Ehlers-
Danlos’. Takayasu’s arteritis as one representative
vasculitis of large vessels is known to affect multiple
territories at the same time with inflammatory ste-
nosis of the subclavian arteries, aorta, mesenteric
arteries, renal arteries and other vessels. In Marfan’s
or Ehlers-Danlos’ disease, multifocal involvement
by aneurysms or dissections is a typical complica-
tions which may already occur in children and ado-
lescents.
59
4.6
Oncologic Whole-Body MRI
Radiological imaging is essential for the staging,
follow-up and surveillance of cancer. Depending
upon the particular tumor entity, various imaging
modalities and combinations thereof are usually
employed in a multi-modality stepwise diagnos-
tic algorithm. In diagnostic algorithms for tumor
staging, imaging modalities that apply ionizing ra-
diation are still the backbone of clinical work-up
including CT, scintigraphy and PET-CT. However,
for the surveillance of cured cancer patients, there
is a growing need for comprehensive imaging al-
gorithms without the use of ionizing radiation or
nephrotoxic contrast agents. This is particularly
true in young patients with early manifestations
of cancer such as breast cancer patients or patients
with lymphoma.
MRI offers a unique soft tissue contrast and
proved highly effective in the diagnostic assessment
of a variety of tumor entities. Whole-body MRI
exams in oncologic patients should include STIR
and T1 weighted SE (spin echo) imaging in coronal
planes. The lungs should be also examined with axi-
al STIR and HASTE (half-Fourier acquisition single
shot turbo spin echo) pulse sequences. Before the
administration of contrast agent T2w fat-saturated
imaging of the liver as well as T1w SE and STIR se-
quences of the spine in sagittal orientation should be
acquired. During contrast agent application an axial
dynamic 3D GRE (gradient echo) exam of the liver is
recommended followed by T1w and T2w axial brain
scans and T1w fat-saturated axial 2D GRE scans of
the abdomen (Table 4.2).
When a sophisticated examination technique is
employed, whole body MRI enables to precisely as-
sess the T- and M-stage in good correlation with
PET/CT. Recent studies show an overall diagnos-
tic accuracy for TNM-staging of 96% for PET-CT
compared to 91% for whole-body MRI. For N-stage
alone, PET-CT seems to be superior with an ac-
curacy of 93%–97% in the detection of malignant
lymph nodes compared to 78%–82% for MRI. For
the detection of distant metastases PET-CT and
MRI perform equally with an accuracy of 93% and
94%, respectively (Schmidt et al. 2006). The accu-
racy of both whole-body MRI and PET/CT greatly
depends on the site of the primary tumor. In head
and neck tumors and lung cancer PET/CT is supe-
rior, while whole-body MRI is more accurate in tu-
60 H. Kramer

mors of the nervous and musculoskeletal system. matic again with clinical manifestation of pain or
Recently, whole-body MRI at 3 Tesla has been to elevated tumor markers whole-body MRI detected
surveillance of breast cancer patients after suc- metastatic cancer with an accuracy exceeding 90%
cessful cure. In those patients that became sympto- (Schmidt et al. 2008) (Fig. 4.7).

Table 4.2. Protocol of an oncologic whole-body MRI exam for tumor staging containing STIR
and T1 imaging of the entire body as well as pre and post CA imaging of the chest and abdo-
men, the brain and the entire spine

head/neck chest abdomen/pelvis thigh calves

STIR cor STIR cor STIR cor STIR cor STIR cor
HASTE/STIR T2 liver
cor/ax ax

T1 cor T1 cor T1 cor T1 cor T1 cor

T1/STIR T1/STIR
spine sag spine sag

3D VIBE liver
T1 fs + CA
T1, T2 + CA
ax

Fig. 4.7. Surveillance of a previously cured breast cancer patient with newly rising tumor markers. Whole-body MRI de-
tects multifocal involvement of the liver by breast cancer metastases while the corresponding PET-CT shows only one site
of hepatic metastasis
 Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams
4.7
Conclusion
Recent technical developments of CT and MRI tech-
nology allowed a paradigm shift from symptom
and organ oriented imaging algorithms to disease
orientated imaging algorithms. It became possible
to image large anatomic areas and even the entire
body allowing a comprehensive assessment of dis-
eases which are systemic in nature. Time consuming
staging procedures employing multiple modalities
can be replaced by a single comprehensive exam.
Examples are the non-invasive screening for athero-
sclerosis and the surveillance for recurrent tumor
manifestations.
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Diehm C, Kareem S, Lawall H (2004) Epidemiology of pe-
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Fenchel M et al. (2006) Atherosclerotic disease: whole-body
cardiovascular imaging with MR system with 32 receiver
channels and total-body surface coil technology – initial
clinical results. Radiology 238(1):280–291
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Goyen M et al. (2002) Whole-body three-dimensional MR
angiography with a rolling table platform: initial clinical
experience. Radiology 224(1):270–277
Goyen M et al. (2003) Detection of atherosclerosis: systemic
imaging for systemic disease with whole-body three-di-
mensional MR angiography – initial experience. Radiol-
ogy 227(1):277–282
Herborn CU et al. (2004) Whole-body 3D MR angiography
of patients with peripheral arterial occlusive disease. AJR
Am J Roentgenol 182(6):1427–1434
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allel imaging techniques and a whole-body MR imager.
Radiology 236(1):300–310
Leiner T et al. (2005) Magnetic resonance imaging of athero-
sclerosis. Eur Radiol 15(6):1087–1099
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mography of abdomen (CTA) in management of blunt
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Schmidt GP et al. (2008) Eur J Radiol (in press)
Weckbach S (2006) Comprehensive diabetes imaging with
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Wilson GJ et al. (2004) Parallel imaging in MR angiography.
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 Personnel and Structural Prerequisites for Screening-Programs 63

Personnel and Structural Prerequisites 5

for Screening-Programs
Stefan O. Schoenberg, and Maximilian F. Reiser

CONTENTS The design of screening-programs requires a careful

evaluation of the screening population, its spectrum
5.1 Personnel Requirements for Screening 63 and prevalence of disease, the training level and mo-
5.1.1 Patient/Screening Participant 63 tivation of the physician as well as the infrastructure
5.1.1.1 Clinical Information and History 63 for clinical and radiological work-flow, image analy-
5.1.1.2 Follow-Up and Treatment
sis and reporting. In this respect, a close interaction
Recommendations 64
5.1.1.3 Surveillance 66 between the screening participant, the radiologist
5.1.2 Role of the Radiologist in Screening 67 and the referring partners is a key prerequisite. The
5.1.2.1 Training and Experience 67 design of the infrastructure has to aim at defining
5.1.2.2 Screening Radiologist or a consistent, reproducible and clinically practicable
Clinical Radiologist for Screening? 69
5.1.2.3 Communication with
chain of screening recruitment, diagnostic proce-
Referring Physicians 69 dures and follow-up as well as treatment recom-
5.1.2.4 Financial vs Clinical Motivation 69 mendations (Fig. 5.1).
5.1.3 Referring Partners 70
5.1.3.1 Patient Satisfaction vs Advertisement 70
5.1.3.2 Referrals vs Competition and Price 71
5.2 Structural Requirements for Screening 71
5.2.1 Double Reading 71
5.2.2 Scientific Evaluation 72
5.1
5.2.2.1 Study Design 72 Personnel Requirements for Screening
5.2.2.2 Data Evaluation 73
5.2.3 Screening Center vs Radiological 5.1.1
Department with Screening 73 Patient/Screening Participant
5.2.4 Technical Status: Is High-End Equipment
Absolutely Necessary? 74
5.1.1.1
References 74
Clinical Information and History

One initial consideration for including participants

S. O. Schoenberg, MD
Professor and Chairman, Department of Clinical Radiology,
University Hospital Mannheim, Medical Faculty Mannheim,
University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167
Mannheim Germany
M. F. Reiser, MD
Professor and Chairman, Department of Clinical Radiology,
University Hospitals – Grosshadern and Innenstadt, Ludwig-
Maximilians-University of Munich, Marchioninistrasse 15,
81377 Munich, Germany
in a screening program is to exclude symptomatic
disease by careful assessment of medical history. If
a participant presents with clear symptoms relating
to an organ system that is a focus of the screen-
ing-program he or she should be excluded from the
screening procedure and should be directly referred
to a specific clinical assessment of his disease status.
A common example is the participant presenting
with typical signs of chest pain due to ischemic heart
disease with a request for systemic assessment of the
cardiovascular status by whole body magnetic reso-
nance angiography. If the patient has a clear history
of ischemic heart disease it should be refrained from
64 S. O. Schoenberg and M. F. Reiser
Fig. 5.1. Role of the radiologist in the screening algorithm of diseases with high prevalence
proceeding in this direction but rather referring the
patient to an invasive diagnostic work-up by cath-
eter X-ray coronary angiography.
If the participant is completely asymptomatic it
is still highly desirable to gain knowledge about any
pre-existing disease in order to increase the pre-test
likelihood of the diagnostic procedure. According
to Bayes-Theorem the positive predictive value of a
diagnostic test is strongly dependent on the preva-
lence of the disease. Since screening cohorts typical-
ly reveal a low disease prevalence measures should
be taken to increase the pre-test likelihood by care-
fully designed selection criteria within the general
population. This is particularly important for diag-
nostic tests with high costs, technical complexity and
potential side effects such as magnetic resonance
myocardial perfusion imaging with pharmacologi-
cally induced stress by adenosine. In these patients
the Framingham score can be used to increase the
pre-test likelihood for coronary artery disease. If the
Framingham score is less than 10 the patient has a
less than 10% risk of experiencing a myocardial inf-
arction within the next 10 years and thus the risk for a
positive finding of coronary artery disease is too low
to warrant a more extensive diagnostic assessment.
In contrast, if the Framingham score ranges between
10 and 20 the participant falls in the intermediate risk
group for a future cardiac event and thus is a typical
candidate for a further non-invasive assessment for
coronary artery disease. This typically includes pro-
cedures such as ergometry, myocardial scintigraphy
or magnetic resonance myocardial perfusion imag-
ing. If the score is above 20 direct invasive assess-
ment of coronary artery disease by coronary X-ray
catheter angiography should be considered in select-
ed risk groups such as diabetic patients or patients
with cardiac insufficiency. Within the last 5 years
the concept of coronary artery calcium mass quan-
tification as an independent factor for determination
of the Framingham pre-test likelihood has evolved
(Grundy 2001). Although there is no clear correla-
tion between the amount of calcified plaques within
the coronary arteries and the presence of a coronary
artery stenosis the presence of atherosclerotic dis-
ease is confirmed. As a variable the quantified abso-
lute mass of calcium independently affects the calcu-
lation of the so-called modified Framingham score
and thus allows to potentially shift an asymptomatic
screening individual from the low probability group
into the intermediate probability group as a trigger
for further non-invasive imaging assessment of coro-
nary artery disease (Fig. 5.2).
5.1.1.2
Follow-Up and Treatment Recommendations
Once an individual has undergone a diagnostic
screening procedure, the screening interval for the
next screening visit has to be determined. In ad-
dition suspicious findings have to be verified with
regard to their clinical significance and significant
findings have to be managed by the appropriate
treatment recommendations.
For determining of the appropriate screening in-
terval one has to understand the biology and patho-
physiology of the underlying disease to be screened.
The three major types of disease evolution are a
steady progression of the disease, acceleration or de-
celeration of the disease process or a de novo mani-
festation of disease in between the screening visits
also known as interval disease. Another important
consideration is the question if the disease is poten-
tially reversible by modification of the risk factors.
Although atherosclerosis shows a relatively steady
progression various findings may warrant a modi-
fication of the screening follow-up scheme. While
for example a 30% stenosis of the carotid artery may
be safely followed by ultrasound in 2-year inter-
vals, a 60% stenosis needs to be reassessed within
6 months since it is well known from the NASCET
 Personnel and Structural Prerequisites for Screening-Programs 65

Fig. 5.2. A 58-year-old heavy smoker with dyspnoea on exertion without symptoms of coronary artery disease who was
referred to whole-body MRA by his internal medicine physician to rule out any significant stenosis. By his initial Framing-
ham score he was in the low-risk group for a cardiovascular event, however, using the modified score including the coro-
nary calcium mass, he was shifted into the intermediate risk group. Thus, the decision was made to include a cardiac MR
perfusion scan with adenosine stress into the whole-body MRA algorithm which revealed a perfusion defect in the anterior
midpapillar myocardium as a sign for a significant stenosis of the left anterior descending artery

trial that progression to a 70% stenosis puts the pa-
tient at much higher risk for a cerebrovascular inci-
dent and implies surgical or interventional repair.
Similar data is available for renal artery stenoses.
Patients with a 75% stenosis that is considered he-
modynamically significant are known to progress
towards end-stage renal disease with dialysis within
the next 2 years.
In malignant diseases continuous growth of the
tumor is related to an exponential increase of ma-
lignant cells with a direct correlation to metastatic
spread and survival. Thus screening for malignant
diseases requires detection of the tumor at a very
small size, which has direct impact on the selection
of the appropriate screening interval in between
normal studies. The screening interval represents
a trade-off between patient compliance minimizing
negative effects such as from ionizing radiation and
detection of cancers that have arisen in between the
screening interval. For example in a mammography
it is known that approximately between 20% and
60% of all breast cancers arise within the interval
between the screening time points depending on the
fact if a yearly, 2-year or 3-year follow-up is applied.
For example, in Germany screening mammography
is advised in a 24-month-interval in the age group of
50–70 year-old-women to minimize the size of these
cancers at the time of detection during the next
screening visit.
Besides selection of the appropriate screening
interval a clear algorithm needs to be established
with regard to the defi nition of a significant posi-
tive fi nding as well as the diagnostic procedures to
confi rm or exclude a fi nding of questionable sig-
nificance. In this algorithm the sequence of con-
fi rmatory procedures has to be carefully balanced
against potential side effects from more invasive
diagnostic procedures on one hand and false posi-
tive fi ndings that entail unnecessary treatment on
the other hand. Early attempts on screening for
66 S. O. Schoenberg and M. F. Reiser
lung cancer before the ELCAP trial (early lung can-
cer action project) reported a higher morbidity in
patients that had been systematically screened for
lung cancer compared to the non-screened popula-
tion (Marcus et al. 2000). This higher morbidity
was related to substantial side effects from invasive
diagnostic procedures for lesion confi rmation as
well as operative treatment on false positive fi nd-
ings. The design of the ELCAP trial has aimed at
systematically avoiding these complications by de-
signing a clear algorithm for lesion confi rmation
with non-invasive imaging procedures (Henschke
et al. 2006). For base line screening a positive re-
sult on the initial low-dose scan was defined as the
identification of at least one solid or partly solid
non-calcified pulmonary nodule of 5 mm or more
in diameter. If none of the non-calcified nodules
identified met the study criteria for positive re-
sults or if the test was negative a CT was repeated
12 months later. For nodules 5–14 mm in diameter
the preferred option was to perform another CT
at 3 months. If the image showed growth of the
nodule then biopsy ideally by fi ne needle aspira-
tion was to be performed, whereas if there was not
growth the work-up was stopped. Optionally PET
could be immediately performed and biopsy was
initiated if the results were positive. For nodules of
15 mm in diameter or larger irrespective of their
composition immediate biopsy was warranted. In
all participants with completed work-up or biopsy
without diagnosis of lung cancer CT was to be re-
peated 12 months after the base-line CT. For mul-
tiple non-solid nodules identified on base-line CTs
with high suspicion of infection a 2-weeks course of
antibiotics followed by CT one to two months later
was considered an alternative option for lesion fol-
low-up (Libby et al. 2006). However, it is important
to realize that a minimum amount of diameter in-
crease within 3 months follow-up still correlates to
a substantial increase in tumor volume of a malig-
nant pulmonary nodule.
With a standard approach for measurements of
tumor extension by assessment of the longest diam-
eter according to the RECIST criteria subtle growth
might be missed within this short follow-up interval.
In the past few years specific software has become
commercially available for volumetric assessment of
these small nodules in thin-section multi-slice CT
thereby allowing a much more accurate determina-
tion of lesion growth by looking at the total tumor
volume rather than the longest diameter. Also this
approach allows to clearly differentiate nodules
from crossing vessels, thereby improving the reli-
ability of the assessment. It is important to acquire
the data sets with a minimum slice thickness of at
least 1 mm without motion artifacts; thus multi-slice
CT scanners with a minimum number of 16-detec-
tor rows should be utilized to allow for breathhold
times of less than 15 s. As already mentioned, PET
and particularly PET-CT have evolved as powerful
techniques for lesion characterization based on the
amount of 18fluorodeoxyglucose (FDG) uptake. In
combination with CT this uptake can reliably re-
lated to malignant lesion within the size range of
8–10 mm or larger.
5.1.1.3
Surveillance
A number of chronic diseases predispose patients to
significant clinical complications including malig-
nant transformation of chronic inflammatory states
or tissue infarctions in chronic vascular diseases.
The role of screening in these groups with under-
lying pre-existing disease is of particular interest
since the prevalence of diseases is significantly high-
er compared to secondary screening in the normal
asymptomatic population. Per definition this is not
screening in the true sense of searching for disease
in an asymptomatic population but rather surveil-
lance of symptomatic patients for early manifesta-
tion of disease complications. Surveillance is of high
importance since a number of treatment options ex-
ist for addressing these complications with potential
impact on patient survival. Any screening technique
that is used for surveillance has to be as minimally
invasive as possible and at the same time be able to
reliably detect all potential complications arising
from the underlying disease. In addition, the costs
of the screening technique have to be reasonably
balanced against the survival gain for the patients
in order to limit the expenses in view of relatively
short screening intervals. For appropriate selection
of the screening intervals detailed knowledge about
the natural history of the particular disease, the
incidence of complications as well as their relation
to the stage of disease and the potential options for
treatment is mandatory.
One major field for surveillance constitutes the
assessment of cured cancer patients who are either
at risk for relapse of their primary cancer or for ther-
apy-induced secondary cancers in the later phases
after initial cure. Traditionally these patients have
undergone surveillance with a multi-modality ap-
 Personnel and Structural Prerequisites for Screening-Programs
proach of chest X-ray, abdominal ultrasound and
bone scintigraphy optionally complemented by CT
scans. The time interval and organ systems for fol-
low-up were usually defined with respect to the time
post-therapy and the typical routes of metastatic
spread. Narrow screening intervals are typically
chosen in the early phase of post-treatment follow-
up, while in the later phases the time intervals in
between these screening time points are prolonged.
Recently, several studies have been published sug-
gesting evidence that a more intensified and more
systemic approach for surveillance might be war-
ranted in certain tumor entities. In oncology, this
is of particular interest for malignant diseases for
which a number of therapeutic options exist in met-
astatic disease such as renal cell carcinoma. In renal
cell carcinoma, the rate of recurrence for pathologic
stages T1 and T2 is reported to range between 0%
and 5%, while it is increased to rates between 9%
and 22% in stages T3A and B. On the other hand sur-
vival rates range between 63% and 75% after surgi-
cal resection of a locally recurrent tumor with 40%
of the patients remaining in long-term remission
(Stephenson et al. 2004). Therefore, surveillance
for early stages of recurrence is warranted. A recent
study recommended abdominal CT 6, 12, 24 and 36
months postoperatively (Stephenson et al. 2004).
Likewise, patients with surgical treatment of a soli-
tary bone metastasis have an improved survival
compared to those with multiple metastases (Fuchs
et al. 2005). Interestingly, in patients with a low risk
for recurrence according to the UISS criteria meta-
static disease occurs most frequently outside the
abdomen. While the overall 5-year-disease-free in-
terval is greater 90%, 75% of all relapses occur in the
thorax (Lam et al. 2005). This highlights the neces-
sity for an extended anatomic coverage for surveil-
lance including at least thorax and abdomen. While
this is still the domain of spiral CT, whole-body MRI
offers the potential to include other important or-
gan systems such as the central nervous and muscu-
loskeletal system into the diagnostic algorithm. This
holds promise to replace the time-intensive multi-
step multi-modality approach by a single-step com-
prehensive diagnostic assessment (Fig. 5.3).
5.1.2
Role of the Radiologist in Screening
The radiologist that aims at conducting a screening
study has to defi ne the appropriate infrastructure
67
for the screening exam and the appropriate interac-
tion with the referring physician. He or she has to
have the appropriate level of training and experi-
ence to insure a consistent and reproducible quality
in interpreting screening exams and maintaining
the appropriate technical quality of the studies.
Since the infrastructure is cost-intensive and re-
ferral depends on marketing and advertisement,
the physician often fi nds himself within an area
of confl ict between fi nancial, ethical and clinical
motivation.
5.1.2.1
Training and Experience
Apart from the general requirements for board
certification in the field of radiology there are spe-
cific training requirements to conduct screening
studies. Although no generally mandatory require-
ments exist for most of the diseases to be screened,
the individual subspecialty organizations have
published recommendations in terms of number
of screening studies to be completed for an appro-
priate skill level. Defi nite criteria for determination
of the radiological skill level exist for X-ray mam-
mography. According to the EUSOMA guidelines
currently only those physicians are approved for
participating in X-ray mammography screening
programs who read more than 5000 studies per
year (Perry 2001). Recent results from the orga-
nized screening programs in Canada have shown
that the positive predictive value was increased by
34% for those radiologists reading volumes over
2000 mammograms vs volumes of 480–699 mam-
mograms per year (Coldman et al. 2006). How-
ever, on the contrary neither the cancer detection
rate nor the abnormal interpretation rate varied by
reading volume.
Besides the appropriate training for conducting
screening studies the experience of the physician
has to be assessed by means of his intra- and inter-
observer variability for reading the studies. Several
studies have shown that inter-observer variability
greatly affects the consistency of results if several
expert readers are involved in the reading process.
Thus, these readers need to train themselves for a
minimum amount of variation among the different
observers to insure consistency of the reported re-
sults. This also refers to repetitive readings by the
same observer, which should reveal a minimum
amount of variation to allow reproducible assess-
ments in longitudinal screening studies.
68 S. O. Schoenberg and M. F. Reiser

Fig. 5.3. A 70-year-old-male patient with new onset of diffuse pelvic pain 2 years after nephrectomy of the left kidney be-
cause of a renal cell cancer. Due to the non-specific symptoms a pelvic X-ray study was initially performed which revealed
a destruction of the upper margin of the right iliac bone suspicious for a large osseous metastasis. This was confi rmed by a
consecutive CT study. Both CT and an additional radionuclide bone scan did not detect any further osseous metastases. On
the contrary, whole-body MRI exactly delineated the extent of the pelvic metastasis and identified two additional metastases
in the right femur which showed progression on successive CT studies
 Personnel and Structural Prerequisites for Screening-Programs
5.1.2.2
Screening Radiologist or Clinical Radiologist for
Screening?
For certain types of diseases such as breast cancer
with a relatively high prevalence and a clear relation-
ship between early detection and patient survival the
design of an infrastructure for the sole purpose of
screening is desirable for several reasons. First, the in-
cidence of positive findings might be different from a
clinical setting with a lesser number of truly positive,
clinically significant findings. The physician’s inter-
pretation skills have to be adapted to this specific set-
ting in a screening population. Second, as most of the
participants of a mammography screening program
do not reveal any malignant findings, the environ-
ment of the screening facility should reflect the fact
that this is not a clinical setting with symptomatic pa-
tients. Otherwise, the psychological stress might limit
the extent of participation in the screening program.
Third, only if the physician is primarily involved in
interpreting screening exams, a systematic analysis
of his or her intra- and inter-observer variability in
cross-sectional and longitudinal studies can be per-
formed for reasons of quality assurance.
On the other hand, in diseases with low preva-
lence and high technical demands for performing the
screening studies the screening process may be inte-
grated into a clinical academic setting. One reason
that speaks in favor of this scenario is that diseases
with a low prevalence might result in a too low positive
predictive value to warrant imaging in a sole screen-
ing setting. For the radiologist it might be important
to reflect his or her assessment for positive and nega-
tive findings by reading clinical studies with a high
prevalence of disease in parallel. This pseudo-preva-
lence might insure a more consistent interpretation of
potentially significant positive findings. Second in a
clinical academic setting treatment paths for a large
number of different positive findings are well estab-
lished with the appropriate skill level of the physician
carrying out the treatment. This might be particu-
larly important for whole body imaging techniques
that might reveal a number of unexpected, potentially
clinically relevant findings in any organ system.
5.1.2.3
Communication with Referring Physicians
Any screening program can only succeed if truly
positive findings are treated with cure and minimum
amount of complications and the patient is reassured
69
in case of negative findings. It is even more critical
to establish an algorithm for findings of questionable
significance, which may comprise the largest frac-
tion in some disease entities that are screened. Here,
a clearly defined interaction between the screening
radiologist and the referring physician responsible
for the treatment is mandatory. The key goal is to
maintain a balance between over-diagnosis and sub-
sequent over-therapy on the one hand and under-
treatment resulting from under-diagnosis on the
other hand. Over-treatment may result in a dispro-
portional number of complications in patients with
false positive findings, while under-treatment may
postpone appropriate care due to false reassurance
of the patient. Ideally, clinically practicable, low cost
algorithms with short term feed-back between the
radiologist and the referring physician are desirable.
One representative example is the above mentioned
strategy for short term handling of multiple non-solid
nodules by a course of antibiotics followed by repeti-
tive imaging for a further decision process, if these
nodules are of inflammatory or neoplastic origin.
5.1.2.4
Financial vs Clinical Motivation
In contrast to symptomatic patients that have a vari-
able level of psychological strain asymptomatic in-
dividuals may have variable degrees of motivation
to participate in a diagnostic imaging procedure.
Despite the clear association between positive find-
ings on screening exams and patient survival the par-
ticipation in screening studies of mammography and
colonoscopy for breast and colon cancer is below 30%
in the age group of 50 and beyond in Germany. For
other disease entities such as lung cancer the inter-
est in screening is even lower. On the other hand the
technical and personnel requirements for screening
might be extensive (see Sect. 5.2.4) and are depend-
ing on a certain influx of participants for appropriate
amortization of equipment. This may require some
level of advertisement for recognition of the screen-
ing study among the general population to increase
the number of participants. In addition, appropri-
ate financial compensation is necessary to finance
the specific infrastructure and diagnostic algorithms
including double reading (see below), expert assess-
ment, quality assurance and subsequent work-up
of findings. Therefore, attempts have to be made to
ensure appropriate reimbursement from health care
providers or third party funding such as companies
interested in screening of their employees.
70 S. O. Schoenberg and M. F. Reiser
On the other hand, the reimbursement codes for
screening are not well defined yet, potentially giv-
ing rise to a primarily financially motivated recruit-
ment of those screening participants that are willing
to pay high rates for participating in the screening
study. This might artificially induce a selection bias
towards a wealthier subgroup of the population
which does not necessarily represent a balanced
cross-sectional cohort for a particular disease en-
tity. In addition, young participants who are not true
candidates for a certain screening program of a par-
ticular age-related disease might be attracted which
may further reduce the overall prevalence within
the screening population and potentially increase
the number of false positives. False positive fi ndings
are considered a major cost factor since further in-
vasive confirmation does not result in a reduction
but rather a potential increase in morbidity and thus
is of no socio-economic value.
5.1.3
Referring Partners
Participation in a screening program can be in-
creased by the initiative of health care providers,
self referral or advertisement. Generally, health
care providers have an interest to raise the lev-
el of participation in those screening programs
that potentially can reduce morbidity and thus
decrease health care costs. So far only a few ap-
plications fall in this category including screening
for breast, colon and prostate cancer. Newly aris-
ing programs such as screening for colon cancer
with CT and MRI colonography, screening for
cardiovascular disease with whole-body MRI or
screening for lung cancer with low dose chest-CT
may benefit from systematic advertisement. This,
however, has to be done on a medically justified
basis in close coordination with a referring and
treating physician. Self referral of the screening
participant is motivated by various reasons rang-
ing from knowledge about the threat of certain
diseases to the wish for ruling out any existence
of an undefined and potentially life threatening
disease.
5.1.3.1
Patient Satisfaction vs Advertisement
It is of ongoing debate, if screening programs with
potentially clinically significant fi ndings do rep-
resent a reassurance for the individual or impose
a psychological stress particularly in the case of
falsely positive fi ndings. A large recent survey in
the United States concluded that the major per-
centage of the population has a high interest to
participate in a screening program. In this survey,
most individuals would be willing to participate
in a study, if the detected diseases could be po-
tentially cured and if the program participation
was for free. The majority would be still willing
to participate, if they had to pay for the exam.
Interestingly, still approximately two thirds of the
surveyed individuals declared their willingness for
participation even if the detected diseases could
not be cured (Brant-Zawadski 2006). However,
this requires a strong alliance with the referring
partners because management of the participants
after a completed screening study has to be car-
ried out co-jointly with these physicians. This is
of particular importance for true and false positive
fi ndings. In case of true clinical fi ndings from the
screening study the referring physician often has
to deal with further management of the patient
in terms of an invasive treatment. For fi ndings of
questionable clinical significance the judgment of
the referring physician is crucial to either reas-
sure the participant that these fi ndings are insig-
nificant and can be neglected until a repeated fol-
low-up exam is performed or to defi ne the least
invasive confi rmatory diagnostic test together with
the screening radiologist to defi nitely rule out any
significance of the fi ndings (Fig. 5.4).
Particular problems arise if the detected dis-
ease cannot be cured. In that case a clear strategy
needs to be designed together with the patient in
order to provide the best treatment option to pro-
long the patient’s life and secure best possible qual-
ity of life. Also clinical and psychological support
needs to be provided to those patients who errone-
ously underwent invasive treatment for a false posi-
tive finding with the consequence of a transient or
persistent increase in morbidity. If the latter two
groups of screening participants are left alone with
their screening exams there is a high likelihood of
dissatisfaction. This discontent might transform
into anger on the referring physician or screening
radiologist with potential legal conflicts resulting
hereof. Thus, a co-joint and transparent advertise-
ment of screening programs with clear specification
of the pros and cons as well as management of the
potential patient is a key prerequisite for participant
satisfaction.
 Personnel and Structural Prerequisites for Screening-Programs
Fig. 5.4. Critical issues for the further management of individuals related to the results of screening studies
5.1.3.2
Referrals vs Competition and Price
The economic success of a screening program ranges
in between the magic triangle of third party funding
(health care providers, industry), rate of reimburse-
ment and cost for the infrastructure. As discussed
in the previous and the following sections of this
chapter, significant costs arise for the screening ra-
diologist to maintain an adequate infrastructure of
well-trained readers, close interaction with a refer-
ral physician and state-of-the-art equipment. Thus,
reimbursement has to compensate for maintaining
adequate quality of the screening program. As only a
few screening programs are financed by health care
providers, many diagnostic exams have to be di-
rectly funded by the participant himself. Therefore,
a clear definition of the expectations of the partici-
pant and the benefits for a certain price is manda-
tory. This is of particular relevance for the issue of
follow-up or confirmatory studies that may be re-
quired during the course of the screening program.
Since reimbursement rates are not well defined yet,
competition in the private market may arise hereof
with different levels of benefits for a certain price.
As mentioned earlier the main costs for the screen-
ing provider are not the diagnostic procedure itself
but the management of the adequate follow-up, con-
firmation of positive findings and potential treat-
ment. So far, this is frequently laid into the hands
of the general insurance providers, who have to deal
with the fi ndings arising of a screening study. This,
however, may change in the future. Thus a finan-
cially successful but socio-economically acceptable
71
screening program has to balance its profit margins
against the responsibility for follow-up and man-
agement of the screening individual. In any case,
the indications for the different types of screening
studies have to be strictly regarded before financial
aspects can be considered.
5.2
Structural Requirements for Screening
The structural design of the screening program
has to address the number of readers assessing the
imaging study, their individual responsibility and
authority in the reading process including the al-
gorithm for establishing the final diagnosis. Also,
one has to agree upon a well defined classification
scheme for reporting the findings arising from the
screening study in terms of clinically insignificant
and significant findings as well as those requiring
further follow-up or invasive confirmation.
5.2.1
Double Reading
Large screening studies such as screening for lung
cancer or breast cancer usually require the data
sets to be read separately and independently by
two board-certified radiologists with subspecialty
training. The final diagnosis is either established
by immediate agreement between the two blinded
72 S. O. Schoenberg and M. F. Reiser
readings, discussion of the separately assessed find-
ings in consensus or by resolving discrepancies be-
tween the readers by a third reader with fi nal author-
ity. In the ELCAP-trial each low dose CT was read
separately by two board certified chest radiologists.
The findings on the presence and number of nod-
ules were separately recorded and then discussed,
and the consensus findings were documented for
the study. When the two readers could not reach
consensus the case was presented to a third expert
reader and the adjudicated reading became the final
(Henschke et al. 1999).
Similar designs were chosen for dedicated breast
cancer screening programs according to the Euro-
pean guidelines for quality assurance in mammog-
raphy screening. Similar to the ALCAP-trial dis-
crepant findings are resolved by arbitration through
a third reader. One of the well established screen-
ing programs in Europe is the Dutch Nationwide
Breast Cancer Screening Program, that was gradu-
ally implemented between 1989 and 1997 and offers
biannual screening mammography to women aged
50–69 years with an overall attendance rate of about
80%. In this program, screening mammograms are
read independently by two radiologists, who must
reach a consensus as to weather the woman should
be referred for further examination. If consensus
about the referral necessity is not reached between
the initial two radiologists the screening mammo-
gram is subjected to arbitration by a panel of three
randomly selected screening radiologists. Out of
a total of 65,779 women who underwent screen-
ing mammography the two screening radiologist
initially disagreed about the necessity of referral in
0.5% of the cases. Consensus could not be reached
in 0.28% of the cases after viewing these discrepant
cases together. The arbitration panel referred 89 of
these 183 women for further examination reveal-
ing breast cancer in 20 cases. However, given the
relatively small group of overall discrepancies and
the relatively low costs of further diagnostic assess-
ment, the authors of the study considered referral
of all women in cases of initial reader disagreement
still being acceptable in terms of cost effectiveness.
They therefore concluded that an arbitration panel
may not be necessary in cases in which two readers
cannot reach a consensus (Duijm et al. 2004). In the
Bavarian Mammography Screening the role of the
third reader in case of discrepancies between fi rst
and second reader is not arbitration but referral of
the women for further assessment. Out of 88,300
women, who have been screened, 6.7% of the cases
were subjected to third reading. 2.6% of these cases
underwent further assessment by imaging (1.6%) or
histological verification (1%) (Willgeroth et al.
2005).
5.2.2
Scientific Evaluation
5.2.2.1
Study Design
The aim of a well designed screening study is to
generate statistically valid data that are applicable
to the general population. One of the key issues of a
prospectively designed study is the selection of the
number of cases to be screened in order to prove
the significance of a test result. This case estimate
is based on the assumed prevalence and incidence
of findings, the presumed accuracy of the screen-
ing test as well as the expected difference in test
performance compared to apparently established
algorithms. Particularly for the latter aspect, an ap-
propriate case estimate is of high importance since
insignificant results for the performance of a new
screening test compared to traditionally established
algorithms may be solely related to an underpow-
ered study.
In risk groups with a presumed higher prevalence
of disease compared to the general population ben-
efits of screening can only be proven if the findings
are compared to a healthy control group. Otherwise
the high incidence of positive findings may be con-
sidered entirely artifactual if the prevalence of these
findings is unknown for the general population.
One important example has been the screening for
hepatocellular carcinoma in individuals exposed to
thorotrast. In this risk group a significantly higher
incidence as well as mortality from hepatocellular
carcinoma could be proven by systematically com-
paring the findings to an age matched control group
in a prospectively designed longitudinal study (van
Kaick 2006).
In addition, the parameters for conducting the
screening study have to be designed in advance. This
refers to technical parameters related to the data ac-
quisition itself as well as to parameters indicating
the performance for data analysis. One thorough
– fully defined list of performance indicators is list-
ed in the European guidelines for quality assurance
in breast cancer screening and diagnosis. Here, for
example, both technical parameters such as target
 Personnel and Structural Prerequisites for Screening-Programs
optical density, spatial resolution or glandular dose
are defined as well as minimum requirements that
address the rate of screening participation in the
target population, the percentage of participants for
further assessment, the breast cancer detection rate,
interval cancer rate as well as the proportion of in-
vasive screen-detected cancers with negative lymph
nodes. These performance indicators are crucial to
define the quality levels during the course of a study
in order to generate appropriate data that prove the
hypothesis of a screening study.
5.2.2.2
Data Evaluation
The key requirement for valid analysis of data aris-
ing from a screening study is the consistent, clearly
defined and reproducible reporting of the findings
in a standardized reporting scheme. This reporting
scheme has to fulfi l several requirements. First, it
has to be able to balance the different positive and
negative findings in terms of their significance as
well as to unambiguously subcategorize the find-
ings in those that do not require further manage-
ment, those that have to be followed up by further
imaging studies and those that immediately require
invasive confirmation preceding treatment. In addi-
tion, the rating scheme must have a low intra- and
inter-observer variability, e.g. the rating has to be
reproducible among different readers as well as by
the same reader in repetitive assessments. Addition-
ally, it has to be accepted internationally among the
radiology community.
Probably the most known categorizing system
is the Breast Imaging Reporting and Data System
(BI-RADS) initially published by the American Col-
lege of Radiology in 1992. BI-RADS has been well
accepted and has been increasingly adopted as a
system for breast imaging reporting particularly
for mammography. It has evolved over time to also
categorize the lesions found on breast sonography
and MRI. This system aims at standardizing the lan-
guage for defining and grading of radiologic find-
ings within the breast and recommending the ap-
propriate further diagnostic and therapeutic steps.
However, studies found only a moderate overall in-
tra- and interobserver agreement for the BI-RADS
classifications. While there is relatively high agree-
ment for category 1 and 2 (negative study and be-
nign finding, respectively) as well as for category 5
(finding highly suggestive of malignancy), there has
been a relative high percentage of discordance par-
73
ticularly for category 3 (probably benign finding). In
one study the discordance with reporting category 3
exceeded 50% with overlap both to lower and higher
categories (Lehman et al. 2002). The problem is that
this may result both in over-diagnosis (biopsy for
category 2 lesions) and under-diagnosis (normal
interval follow-up in category 4). It can be consid-
ered a weakness of standardized reporting systems
if too many categories with only subtle differences
among each category are provided. The more sub-
tle these differences are, the better the training has
to be for those radiologists using these systems on a
regular basis. In a recent study from Florence on 12
dedicated breast radiologists with little prior work-
ing knowledge of BI-RADS who were reading a set
of 50 breast lesions (29 malignant, 21 benign) major
disagreement occurred for intermediate categories 3
and 4 with insufficient intra- and interobserver con-
sistency (Ciatto et al. 2006). Thus, familiarizing
radiologists with a standardized reporting system
and limiting the number of categories to those with
clearly defined differences are key prerequisites for
data evaluation in a screening setting.
5.2.3
Screening Center vs Radiological Department
with Screening
For the decision of establishing a specialized screen-
ing center vs performing screening studies within
a clinical radiological department different aspects
have to be taken into account including statistical
considerations, workflow and clinical expertise.
One has to be aware of the fact that individuals for
secondary screening should be by definition asymp-
tomatic without clinical manifestation of a disease.
This results in three major differences to those in-
dividuals who are being referred for symptoms. As-
ymptomatic screening participants are usually self-
motivated, expect reassurance of their healthiness
and usually require no further invasive diagnostic
work-up or treatment in the majority of cases. Also,
the radiologist expects the prevalence of findings to
be lower than in a pre-selected symptomatic patient
cohort even for those diseases that have a relatively
high prevalence in the general population and are
thus ideally suited for screening. These reasons have
led to the trend to assess asymptomatic individu-
als in dedicated screening centers in order to not
mix their group characteristics with those of symp-
tomatic patients. It can be argued that this indeed
74 S. O. Schoenberg and M. F. Reiser
increases participation in the screening program,
ensures a more standardized screening approach
and reduces overestimation of the true prevalence
of a disease.
In a clinical radiological department with a broad
diagnostic and therapeutic spectrum, on the other
hand, the radiologists might encounter certain dis-
eases more frequently due to pre-selection of the re-
ferred patients. For those patients with a known dis-
ease the workflow for further diagnostic work-up and
treatment is frequently optimized. This also includes
the use of expensive or complex imaging modalities
for disease verification that can only be operated eco-
nomically if used for patients and positive screen-
ing individuals together. Examples of this are the
follow-up of small 5–14 mm pulmonary nodules on
high-resolution multi-slice CT data sets using volu-
metric post-processing software or the characteriza-
tion of these nodules by PET or PET-CT, respectively.
Of course, this further work-up can also be initiated
through a dedicated screening center by referral to a
clinical department; however, this requires thorough
optimization of the work-flow in order to not increase
the rate of study drop outs or under-diagnosis.
5.2.4
Technical Status:
Is High-End Equipment Absolutely Necessary?
Screening for a disease with a high prevalence in
the general population, reliable and safe detection
by diagnostic studies and high possibility for cure
should be accessible at little or even no cost for every
individual who meets the inclusion criteria. This re-
quires the use of equipment that is relatively widely
available and operates at a reasonable cost level. In
the past, this has led to the assumption that cer-
tain minimum standards should be defined for the
technical level of diagnostic equipment. However,
accuracy may greatly deteriorate if the technical
standard falls below a high standard level. These
challenges become most prominent if screening is
used in areas in which the technical capabilities of
the diagnostic equipment are rapidly evolving. One
representative example is CT colonography. While
the initial larger study by Pickhardt et al. could
demonstrate a sensitivity of approximately 90% for
detection of colon polyps exceeding 6mm in size, a
successive study by Rockey et al. revealed only 30%
sensitivity (Pickhardt et al. 2003; Rockey et al.
2005). However, the first study was using a multi-
slice CT scanner with four respectively eight detec-
tor rows in combination with 3D visualization of
the colon while the latter study was performed on
single-, dual- and four-slice CT with 2D visualiza-
tion of the data.
In addition, state-of-the-art equipment is man-
datory for those diagnostic exams exposing the pa-
tient to ionizing radiation. In a study by Graser et
al. (2006) radiation exposure from CT colonography
could be reduced by approximately 30% using mod-
ulation of the tube current, a technique that has just
been recently introduced.
In conclusion, high-end equipment is frequently
mandatory for screening particularly in rapidly
evolving fields. In order to justify the costs, this
equipment should be primarily installed in centers
with high throughput of screening studies to ensure
its economic use. In areas of rapidly advancing tech-
nology, some financial commitment of the screen-
ing individuals may be unavoidable for the sake of
adequate quality.
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268

Technical Prerequisites
6.1 Whole-Body MRI
Olaf Dietrich and Stefan O. Schoenberg
CONTENTS
6.1.1 Technical Basics of Whole-Body MRI 77
6.1.1.1 Hardware Restrictions 77
6.1.1.2 Acquisition Strategies 78
6.1.1.3 RF Coil System 80
6.1.2 Hardware for Whole-Body MRI 80
6.1.2.1 Conventional MR Systems 80
6.1.2.2 Rolling-Table-Platform MRI 80
6.1.2.3 Dedicated Whole-Body MRI Systems 81
6.1.3 Parallel Imaging 81
6.1.3.1 Accelerating MRI 81
6.1.3.2 Technical Implementation of
Parallel Imaging 82
6.1.3.3 Advantages and Disadvantages of
Parallel Imaging 82
6.1.4 MR Protocols and Pulse Sequences
References 86
6.1.1
Technical Basics of Whole-Body MRI
Magnetic resonance imaging (MRI) has the substan-
tial advantage over other imaging modalities that an
excellent soft-tissue contrast for assessment of mor-
phology can be combined with evaluation of func-
tion and metabolism. Due to the lack of exposure to
radiation or iodinated contrast agents, imaging can
be multiply repeated and extended to the entire body
within a single MR scan. Thus, it is not surprising
that whole-body MRI has been discussed since the
early beginnings of clinical MRI, and is mentioned,
e.g. in articles by Lauterbur (1980), Mansfield et
al. (1980), and Edelstein et al. (1980).
O. Dietrich, PhD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistraße 15, 81377 Munich, Germany
S. O. Schoenberg, MD
Professor, Department of Clinical Radiology, University Hospital
Mannheim, Medical Faculty Mannheim, University of Heidel-
berg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
Technical Prerequisites: Whole-Body MRI 77
6
In contrast to organ-related MRI, which is usually
focused on a relatively small anatomic region such
as the brain or the abdomen, data from a substantial
portion of the human body – ideally from head to
toe – is acquired in whole-body imaging. An early
demonstration is given in the article by Edelstein
et al. (1980) with axial MRI sections from the head,
thorax, abdomen, and the thighs of a subject.
Whole-body MRI in the broader sense includes
all kinds of protocols that acquire data from an
extensive scan range in head-foot direction – not
necessarily with identical scan parameters, image
contrasts, or pulse sequence types for all examined
84
anatomic regions. In the narrower sense, whole-
body MRI refers to the integrated acquisition of data
with identical contrast from a substantial portion of
the human body such that it can be composed to a
single large data set after the acquisition. In the past,
this appealing comprehensive approach was highly
restricted due to limitations in speed and spatial res-
olution of the acquisitions. Only new MRI technol-
ogy and acquisition techniques introduced in recent
years enabled the fast acquisition of high-quality
and high-resolution data from a large scan range in
head-foot direction as described below.
6.1.1.1
Hardware Restrictions
All acquisition strategies for whole-body MRI are
limited by two geometrical restrictions of each MRI
system: the maximum possible field of view in head-
foot direction and the maximum possible range of
table movement within the magnet (Fig. 6.1.1). The
choice of the most adequate or efficient whole-body
imaging technique depends on these system prop-
erties.
The maximum possible field of view in head-foot
direction is typically somewhere between 30 cm
78 Olaf Dietrich and Stefan O. Schoenberg
Maximum possible
field of view in
head-foot direction
b field of view (shown in light
Maximum possible range of table movement
and 60 cm and depends on the physical properties
of the electromagnetic coils that generate the static
(B0) magnetic field, the gradient fields, and the RF
electromagnetic field (B1). Inside the allowed field of
view, all fields generated by these coils are required
to be within very strict limits with respect to the
homogeneity of the B0 and B1 fields as well as the
linearity of the gradient fields. Enlarging the field of
view in axial direction is theoretically possible but
requires considerably larger magnets and coils and,
thus, would dramatically increase the size and the
costs of an MRI system. Consequently, the oppo-
site development could be observed in recent years:
magnets became shorter and the maximum field of
view in axial direction was rather reduced than in-
creased. Geometric disadvantages of this approach
can be compensated at least to a certain degree by
improved imaging strategies and protocols.
The second restriction mentioned above, namely
the maximum possible range of table movement
within the magnet, can be extended much more
easily using an optimized mechanical table con-
struction. Indeed, several recently introduced MRI
systems now offer examination tables that can be
moved by more than 200 cm through the magnet
and thus enable comfortable whole-body examina-
tions without the need for time-consuming reposi-
tioning of the patient.
Fig. 6.1.1a,b. Hardware restric-
tions relevant for whole-body
MRI. a The maximum possible
blue) in head-foot direction re-
stricts the anatomic range that
can be acquired in a single scan;
its typical size is about 50 cm.
b The maximum possible range
of table movement restricts the
total field of view accessible in a
whole-body protocol; this range
is typically between 160 cm and
210 cm
6.1.1.2
Acquisition Strategies
Two basic approaches of whole-body MRI can be
distinguished (Fig. 6.1.2): successive imaging of sev-
eral anatomic “stations” with table movement be-
tween scans (and subsequent composition of data
sets) or, alternatively, scanning during continuous
table movement. In both cases, image orientation
can be arbitrary, and is typically either transver-
sal or coronal; both techniques can be used with
two-dimensional or three-dimensional acquisition
schemes.
The multi-station approach is less demanding
with respect to the acquisition technique. It often
works with protocols that are very similar to those
used for conventional scanning of the corresponding
anatomic region. These protocols are run consecu-
tively for each station with a certain image overlap
in axial direction (of, e.g. 5 cm) between adjacent
stations (Kramer et al. 2005; Schmidt et al. 2005).
The overlapping areas are used to seamlessly fuse
the separate data sets into a single whole-body data
set during post-processing. An advantage of this ap-
proach is that image geometries (total field of view,
aspect ratio of field of view in readout and phase-en-
coding direction, double-oblique slab orientations)
can be chosen very flexible and independently for

a Whole-body MRI with 5-station approach
b Moving-table MRI, axial acquisition
c Moving-table MRI, coronal acquisition
Fig. 6.1.2 a–c. Acquisition strategies for whole-body MRI. a Whole-body acquisition in five separate stations (colour-coded
from red to blue); each station is acquired in coronal orientation. b Moving-table MRI with acquisition of axial slices. Dur-
ing scanning, the patient is being moved continuously through the magnet. c Moving table MRI with coronal acquisition.
The patient is continuously moved as in b, but data is acquired in coronal orientation
every station, restricted only by the capabilities of
the post-processing software. Disadvantages of the
multi-station approach are geometric distortions in
areas that are distant (in axial direction) from the
isocentre of the magnet. These distortions can com-
plicate the fusion of the acquired data sets, in partic-
ular, since distortions generally look different at the
superior and inferior border of the field of view. In
addition, the multi-station approach is less time-effi-
cient than continuous scanning since the acquisition
must be paused during table movement. Finally, the
current development of scanners with reduced fields
of view in head-foot direction requires an increased
number of stations to cover the whole body. E.g. in-
stead of four stations with a head-foot field of view
of 50 cm and 5 cm overlap to cover a total length of
180 cm, some newer scanners require protocols with
35-cm fields of view in head-foot direction and, thus,
need six stations (including station overlap) to cover
the same volume. This further reduces the time-ef-
ficiency of the multi-station approach.
Scanning during continuous table motion requires
specific scanner hardware, pulse sequences and re-
construction algorithms, and, thus, is more compli-
cated to implement than the multi-station approach.
Technical Prerequisites: Whole-Body MRI 79
Station 1 Table position z
Station 2
Station 3
Time t
Station 4
Station 5
Table position z
Time t
Table position z
Time t
However, it is generally more time-efficient than mul-
tiple consecutive acquisitions and less sensitive to
geometric distortions since the field of view in axial
direction can be restricted to a relatively small area
in the exact isocentre of the magnet, which is par-
ticularly advantageous in scanners with ultra-short
magnets. An obvious precondition for this approach
is that the table can be moved automatically during
scanning and is controlled by the pulse sequence in-
stead of the conventional user interface at the magnet.
Numerous acquisition schemes have been proposed to
implement continuously moving table MRI for differ-
ent pulse sequences or different image orientations.
A relative simple approach is the continuous acquisi-
tion of a single axial slice in the isocentre during table
movement using an ultra-fast or single-shot sequence
(Barkhausen et al. 2001). In this case, only the slice
position must be updated appropriately in order to
reconstruct the whole-body data set. However, acqui-
sitions with slower sequences, coronal orientation, or
three-dimensional Fourier encoding require more
substantial changes to the sequence and reconstruc-
tion technique in order to correct for motion effects
during the acquisition (Dietrich and Hajnal 1999;
Kruger et al. 2002).
80 Olaf Dietrich and Stefan O. Schoenberg
6.1.1.3
RF Coil System
A further point to consider is the RF receiver coil
system of scanners used for whole-body MRI. Coils
are required in order to detect the RF signals that
are emitted from the currently scanned anatomic re-
gion. These coils can either be positioned statically
at the isocentre of the magnet such as the standard
body coil, which is integrated in most clinical MRI
systems. Alternatively, surface coils covering a spe-
cific anatomic region can be used; these coils are
positioned at or within the scanner table, i.e. they
have a fi xed position with respect to the scanned
subject. The main advantage of such surface coil sys-
tems is that they are positioned considerably closer
to the subject and, thus, provide a substantially
higher signal-to-noise ratio allowing for fast imag-
ing or higher spatial resolution. On the other hand,
even lightweight surface coil systems lying on the
thorax or abdomen can potentially reduce patients’
comfort during the examination. Furthermore, all
coil elements must be connected to the MRI system,
which requires a considerable amount of cabling
and a large number of connecting plugs increasing
the complexity of the hardware and of the required
examination setup.
6.1.2
Hardware for Whole-Body MRI
6.1.2.1
Conventional MR Systems
Conventional MR systems are generally suited for
whole-body MRI although certain restrictions par-
ticularly with respect to the total examination time
must be accepted. These systems often will not be
technically capable of scanning during continuous
table movement; thus, a multi-station approach will
typically be chosen. The range of table movement
is frequently limited as well so that scanning from
head to toe may require repositioning the subject
from a head-first position to a feet-first position in
order to acquire data from the lower extremities.
Obviously both, the multi-station approach as well
as repositioning of the patient will increase the total
examination time.
Conventional systems may not provide the pos-
sibility to connect a sufficient number of coil ele-
ments to cover the subject completely with surface
coils; in this case, scanning can be performed with
the built-in body coil at least for some anatomic re-
gions. E.g. MRI of the brain may be performed with
the dedicated head coil, followed by examinations
of the thorax and abdomen using the built-in body
coil. Since the acquisitions with the body coil exhibit
a lower signal-to-noise ratio, either the spatial reso-
lution must be reduced or the number of averaged
signals must be increased – the latter again pro-
longing the total examination time. Alternatively,
dedicated surface coil systems could be used for all
anatomic regions but would have to be re-positioned
and plugged in between successive acquisition sta-
tions which would substantially increase the total
examination time.
A further limitation of conventional MR scan-
ners is the gradient system whose performance is
particularly important for fast and ultra-fast se-
quences such as spoiled gradient-echo techniques
or fully balanced steady-state free-precession (SSFP)
sequences. Conventional gradient systems are re-
stricted to lower maximum gradient strengths and
longer minimum rise times and, thus, increase the
minimum echo time and repetition time of these
pulse sequences and hence prolong the total exami-
nation time for whole-body MRI.
6.1.2.2
Rolling-Table-Platform MRI
Conventional MRI systems can be extended with ad-
ditional hardware devices to accelerate whole-body
MRI. This has been demonstrated e.g. by Ruehm
et al. (2000) and Barkhausen et al. (2001) with a
device called BodySURF or AngioSURF (SURF: sys-
tem for unlimited rolling field of view). This device
consists of a rolling table platform for the patient
placed on seven pairs of roller bearings on top of
the patient table. The rolling table platform is pulled
manually through the magnet such that the patient
can be scanned in the isocentre from head to toe.
Two elements of the spine coil integrated in the scan-
ner table and a flexible body phased-array coil are
used for signal reception. These surface coils remain
fi xed at the isocentre of the magnet while the patient
is moved between these surface coils. Thus, a better
fi ll factor and improved signal-to-noise ratio can
be achieved than with the conventional body coil

(integrated in the magnet). Compared to a set of
surface coils lying directly on top of the patient, the
fi ll factor and signal-to-noise ratio of the BodySURF/
AngioSURF system is still reduced, but, on the other
hand, the coil setup is less complex and the patient
comfort is slightly increased.
This rolling-table-platform approach has been
used in various whole-body applications, e.g. for
whole-body MR angiography with data acquisition
in five (Ruehm et al. 2000) or six (Herborn et al.
2004) stations or for whole-body STIR MRI in sev-
eral stations (Ghanem et al. 2006). It is also com-
patible with acquisitions during continuous table
movement as demonstrated by Barkhausen et al.
(2001) using a real-time TrueFISP sequence and a ta-
ble speed of 5 cm/s. With this approach, whole-body
examinations with a 150-cm field of view in axial
direction could be performed in a total scan time of
about 30 s which is comparable to CT examination
times. However, the obtained spatial resolution of
only 2 × 4 × 8 mm³ voxel size is substantially lower
than in dedicated state-of-the-art MRI scans.
6.1.2.3
Dedicated Whole-Body MRI Systems
Recently, several MRI systems have been introduced
that were specifically designed for whole-body ap-
plications (Schmidt et al. 2004; Kramer et al. 2005;
Schlemmer et al. 2005; Fenchel et al. 2005). In
contrast to earlier approaches, whole-body MRI is
made possible with these newer systems in a rea-
sonable examination time and, in particular, with
an image quality comparable to the one of a dedi-
cated examination of an anatomic region. This is
achieved by combining different techniques such as
newly developed surface matrix coil systems, fully
software-controlled table movement, improved im-
age post-processing software, and accelerated im-
age acquisition using parallel-imaging techniques
(described in detail in Sect. 6.1.3).
A key feature of these dedicated whole-body MRI
scanners is an optimized multi-element surface coil
system that covers the patient completely and allows
MRI with high signal-to-noise ratio. These matrix
coil systems consist of up to about 100 coil elements
(cf. Fig. 3 in chapter “Diagnostic algorithms for
whole-body exams” by H. Kramer) that are simulta-
neously connected to the scanner hardware and can
be selected individually or automatically as saved
in the protocol. The number of coil elements in the
Technical Prerequisites: Whole-Body MRI 81
isocentre that actively receive signals is consider-
ably lower than the total number of coil elements;
typically, 20–30 elements can be used in parallel for
RF reception requiring 20–30 parallel RF channels.
Providing up to 32 parallel RF channels is also an
important precondition for the flexible application
of parallel imaging as described below.
In addition to enhanced RF technology, dedi-
cated whole-body scanners require also appropriate
image reconstruction systems. By receiving data in
parallel from 32 RF channels, the total amount of
image data is increased by a factor of 32 compared
to conventional MRI systems. This huge amount of
data should be processed and reconstructed in rea-
sonable time requiring both a large RAM of several
gigabytes and fast main processor technology.
6.1.3
Parallel Imaging
6.1.3.1
Accelerating MRI
MRI acquisitions can be very time-consuming since
k-space data is typically acquired line by line and
the pulse sequence must be repeated for each of
these lines in order to build up a full data set in k-
space. Even with the minimum possible echo times
and repetition times, the total acquisition time of a
data set may be unacceptably long for many state-of-
the-art MRI applications such as fast dynamic MR
angiographies, perfusion MRI, MR imaging of the
cardiac function, or, in particular, for high-resolu-
tion whole-body MRI with very large data sets.
Consequently, accelerating MRI has been one of
the key incentives that resulted in the enormous
technical progress of MRI during the last two dec-
ades. While early milestones in the history of accel-
erated MRI were fairly general improvements such
as the introduction of fast gradient-echo or turbo-
spin-echo pulse sequences or the partial-Fourier ap-
proach in the mid-1980s, subsequent developments
became more and more specific and limited to cer-
tain applications. These include in particular tech-
niques such as key-hole imaging or echo sharing
that were especially designed for fast dynamic MRI
applicable only with a small number of very specific
pulse sequences and imaging protocols.
82 Olaf Dietrich and Stefan O. Schoenberg
In contrast to these specifics approaches, an idea
for accelerated acquisitions proposed in the second
half of the 1990s has found wide acceptance in virtu-
ally all areas of MRI: this approach is now known as
parallel imaging, parallel MRI, (partially) parallel
acquisition (PPA), or parallel acquisition techniques
(PAT) (Dietrich et al. 2002; Heidemann et al. 2003;
Bammer and Schoenberg 2004; Schoenberg et al.
2007).
Parallel imaging soon turned out to provide ex-
traordinary advantages in almost all areas of MRI,
and thus, became one of the most important techni-
cal advances in current MRI technology. This was
possible since parallel imaging can be applied to
practically all types of pulse sequences and imaging
protocols, ranging from high-resolution morpho-
logical imaging over various functional imaging
techniques to ultra-fast dynamic MRI. In addition to
substantially accelerated imaging, parallel MRI has
been found to increase robustness of MR examina-
tions and to reduce blurring of single-shot acquisi-
tions as well as susceptibility and motion artefacts.
6.1.3.2
Technical Implementation of Parallel Imaging
The basic idea of parallel imaging is to employ sev-
eral independent receiver coil elements in parallel to
reduce the number of required phase-encoding steps
for a given matrix size. Thus, a certain amount of the
spatial encoding originally achieved by the phase-
encoding gradients is now substituted by evaluating
data from several coil elements with spatially differ-
ent coil sensitivity profi les. The reduction of phase-
encoding steps is achieved by reducing the sampling
density in k-space as illustrated in Figure 6.1.3, i.e.
k-space is undersampled by acquiring only every
second or, more general, every R-th line for an R-fold
acceleration. As a consequence, a straight-forward
conventional image reconstruction of these data sets
would result in several images (one from each coil
element) with reduced field of view in phase-encod-
ing direction and, hence, severe aliasing artefacts.
In order to reconstruct a single image set without
aliasing artefacts, specific parallel-imaging recon-
struction algorithms are required, which are sub-
stantially more complicated than the conventional
Fourier transform.
Raw data reduction factors (R) between 2 and 6
can typically be achieved with parallel imaging in a
single direction; a combination of reduced sampling
densities in two phase-encoding directions is pos-
sible in 3D MRI and results in higher total reduction
factors. The maximum reduction factor is limited by
the number of independent coil elements or sepa-
rate receiver channels of an MRI system. Thus, the
most important precondition for the applicability
of parallel imaging is a multi-channel MRI system
with several parallel receiver channels as well as ap-
propriate multi-channel coil systems.
Technically, data acquisition for parallel MRI is
very similar to acquisition schemes of conventional
pulse sequences. Most relevant techniques of MRI
can relatively easily be adapted to parallel imaging,
since the data acquisition is essentially equivalent
to an acquisition of a reduced (rectangular) field of
view in phase-encoding direction.
To reconstruct images from undersampled k-
space data, it is important to know the coil sensitiv-
ity profi les of each coil element, which describe the
spatial intensity distribution of the received signal
as shown in Figure 6.1.3a. Coil sensitivity profi les
can be measured either at the beginning of an ex-
amination for a specific coil configuration or inte-
grated in the accelerated scan as additional k-space
lines, which are also referred to as auto-calibration
signals. The integrated acquisition of coil sensitivity
profi les slightly increases the scan duration but sub-
stantially improves the robustness of acquisition,
since the influence of motion between the measure-
ment of the coil sensitivities and the actual scan is
reduced.
As mentioned above, image reconstruction of
parallel-imaging raw data is algorithmically and
computationally much more demanding than con-
ventional Fourier-transform reconstruction, and
considerable efforts have been made to develop op-
timized reconstruction algorithms. Today, several
alternative reconstruction techniques are used for
parallel imaging (Blaimer et al. 2004; Griswold
2007); the most common approaches are known
by the acronyms SENSE (Pruessmann et al. 1999),
SMASH (Sodickson and Manning 1997), and
GRAPPA (Griswold et al. 2002).
6.1.3.3
Advantages and Disadvantages of
Parallel Imaging
The major challenge for the successful implementa-
tion of parallel imaging in clinical routine was the
required multi-channel MRI technology which ini-
 Technical Prerequisites: Whole-Body MRI 83

Fig. 6.1.3a–c. Data acquisition and image reconstruction in parallel MRI. a Data is acquired by four coil elements with
different spatial sensitivity profi les in parallel. b Four sets of reduced raw data are available for image reconstruction. Each
of these data sets corresponds to an aliased image from one of the coil elements. c Specific reconstruction algorithms are
required to reconstruct the image in parallel MRI (with permission from: Schoenberg SO, Dietrich O, Reiser MF (2007)
Parallel imaging in clinical MR applications. Springer, Berlin Heidelberg New York)

tially limited its widespread use. Only few MRI sys-
tems had already provided this ability when parallel
imaging became generally known, but since then
the number of receiver channels has been substan-
tially increased from year to year. Simultaneously,
the image reconstruction systems became substan-
tially faster such that large parallel-imaging data
sets could be processed. Thus, parallel imaging can
now be clinically used at the vast majority of all
clinical and research sites.
The main disadvantage of parallel imaging apart
from hardware requirements is a reduced signal-to-
noise ratio (SNR), which is described by two factors:
the effects of the reduced scan time and the so-called
geometry factor (g-factor). Accelerating an acquisi-
tion by a factor, R, reduces the SNR by the same ex-
tent as decreasing signal averaging from R-fold to 1,
i.e. SNR is reduced to the square root of 1/R. In addi-
tion, SNR will be locally decreased if the coil geom-
etry (i.e. the spatial arrangement of coil elements) is
not ideal with respect to the chosen phase-encoding
direction and acceleration factor. This influence is
described by the g-factor, a spatially varying quan-
tity with values greater than or equal to one. Thus,
the signal-to-noise ratio, SNR R, of a parallel-imag-
ing acquisition with acceleration factor, R, can be
summarized (Pruessmann et al. 1999) as
where SNR0 is the SNR without parallel imaging and
g is the g-factor.
It should be noted that a particular difficulty aris-
ing from the spatially varying g-factor and, thus,
from the spatially varying noise level is the reliable
84 Olaf Dietrich and Stefan O. Schoenberg
measurement of signal-to-noise ratios in images ac-
quired with parallel MRI. Due to the variable noise
level it is not possible to determine the image noise
in a background region and extrapolate this value
to the foreground region of interest; instead, more
sophisticated techniques of SNR measurement must
be employed for parallel imaging data (Dietrich et
al. 2005; Reeder 2007).
The most important advantage of parallel imag-
ing is of course the reduced acquisition time or, if
the scan time is held constant, the increased spa-
tial resolution. This is particularly important in
breath-hold applications with sufficient SNR such
as contrast-enhanced pulmonary or renal MR angi-
ography where the SNR loss due to parallel imaging
is not critical. Further advantages of reduced scan
times are higher temporal resolution in dynamic
MRI, less sensitivity to motion, and increased pa-
tient through-put. In addition, several single-shot
techniques such as echo-planar imaging or single-
shot turbo-spin-echo sequences benefit from paral-
lel imaging, since shorter echo trains result in re-
duced blurring as well as decreased susceptibility
effects and geometric distortions.
High-resolution whole-body MRI in particular
benefits from acceleration with parallel-imaging
techniques because of the very large amount of data
typically acquired in these examinations. Therefore,
dedicated whole-body MRI systems (cf. Sect. 6.1.2.3)
are now designed for the flexible application of par-
allel imaging in all slice orientations. This includes
a large number of (e.g. 32) parallel receiver chan-
nels and coil arrays with elements that are arranged
around the subject and allow for high acceleration
factors in all spatial directions. In order to cope with
the large amount of acquired data and the compli-
cated image reconstruction algorithms, the recon-
struction systems have also been extended accord-
ing to the demands of parallel-imaging techniques.
6.1.4
MR Protocols and Pulse Sequences
Today, whole-body MRI can be performed with an
image resolution and signal contrast comparable
to the one of dedicated imaging of a single organ.
Whole-body MRI may comprise several different
morphological and functional whole-body exami-
nations including whole-body T1-weighted or T2-
weighted MRI, short-TI inversion-recovery (STIR)
MRI, or contrast-enhanced whole-body MR angi-
ography (MRA). In the following paragraphs, some
typical protocol parameters are presented that can
be realized with dedicated state-of-the-art whole-
body MRI systems.
An example of a whole-body MRA examina-
tion is shown in Fig. 6.1.4a. The protocol consists
of four stations covering the carotid arteries, the
abdominal vessels, the upper-leg, and the lower-leg
arteries, and is acquired with two separate injec-
tions of a gadolinium chelate contrast agent. Ul-
tra-fast three-dimensional spoiled-gradient-echo
sequences are used for all stations. The carotid
MRA is acquired fi rst immediately followed by a
table movement to the lower-leg territory. If this
table movement is sufficiently fast, i.e. faster than
the transit time of the contrast bolus passing from
the carotid arteries to the lower legs, this allows the
acquisition of a pure arterial contrast in the lower
legs. A second injection is performed to acquire
data of the abdomen and the upper legs. Using a
3-Tesla whole-body system with dedicated surface-
coil systems and parallel imaging with acceleration
factors of R = 2 or R = 3, an isotropic spatial reso-
lution of less than 1 × 1 × 1 mm³ can be obtained
in the carotid and the lower-leg territory. In the ab-
domen and the upper legs, a slightly lower isotropic
spatial resolution of less than 1.2 × 1.2 × 1.2 mm³
is obtained due to the larger slab volume and the
required shorter scan times. Similar protocols with
slightly reduced spatial resolutions are also feasi-
ble on dedicated 1.5-Tesla whole-body scanners
(Kramer et al. 2005).
Examples of whole-body MRI with STIR and T1
contrast are shown in Fig. 6.1.4b,c, respectively.
These data sets are acquired with two-dimensional
turbo-spin-echo sequences in coronal orientation
covering five stations from head to toe on a 1.5-Tesla
whole-body scanner. Again, dedicated surface coil
systems and parallel imaging with acceleration fac-
tors of R = 2 or R = 3 were applied. T1-weighted
images are acquired with an in-plane resolution
of 1.1 × 1.3 mm², STIR images with a resolution of
1.3 × 1.8 mm²; the slice thickness was 5 mm in all
body regions. The total acquisition time for all five
stations is about 17 min for the T1-weighted scans
and 11 min for the STIR scans (Schmidt et al. 2005).
In screening protocols, these whole-body acquisi-
tions are typically combined with further examina-
tions such as perfusion and functional cardiac MRI,
high-resolution HASTE imaging of the lungs, or dif-
 Technical Prerequisites: Whole-Body MRI 85

a b c

Fig. 6.1.4a–c. Examples of whole-body acquisitions. a Contrast-enhanced MR angiography, acquired in four stations; shown
is a maximum-intensity projection (MIP) reconstruction of the three-dimensional data set. b STIR MRI acquired in five
stations. c T1-weighted MRI acquired in five stations

fusion-weighted brain MRI. In addition to conven- dimensional driven-equilibrium turbo-spin-echo-

tional morphological whole-body acquisitions, it has
recently been demonstrated that diffusion-weighted
whole-body imaging with background body signal
suppression (DWIBS) may be useful to screen for en-
larged lymph nodes and malignancies (Takahara
et al. 2004).
The spatial resolution of whole-body MRI can
be further improved with newly developed pulse
sequences such as the recently introduced three-
based sequence with variable flip angles called
SPACE (Sampling Perfection with Application-op-
timized Contrasts using different flip-angle Evo-
lutions) (Lichy et al. 2005). This sequence type
provides a higher SNR due to the excitation of a
three-dimensional slab instead of a single slice, and
a faster acquisition because of longer echo trains.
Thus, a higher in-plane resolution and reduced slice
thickness (up to high-resolution isotropic data sets)
86 Olaf Dietrich and Stefan O. Schoenberg
become feasible for T1-weighted or STIR acquisi-
tions in reasonable scan times.
Whole-body applications based on continuous
table movement have not yet reached the spatial res-
olution which is routinely obtained with the multi-
station approach although considerable progress
has been made recently. E.g., Zenge et al. (2005) de-
scribed sagittal and coronal moving-table MRI with
an in-plane resolution of 1.6 × 1.6 mm²; however,
they only acquired 13 slices of 10 mm thickness with
a slice gap of 15 mm. The total acquisition time was
119 s for a coronal whole-body acquisition. Thus, the
moving-table approach appears particularly useful
for very fast whole-body screening scans for which
a reduced spatial resolution is acceptable. Cur-
rently, voxel sizes of 1.3 × 1.3 × 1.8 mm3 have been
already introduced for the first clinically available
whole-body MRA protocols using continuous table
movement. Considering the increasing availability
of ultra-short magnets and the continuing develop-
ment of improved imaging strategies, a growing im-
portance of moving-table MRI must be expected in
the near future.
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 Technical Prerequisites: CT 89

Technical Prerequisites 6
6.2 CT
Christoph Becker, Anno Graser, and Peter Herzog

CONTENTS the potentials risks associated with the exposure

to ionizing radiation, preventive imaging can not
6.2.1 General Conditions for Screening by CT 89 be recommended outside of scientific trials. Long-
term prospective cohort studies with well-defi ned
6.2.2 Screening for Coronary Artery Disease 89
endpoints are still missing. For risk-benefit analyses
6.2.3 Screening for Lung Cancer 91 radiation exposure has to be assessed. Reduction of
6.2.4 Screening for Colon Cancer 92 radiation exposure will increase the likelihood of
6.2.4.1 Preparation of the Colon 93 a positive outcome. Therefore, strategies to reduce
6.2.4.2 Colonic Distension 93 the amount of radiation according to the ALARA
6.2.4.3 Stool and Fluid Tagging 94
(as low as reasonable achievable) principle should be
References 94 employed in order to avoid potential harmful effects
associated with screening by CT.
Newest generations of CT scanners support these
efforts by patient-adapted automated dose exposure
6.2.1 control.
General Conditions for Screening by CT

With multi detector row CT (MDCT), high resolu-

tion scans of large ranges can be acquired within
a couple of seconds. Morphologic changes within
different organs are readily detected so that this
modality appears suitable for screening examina-
tions. MDCT of the heart, lungs and colon have been
employed for preventive imaging in asymptomatic
patients. In numerous studies, technical require-
ments, feasibility and postprocessing tools aiding
in the detection of pathological conditions have been
explored.
The major drawback of screening by CT is the
inherent exposure to ionizing radiation. As long
as no clear evidence exists that early diagnosis of
life threatening pathological conditions outweighs
C. R. Becker, MD, Professor
A. Graser, MD
P. Herzog, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
6.2.2
Screening for Coronary Artery Disease
Initially, CT of the coronary arteries was performed
with electron beam CT (EBCT). Lack of any mov-
ing items in this scanner type allows for exposure
times as short as 100 ms. Scan acquisition in this
scanner was triggered by the ECG signal to the mid-
diastole phase of the cardiac cycle to reduce car-
diac motion artifacts further. The initial purpose of
this scanner was to measure myocardial perfusion
(Boyd 1983). Conversely, it has early turned out,
that EBCT is also well suited to detect coronary
calcifications as a surrogate marker for coronary
atherosclerosis (Agatston et al. 1990). Further at-
tempts have also been made to use this scanner
for coronary CT angiography and plaque imaging.
However, low spatial resolution (3 mm) and high
image noise of EBCT limited the investigation to
the most proximal portions of the coronary arteries
(Schmermund et al. 1998).
90 C. Becker, A. Graser, and P. Herzog
Conventional mechanical CT scanners with an
X-ray tube and detector ring rotating around the
patient have also increased in speed within the re-
cent years. The scan mode dedicated to coronary
CT is called retrospective ECG gating (Flohr and
Ohnesorge 2001). For this technique the spiral CT
scan is acquired with a small pitch (table feed per
gantry rotation < 0.3). The following image recon-
struction is then performed also in the slow mo-
tion diastolic phase of the cardiac cycle. Coronary
calcium quantities measured with the first clinical
available multi-detector-row CT (MDCT) scanner
with 4-detector-rows and a temporal resolution of
250 ms are well comparable to data derived from
EBCT (Becker et al. 2000; Carr et al. 2005).
A 4-detector-row CT with 500 ms gantry rotation
time is the minimal requirement for a coronary cal-
cium measurement with MDCT. Coronary calcium
screening can be performed without contrast media
and with 3-mm slices. Retrospective ECG gating is
superior to acquire the entire volume without any
gaps and to reconstruct the images with overlapping
increment. An overlapping slice reconstruction may
help to improve the reproducibility (Ohnesorge et
al. 2002). Depending on the MDCT scanner used the
scan time is in the range of 5–20 s and the entire in-
vestigation can be completed within 5 min. In total
40–80 slices are generated for one complete investi-
gation.
As a fundamental requirement for screening the
radiation exposure for coronary calcium scanning
needs to be reduced to a minimum (approximately
1–2 mSv for coronary calcium screening). In par-
ticular, for the assessment of coronary atheroscle-
rosis in asymptomatic subjects, it is desirable to
avoid any redundant radiation. Based on the ECG
signal, the X-ray tube current can be switched to
its nominal value during the diastolic phase and
may be reduced significantly during the systolic
phase of the heart beat, respectively. The technique
is called prospective ECG tube current modulation
or ECG pulsing. This technique is most effective in
patients with low heart rates and only works with
regular sinus rhythm. If the heart rate is around 60
beats per min, the radiation exposure will be re-
duced by approximately 50% by using ECG pulsing
(Jakobs et al. 2002).
Even the tiniest calcification will become visible
by the reconstruction with a dedicated non-edge en-
hancing soft tissue kernel. After the reconstruction
the image data need to be analyzed and post-proc-
essed using a dedicated workstation. After identifi-
cation of calcified coronary lesions, the workstation
may automatically display the quantities of coronary
calcium as Agatston score, volume equivalent and
absolute mass. According to the method proposed
by Agatston, any dense structure in the CT image
> 130 HU in density is defined as calcification. The
area of this calcification is multiplied by a factor that
depends on the peak density of the lesion. A factor
between 1 and 4 is used for a peak density of 130–
199 HU, 200–299 HU, 300–399 HU and > 400 HU, re-
spectively. The sum of all lesions in all four coronary
vessels (left main, left anterior descending, circum-
flex and right coronary artery) then corresponds to
the total Agatston score (Agatston et al. 1990). This
algorithm requires specific EBCT image quality and
non-overlapping slice thickness of 3 mm. Therefore;
the Agatston quantification method is only of lim-
ited value for MDCT and even difficult to reproduce
by different EBCT scanners.
Originally, the investigation with the first EBCT al-
lowed only for acquisition of half of the entire heart
because not more than 20 slices could be acquired at
once. The limited reproducibility by this approach
became obvious (Hernigou et al. 1996) and because
of that various authors suggested algorithms to im-
prove the reproducibility. To track the progression
of calcium in the course of a therapeutic treatment,
it was necessary to introduce the calcium volume
equivalent (Callister et al. 1998). With isotropic in-
terpolation, overlapping slice acquisition can be sim-
ulated by a workstation and the reproducibility of the
quantification can be improved to a certain degree.
However, real overlapping slice acquisition and re-
construction is always superior to isotropic interpola-
tion and should be applied when MDCT (Ohnesorge
et al. 2002) with retrospective ECG gating is used.
The volume equivalent as well as the Agatston score
is limited by the fact, that the quantity of the calcium
volume depends on the image quality and on scan pa-
rameters and therefore these values cannot easily be
transferred from EBCT to MDCT.
In general, it is possible to quantify the abso-
lute amount of coronary calcium by using a stand-
ard calibration phantom in CT (Ulzheimer and
Kalender 2003). For this standardization the
calibration phantom must be scanned with those
parameters, which will later be used for the patient
investigation. As the mass of the calcium particles
in the phantom are known, it is possible by measure
the volume and density of the calcium from the CT
image and then to determine the calibration factor
for absolute quantification.

However, in investigations of patients the accu-
racy of the measurement may also be influenced by
the different patient sizes. The X-ray absorption is
different in thin as compared to obese patients, in
whom beam hardening will occur, resulting in dif-
ferent densities for the same amount of calcium de-
pending on the patients size. Therefore, the calibra-
tion phantom needs to be scanned with “fat rings”
simulating different patient sizes and delivering
different calibration factors. In investigations of pa-
tients the scout view will be used to determine the
diameter of the chest for the selection of the appro-
priate calibration factor. In practice, the calibration
phantom is measured without, one and two fat rings,
respectively. For a chest diameter < 30, 30–38 and
> 38 cm the calibration factor with no, one and two
fat rings is used, respectively.
Recently an “International Consortium on Stand-
ardization in Cardiac CT” has tried to establish a
standardized algorithm for coronary calcium meas-
urements for all different CT vendors. This consor-
tium also tries to built up a database by collecting
data obtained in a standardized fashion to provide
reference values for the absolute mass of coronary
calcium (McCollough et al. 2003).
6.2.3
Screening for Lung Cancer
MDCT, with the ability of examining the entire
thorax with thin slice sections in one breath hold,
aids in the non-invasive evaluation of indetermi-
nate pulmonary nodules. A collimation of 1 mm
or below should be selected for scanning. The
pitch can be increased up to 1.75, depending on
the capabilities of the scanner and the number of
detector rows. Scan time should not exceed 25 s
for a acceptable breath hold time. If only the lung
parenchyma has to be evaluated for pulmonary
nodules, as it is the case in lung cancer screening,
tube current and the resulting radiation dose can
be drastically reduced compared to a staging CT
of the thorax (Swensen 2002). In such cases no
i.v. contrast material needs to be administered.
For appropriate evaluation of the mediastinum
and the chest wall, standard radiation dose set-
tings and intravenous contrast administration is
required. In most cases, a tube voltage of 120 kV
is appropriate for examining the thorax. In par-
Technical Prerequisites: CT 91
ticular in a screening setting, a lower tube voltage
of 100 kVp or 80 kVp can be employed to further
decrease the radiation dose (Huda 2002). Recon-
struction should be performed using a medium
sharp lung kernel and an overlapping increment.
Reconstructed slice thickness should be slightly
greater than collimation to reduce noise and to
smooth pitch artefacts.
With recent generations of MDCT scanners, a da-
tasets of 500–600 axial images is created for further
post-processing. A secondary reconstruction with
a greater section thickness (e.g. 6 mm) can be ob-
tained in order to generate a second data set with a
reasonable number of images suited for fi lming or
printing.
Reading should be performed using a worksta-
tion. To avoid reading an excessive number of in-
dividual axial slices (500–600) image by image, a
thin sliding MIP, MPR or VRT reconstruction can
be used for a more effective reading. Thin sliding
MIPs have already proven to be the most suitable for
delineating small pulmonary nodules and to distin-
guish them from pulmonary vessels.
Typical patterns of calcification and fatty tissue
within a pulmonary nodule are highly suggestive of
a benign lesion.
Thin slices enable to better analyze the internal
structure of a nodule while thicker slices may ob-
scure fat or small calcifications due to partial vol-
ume effects. Those subtle features the benign na-
ture of a particular intrapulmonary nodule, e.g. a
hamartoma.
Histogram analysis may be useful to detect cal-
cifications or fat when present only in few voxels.
The number of voxels containing fat and calcium
densities as well as the overall density can be deter-
mined.
Appropriate histogram analysis can only be ob-
tained when thin slices are used so that major par-
tial volume effects are excluded whereas thick slices
would show average densities around soft tissue
values. The best way to obtain such histograms is
to apply the algorithm generating the histogram to
a segmented 3D-dataset. When using segmented
data, the histogram will contain only data from the
nodule. Using 3D-data ensures that the histogram
contains data from the entire nodule and not only
from individual slices in which relevant areas may
not be included. Generating segmented datasets and
applying them to histogram analysis require dedi-
cated software that is not yet implemented in stand-
ard PACS environments.
92 C. Becker, A. Graser, and P. Herzog
The segmentation of 3D-datasets is a mathemati-
cal process that divides the dataset in areas with the
same properties. When segmenting pulmonary nod-
ules, each voxel of the dataset is evaluated and clas-
sified as either being part of the nodule or not. In this
process, the greyscale image data are transformed
into a binary image (2 value image). The algorithm
determines the borders (surface) of the nodule based
on HU-values of the individual voxel. For this rea-
son the segmentation process is primarily based on
a thresholding processes. A threshold of 200 HU
has proven to be most efficient for the segmentation
of round pulmonary lesions. While a solid soft tis-
sue mass has higher HU-values than -200 HU (most
commonly around 70–80 HU if not calcified), even
with thin slice isometric data a higher threshold
would cause underestimation of the nodule size or
shape due to partial volume effects. This algorithm,
of course, can only segment a nodule that has no
contact to other non-nodular structures.
Therefore, the segmentation of lesions that are at-
tached either to vessels, bronchi or the pleura is a con-
siderable challenge for all segmentation algorithms.
Such structures should be identified and then sepa-
rated from the nodule. One possible solution is to use
an algorithm that aims at fitting a spherical outline
into each identified structure and reducing its radius
until both structures are separated. This method has
the disadvantage of changing the number of voxels
defining the nodule; thereby also changing the vol-
ume of the nodule. A more suitable method is to use a
morphological opening filter to smooth the surface of
a nodule and to eliminate structures connected to its
surface. This is a quite common method in digital im-
age processing but has not yet found widespread use
in the context of medical imaging. Using mathemati-
cal operators, irregularities of the contour are elimi-
nated by erosion and the “shrinking” of the volume is
compensated by a final dilatation procedure.
This, potentially, is a rather effective, albeit sim-
ple way of distinguishing nodules from surround-
ing structures and to eliminate the latter. This way,
most of the lesions attached to vessels, bronchi or
the pleura can be separated correctly. Other algo-
rithms have been developed and are already in the
process of clinical evaluation which may further
facilitate segmentation of pulmonary nodules from
surrounding structures (Kido et al. 2002).
With thin slice MDCT-data accurate CT-volum-
etry can be performed based on automated segmen-
tation algorithms as described above. Since growth
is the very hallmark of malignancy, such tools may
be the most suitable method for the non-invasive
characterization of lung lesions and help to avoid
unnecessary invasive procedures with the morbid-
ity and mortality inherent to it.
Whether lung cancer screening will be accept-
ed as a beneficial method to be recommended for
populations at increased risk of lung cancer largely
depends on its ability to reduce mortality and/or
morbidity at acceptable costs and harmful effects.
In order to achieve this, it is mandatory to reduce
radiation exposure as much as possible, to avoid in-
vasiveness in the work up of suspicious lesions and
to guarantee the highest possible accuracy in the
management of screened individuals.
6.2.4
Screening for Colon Cancer
CT colonography (CTC) has great potential of becom-
ing an important alternative technique to screen for
colorectal neoplasia. Imaging the colon traditionally
required use of an endoscope. Theoretically, con-
ventional video endoscopy allows for visualization
of the entire colon as well as removal of lesions for
histopathologic work up. Data from several centers
suggest that CTC surpasses barium enema and ap-
proaches conventional colonoscopy in the detection
of colorectal adenomas (Pickhardt et al. 2003; Yee
et al. 2001). In this chapter, technical prerequisites
for CT colonography will be summarized.
The arrival of multidetector row CT (MDCT) made
CT colonography faster and enabled screening for
small colonic lesions due to its superior spatial reso-
lution. Technical limitations of single slice CT, such
as long scanning times and poor resolution could be
overcome. Large volume coverage and thin collima-
tion at very short scan times of as little as 7–8 s per pa-
tient position has become reality with the introduction
of 64-MDCT scanners. In order to achieve ultra high
resolution, image reconstructions should be based
on overlapping sub-millimeter slices. The enormous
amount of data per examination has to be handled by
PACS and the 3D post-processing workstation. The im-
portance of image postprocessing and three-dimen-
sional image reconstructions has been emphasized by
several authors (Pickhardt et al. 2003; Vos et al. 2003;
Yasumoto et al. 2006). These technical prerequisites
will help to cut reading time and increase sensitivity as
opposed to evaluation of axial slices only.

Before CT data acquisition, the patient is required
to undergo certain preliminary steps to produce a
diagnostic study. Fundamental to the performance
of high quality CT colonography examinations is
complete cleansing colon and good distension of the
colon, thus allowing for optimum sensitivity and
specificity for polyp and cancer detection. Incom-
plete cleansing of the colon may result in false-nega-
tive and false positive readings. Poor distension of
the colon may cause missing of lesions and simulate
annular carcinoma (Fletcher et al. 1999). Current
CT colonographic protocols include scanning in su-
pine and prone positions so that segments of the co-
lon with poor cleansing or collapse in one position
can be re-evaluated in the opposing position.
6.2.4.1
Preparation of the Colon
Adequate bowel preparation is essential for accurate
CT colonography examinations. Residual fluid may
obscure polyps on two-dimensional and endolumi-
nal images. Residual solid stool may mimic a true
polyp and, if present in large quantities, obscure
polyps. Bowel preparation for CT colonography is
similar to that used for other total colon tests (air-
contrast barium enema and video colonoscopy) and
consists of two parts: limiting oral intake to clear
liquids or a low-residue diet starting 24 h before
the test and ingestion of a cathartic or laxative that
promotes evacuation of colonic contents. Saline ca-
thartics such as sodium phosphate (phospho-soda)
and magnesium citrate are highly osmotic agents
that contain inorganic ions that remain within the
small bowel lumen and increase intra-luminal fluid,
which subsequently induces peristalsis and evacua-
tion. While sodium phosphate has been reported to
cause electrolyte shifts preventing its use in patients
with impaired renal function and cardiac insuffi-
ciency, this is not the case with magnesium citrate.
Electrolyte lavage preparations in a non-absorb-
able medium such as polyethylene glycol are ad-
ministered in large volumes for colonic cleansing.
Mixtures of these different cleansing agents can be
administered in order to add their laxative effects.
At our department, preparation for CT colonogra-
phy consists of orally ingestion of four bisacodyl
tablets (5 mg each) as well as 3–4 L of polyethylene
glycol solution the day before CTC. Polyethylene gly-
col is a highly effective at cleansing the bowel but
may leave some residual fluid behind. Therefore,
Technical Prerequisites: CT 93
this preparation is called “wet prep”. Combining
PEG with bisacodyl increases bowel peristalsis and
may help reducing these residues.
Studies comparing the efficacy of oral sodium
phosphate and polyethylene glycol electrolyte so-
lutions before fiberoptic colonoscopy have found
no significant difference in the quality of bowel
cleansing between these two agents (Afridi et al.
1995; Marshall et al. 1993) or that sodium phos-
phate is more effective than the lavage solution
(Cohen et al. 1994).
6.2.4.2
Colonic Distension
Adequate distension of the colon for CT colonogra-
phy is equally important as proper bowel cleansing
to achieve diagnostic images of the colonic lumen
on CT colonography. Poorly distended or collapsed
segments of colon make it difficult to detect polyps
and may mimic colon carcinomas that narrow the
lumen. Atmospheric air can be instilled into the
colon with the patient in decubitus position on the
scanner table using a rectal enema tip connected to
an insufflator bulb or 100-mL syringes, the latter of-
fering the advantage of providing the exact amount
of air instilled.
Although there are individual differences in co-
lonic volume, approximately 2 L of air is generally
required for adequate distension of the entire colon.
After repositioning into the supine position, a scout
image of the abdomen and pelvis is acquired and
additional air may be insufflated if the entire colon
is not well distended. After data acquisition in the
supine position, the patient is placed into the prone
position, another scout image is obtained, and addi-
tional air insufflation is administered, if needed.
In most institutions, room air is used for colonic
distension because it is readily available. Room air
is composed of approximately 80% of nitrogen and
therefore there is no diffusion gradient across the
colonic wall. Occasionally, patients will develop se-
vere abdominal pain which may last several hours
after the end of the CTC examination. In contrast
to room air, carbon dioxide is absorbed at least 35
times faster by the colonic wall due to the steep dif-
fusion gradient. Studies comparing room air and
carbon dioxide for colonic distension described a
significant reduction of abdominal pain and cramp-
ing. Due to its constant diffusion through the colon-
ic wall CO2 should be administered by automated,
94 C. Becker, A. Graser, and P. Herzog
continuous insufflation using a dedicated device
(Burling et al. 2006). Distension will be better us-
ing an automated CO2 insufflator. Moreover, there is
less risk of complications as the maximum pressure
is limited by the device and there is no interaction
with the insufflation process.
The use of hyoscine-N-butylbromide (buscopan;
not FDA approved), an anticholinergic drug, or glu-
cagon for CTC has been investigated. Rogalla et al.
found that buscopan significantly improves colonic
distension as compared to glucagon, and that gluca-
gon helps to distend the colon as compared to proto-
cols without pre-medication (Rogalla et al. 2005).
6.2.4.3
Stool and Fluid Tagging
Currently patients are required to undergo a full
bowel cleansing regimen before CT colonography.
Reportedly, this is the most tedious part of the en-
tire examination (Lefere et al. 2002). However, in-
vestigators have made significant progress in iden-
tifying methods to label residual fluid and stool
with positive oral contrast agents so that there is
easier differentiation from the homogeneous soft
tissue density of polyps. This technique has been
evaluated with and without use of colonic cleans-
ing agents. However, the goal is to eventually com-
pletely eliminate the need for a cathartic agent,
which should lead to increased patient acceptance
of CT colonography. Once residual fluid and stool
are tagged with a positive contrast agent, electronic
subtraction of the high-density material may then
be performed.
A recent study suggests that the sensitivity of
CTC with a “minimal prep” protocol may be almost
equal to studies performed with full bowel prepara-
tion (Iannaccone et al. 2004) with high per-patient
sensitivity and specificity of around 90% and a 95%
sensitivity for polyps > 8 mm in size.
In summary, CT colonography may play an im-
portant role in colorectal cancer screening. Its ac-
ceptance will depend on reduced preparation proto-
cols and use of carbon dioxide rather than room air
for colonic distension. Radiation exposure is also a
critical issue for the acceptance of this modality. In
addition, clinical trials are still needed to prove that
recent encouraging results can be reproduced.
The high intrinsic density difference between co-
lonic wall and lumen can be used for low dose scan-
ning. At our institution, standard settings are a tube
current of 120 kV and mAs settings of 100 mAs (su-
pine position) and 40 mAs (prone position). In addi-
tion, sophisticated x, y, and z-axis dose modulation
algorithms allow for further reduction of radiation
exposure by 35% (Graser et al. 2006).
CT colonography is dealing with a high-contrast
situation, namely the contrast between the air or CO2
within the lumen at 1000 Hounsfield Units (HU)
and the colonic wall itself which normally measures
around 40–50 HU. Therefore, scans can be acquired
using low dose settings.
References
Afridi SA, Barthel JS, King PD, Pineda JJ, Marshall JB (1995)
Prospective, randomized trial comparing a new sodium
phosphate-bisacodyl regimen with conventional PEG-ES
lavage for outpatient colonoscopy preparation. Gastroin-
test Endosc 41:485–489
Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Via-
monte M, Detrano R (1990) Quantification of coronary
artery calcium using ultrafast computed tomography. J
Am Coll Cardiol 15(4):827–832
Becker CR, Jakobs TF, Aydemir S et al. (2000) Helical and
single-slice conventional CT versus electron beam CT for
the quantification of coronary artery calcification. AJR
Am J Roentgenol 174(2):543–547
Boyd D (1983) Computerized transmission tomography of
the heart using scanning electron beams. In: Higgins C
(ed) CT of the heart and the great vessels: experimental
evaluation and clinical application. Futura Publishing
Company, Mount Kisco, New York
Burling D, Taylor SA, Halligan S et al. (2006) Automated
insufflation of carbon dioxide for MDCT colonography:
distension and patient experience compared with manual
insufflation. AJR Am J Roentgenol 186:96–103
Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P
(1998) Coronary artery disease: improved reproducibility
of calcium scoring with an electron-beam CT volumetric
method. Radiology 208(3):807–814
Carr JJ, Nelson JC, Wong ND et al. (2005) Calcified coronary
artery plaque measurement with cardiac CT in popula-
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study of atherosclerosis (MESA) and coronary artery risk
development in young adults (CARDIA) study. Radiology
234(1):35–43
Cohen SM, Wexner SD, Binderow SR et al. (1994) Prospec-
tive, randomized, endoscopic-blinded trial comparing
precolonoscopy bowel cleansing methods. Dis Colon
Rectum 37:689–696
Fletcher JG, Johnson CD, MacCarty RL, Welch TJ, Reed
JE, Hara AK (1999) CT colonography: potential pitfalls
and problem-solving techniques. AJR Am J Roentgenol
172:1271–1278
Flohr T, Ohnesorge B (2001) Heart rate adaptive optimiza-
tion of spatial and temporal resolution for electrocardio-

gram-gated multislice spiral CT of the heart. J Comput
Assist Tomogr 25(6):907–923
Graser A, Wintersperger BJ, Suess C et al. (2006) Dose reduc-
tion and image quality in CT colonography using tube
current modulation. AJR Am J Roentgenol 187:695–701
Hernigou A, Challande P, Boudeville JC, Sene V, Grataloup
C, Plainfosse MC (1996) Reproducibility of coronary cal-
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Huda W (2002) Dose and image quality in CT. Pediatr Radiol
32(10):709–713; discussion 51–54
Iannaccone R, Laghi A, Catalano C et al. (2004) Computed
tomographic colonography without cathartic preparation
for the detection of colorectal polyps. Gastroenterology
127:1300–1311
Jakobs TF, Becker CR, Ohnesorge B et al. (2002) Multislice
helical CT of the heart with retrospective ECG gating:
reduction of radiation exposure by ECG-controlled tube
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(2002) Fractal analysis of small peripheral pulmonary
nodules in thin-section CT: evaluation of the lung-nodule
interfaces. J Comput Assist Tomogr 26(4):573–57
Lefere PA, Gryspeerdt SS, Dewyspelaere J, Baekelandt M, van
Holsbeeck BG (2002) Dietary fecal tagging as a cleansing
method before CT colonography: initial results polyp de-
tection and patient acceptance. Radiology 224:393–403
Marshall JB, Pineda JJ, Barthel JS, King PD (1993) Prospec-
tive, randomized trial comparing sodium phosphate solu-
tion with polyethylene glycol-electrolyte lavage for colon-
oscopy preparation. Gastrointest Endosc 39:631–634
McCollough CH, Ulzheimer S, Halliburton SS, White RD,
Kalender WA (2003) A multi-scanner, multi-manufac-
turer, international standard for the quantification of
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coronary artery calcium using cardiac CT. Radiology
229(P):630
Ohnesorge B, Flohr T, Fischbach R et al. (2002) Reproducibil-
ity of coronary calcium quantification in repeat examina-
tions with retrospectively ECG-gated multisection spiral
CT. Eur Radiol 12(6):1532–1540
Pickhardt PJ, Choi JR, Hwang I et al. (2003) Computed
tomographic virtual colonoscopy to screen for color-
ectal neoplasia in asymptomatic adults. N Engl J Med
349:2191–2200
Rogalla P, Lembcke A, Ruckert JC et al. (2005) Spasmolysis
at CT colonography: butyl scopolamine versus clucagon.
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Schmermund A, Rensing BJ, Sheedy PF, Bell MR, Rumberger
JA (1998) Intravenous electron-beam computed tomo-
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coronary artery stenosis. Am J Cardiol 31:1547–1554
Swensen SJ (2002) CT screening for lung cancer. AJR Am J
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Ulzheimer S, Kalender WA (2003) Assessment of calcium
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Vos FM, van Gelder RE, Serlie IW et al. (2003) Three-dimen-
sional display modes for CT colonography: conventional
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Yasumoto T, Murakami T, Yamamoto H et al. (2006) As-
sessment of two 3D MDCT colonography protocols for
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SD, McQuaid KR (2001) Colorectal neoplasia: perform-
ance characteristics of CT colonography for detection in
300 patients. Radiology 219:685–692
 Technical Prerequisites: Ultrasound 97

Technical Prerequisites 6
6.3 Ultrasound
Stefan Delorme

CONTENTS The interaction between tissue and ultrasound

depends on the size of objects, and the differences
in acoustical impedance found in the tissue. Objects
6.3.1 General Considerations 97 which are significantly larger in diameter than one
6.3.1.1 Physical Principles 97 wavelength, which ranges between 0.4 mm with
6.3.1.2 Sensitivity Issues 97
6.3.1.3 Specificity 98 3.5 MHz (which is most commonly used in the
6.3.1.4 Documentation 98 abdomen), and 0.2 mm with 7 MHz (e.g. for thyroid,
breast, lymph nodes, or testes), will cause a directed
6.3.2 Specific Requirements 98 reflection. Any objects within the range of a wave-
length will cause scattering of the sonographic pulse,
References 99
i.e., a rather undirected reflection. In most organs,
scattering, some degree of reflection, and acoustical
absorption together cause a “speckle” pattern. Each
of these speckles do not represent single objects;
6.3.1 rather they are the result of a complex interaction
General Considerations of these three mechanisms and thereby a somewhat
stochastic process. Nevertheless, the speckle pattern
Ultrasound, as a non-invasive technique without is often characteristic of the tissue, and the bright-
any radiation exposure, appears as a very attractive ness, particularly, is determined mainly by the size of
technique to examine healthy individuals. This is the scattering objects, and the difference in acoustic
not only fostered by rumor or reports in the non- impedance between them and their surroundings.
medical press, but also by medical professionals.
Yet, some in-borne limitations of ultrasound need
to be clearly addressed. 6.3.1.2
Sensitivity Issues

6.3.1.1 As a result of the above, for a structure to become

Physical Principles
First, ultrasound is notoriously limited to examin-
ing organs which are hidden neither by air nor bone
– with the only exception of the basal cerebral arter-
ies. Here, the thin squama of the temporal bone
acts like a membrane and thereby as an acoustic
conductor.
S. Delorme, MD
Professor, Department of Radiology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120
Heidelberg, Germany
visible with ultrasound, it must be large enough
– the threshold is determined by the transmitted
frequency. It must also differ sufficiently from its
surroundings. Either it needs to be reflecting as a
whole (such as a calcification, a vessel, a cyst wall,
etc.) or its microstructure must be different from
that of its surrounding, in a way that it appears either
brighter or darker.
These shortcomings are well illustrated by stud-
ies on the detection of liver metastases using ultra-
sound (Wernecke et al. 1991). First, sonography
suffers from problems with difficult access, such
as in obese patients, which will inevitably make it
98 S. Delorme
perform worse than CT or MRI. Second, ultrasound
performs particularly badly for small metastases,
detecting less than 30%. This is not only a matter
of size, but likewise of contrast. This is nicely dem-
onstrated by recent studies with contrast-enhanced
ultrasound, the sensitivity of which is very well com-
parable with that of CT – simply by increasing the
echogenicity of liver, but not of metastases (Giorgio
et al. 2004; Konopke et al. 2005; Passamonti et al.
2005; Quaia et al. 2003).
6.3.1.3
Specificity
Whenever lesions are seen, this does not neces-
sarily mean that these are relevant. As a matter of
fact, when in a screening setting (i.e., in a healthy
individual) a nodule is seen in the thyroid or liver,
this lesion is very probably clinically irrelevant,
and additional studies may be necessary (e.g.,
scintigraphy and fi ne needle aspiration for thy-
roid nodules, contrast-enhanced CT or MRI for
the liver). In other organs, such as the kidney,
any non-liquid lesion is very probably malignant,
unless CT proves a high fat content indicative of
angiomyolipoma.
6.3.1.4
Documentation
Ultrasound is inherently examiner-dependent and
hard to document. With contemporary equipment,
the possibilities to store large amounts of images,
clips, or fi lms in real time are no more limited. In
smaller organs with rather simple access (e.g., thy-
roid, testes), storing an entire clip of a sweep across
them is possible, and makes sense. A previously
stored clip may help to check retrospectively whether
a seemingly newly detected lesion was simply missed
at a previous scan. This may, however, be much more
difficult to realize for the liver or kidneys, for which
often many views from different points of access are
needed. In the breast, although easy to access, such
sweeps are reproducible to only a limited degree,
because the organ is deformed by the transducer
as it is moved on the skin. There are guidelines for
documentation of standard image sets in order to
ensure at least some degree of reproducibility. In
the thyroid, for example, each lobe is documented
in two planes, and so is every nodule. In the liver,
there are also recommendations of standard sec-
tions together with key structures.
Still, three issues remain:
● How to document healthy organs
● How to document uncountable lesions exten-
sively (thyroid nodules, breast cysts, liver cysts,
etc.)
● How, in the latter case, to document their loca-
tion well enough to make them easy to retrieve
at follow-up
It has to be borne in mind that however extensive
documentation may be, it will be incomplete. Any
views that documentation of healthy organs serves
no good, however, are to be strongly objected to. At
the very least, documentation tells about the exami-
nation condition, the skill of the examiner, and
finally his willingness to examine thoroughly and
systematically.
6.3.2
Specific Requirements
For scanning carotid arteries, a dedicated trans-
ducer for vascular studies is required. The transmit
frequency in B-mode should be 7 MHz or, favora-
bly, above. If the transducer can also be switched to
lower frequencies, it may also be used for the lower
extremities, particularly for the adductor canal. In
any case, a color and spectral Doppler option is
mandatory, with transmit frequencies lower than
5 MHz (usually 3.5 or 2.5 MHz). Low frequencies are
required because of high flow velocities, particularly
in stenoses, and because calcified plaques may be
present. In the adductor canal, again the absorption
is high, and the long distance between transducer
and the femoral artery warrants a low transmit fre-
quency, in order to avoid aliasing. Usually, transduc-
ers for vascular ultrasound are linear arrays about
3–4 cm long. Probes with a larger field of view may
provide a better overview, but may be difficult to
handle in the neck, particularly in patients with
short necks and with impaired mobility.
When screening for malignant tumors, the equip-
ment depends mainly on the location of the organ of
interest. Superficial organs (breast, thyroid, lymph
nodes, testes) require transmit frequencies of 7 MHz
and above – contemporary high-end units oper-
ate at 10–15 MHz. A field of view of 5 cm or above

is mandatory for the breast, and advantageous for
thyroid, lymph nodes, or testes. A color Doppler
option, although not mandatory, may be of help in
individual cases, and is usually already available on
advanced scanners.
Intracavitary devices are occasionally used for
screening purposes, particularly for cancer of the ova-
ries or the prostate. Here, by nature, either mechani-
cal sector scanners are used, or tightly curved arrays
with a highly divergent field of view. The scanning
frequencies range between 5 and 10 MHz.
For the abdomen, curved probes with a frequency
range between 1.5 and 6 MHz are typically used.
Sector scanners may be a useful adjunct in patients
who are difficult to scan, but the resulting images
are poor for the near field. Linear probes are insuf-
ficient for the majority of cases, because of their lim-
ited field of view in the far field, but may occasionally
be helpful for assessing lesions close to the surface.
Ultrasound has been shown to be helpful in detect-
ing hepatocellular carcinomas (HCC) in patients at
risk (i.e., with liver cirrhosis, or hepatitis C), par-
ticularly in combination with measuring serum
alpha-fetoprotein. The missing rate in cirrhotics,
however, is notoriously high (Dodd et al. 1992), and
it is unproven whether lives are actually saved.
Whether or not ultrasound contrast agents should
be used is difficult to judge at the present stage.
Compared to unenhanced ultrasound, they have
under clinical conditions significantly improved
the detection of primary or metastatic liver tumors
(Hohmann et al. 2003; Oldenburg et al. 2005),
while their value in screening still needs to be evalu-
ated in a prospective, controlled fashion. However,
to detect primary tumors in cirrhotic livers is noto-
riously so difficult that, in the near future, wherever
the costs are covered, contrast agents will probably
be given for screening, be their value proven or not.
Ultrasound, simply by being done for a variety of
indications, has completely changed the picture for
renal cell carcinoma (RCC). Formerly almost always
associated with a dismal prognosis, the majority of
RCC is today detected incidentally (Porena et al.
1992; Terada et al. 1989), and in a limited stage with
a definite chance for cure (Porena et al. 1992). Again,
a conventional curved array as used for abdominal
routine scanning is sufficient. Ultrasound contrast
media may help to clarify doubtful cases but have so
far no place in screening.
Technical Prerequisites: Ultrasound 99
Ultrasound is already in wide use for pre- and
postnatal screening for various abnormalities. For
transabdominal examinations of the pregnant,
curved arrays are most commonly used, like for
other abdominal studies. However, with the amni-
otic fluid as an acoustic window, less absorption is
encountered, and higher transmit frequencies can
be used. Postnatal, abdominal scans require high-
frequency curved arrays; the hip is usually scanned
with a linear probe at 5 MHz or above.
References
Dodd GD, Miller WJ, Baron RL, Skolnick ML, Campbell WL
(1992) Detection of malignant tumors in end-stage cir-
rhotic livers: efficacy of sonography as a screening tech-
nique. AJR Am J Roentgenol 159:727–733
Giorgio A, Ferraioli G, Tarantino L et al. (2004) Contrast-
enhanced sonographic appearance of hepatocellular
carcinoma in patients with cirrhosis: comparison with
contrast-enhanced helical CT appearance. AJR Am J
Roentgenol 183:1319–1326
Hohmann J, Skrok J, Puls R, Albrecht T (2003) Charakterisie-
rung fokaler Leberläsionen mit kontrastmittelgestütztem
„low MI real-time“ Ultraschall und SonoVue. Fortschr
Röntgenstr 175:835–843
Konopke R, Kersting S, Saeger HD, Bunk A (2005) Kontrast-
mittelsonographie in der Detektion von Leberraumfor-
derungen - Vergleich zum intraoperativen Befund. Ultra-
schall Med 26:107–113
Oldenburg A, Hohmann J, Foert E et al. (2005) Detection
of hepatic metastases with low MI real time contrast
enhanced sonography and SonoVue(R). Ultraschall Med
26:277–284
Passamonti M, Vercelli A, Azzaretti A, Rodolico G, Calliada
F (2005) Characterization of focal liver lesions with a new
ultrasound contrast agent using continuous low acoustic
power imaging: comparison with contrast enhanced
spiral CT. Radiol Med (Torino) 109:358–369
Porena M, Vespasiani G, Rosi P et al. (1992) Incidentally
detected renal cell carcinoma: role of ultrasonography.
J Clin Ultrasound 20:395–400
Quaia E, Bertolotto M, Forgacs B, Rimondini A, Locatelli M,
Mucelli RP (2003) Detection of liver metastases by pulse
inversion harmonic imaging during Levovist late phase:
comparison with conventional ultrasound and helical CT
in 160 patients. Eur Radiol 13:475–483
Terada Y, Ueki T, Horiuchi D (1989) A study on six cases of
renal cell carcinoma detected by renal ultrasound during
health screening. Nippon Jinzo Gakkai Shi 31:783–790
Wernecke K, Rummeny E, Bongartz G et al. (1991) Liver meta-
stasis detection: comprative sensitivites of US. CT and
MR imaging for preoperative ecaluation. 1(Suppl):169
 Technical Prerequisites: Mammography 101

Technical Prerequisites 6
6.4 Mammography
Rüdiger Schulz-Wendtland

CONTENTS
6.4.1 Technical Prerequisites for
Mammography Screening Exams 101
6.4.1.1 Quality Control (QC) 101
6.4.1.2 QC Measurements and Frequencies 102
6.4.2 Role of Conventional and
Digital Mammography 102
6.4.2.1 Digital Mammography System with
FDA Licence 104
6.4.2.1.1 Senographe 2000 D (GE Medical Systems,
Waukesha, USA) 104
6.4.2.1.2 SenoScan (Fischer Imaging, Denver,
USA) 104
6.4.2.1.3 LDBI (Hologic/Lorad, Bedford,
USA) 104
6.4.2.1.4 Selenia (Hologic/Lorad, Bedford, USA),
Novation (Siemens, Erlangen, Deutschland),
Digital Mammography Systems
Manufactured by Agfa, Instrumentarium,
Giotto 104
6.4.2.1.5 FCR 5000MA (Fujifi lm, Tokyo, Japan;
Siemens, Erlangen, Deutschland) 104
6.4.3 Results from Clinical Studies 104
6.4.3.1 Results from Senographe 2000 D
(GE Medical Systems, Waukesha,
USA) 104
6.4.3.2 Results from SenoScan (Fischer Imaging,
Denver, USA) and LDBI (Hologic/Lorad,
Bedford, USA) 105
6.4.3.3 Results from Selenia (Hologic/Lorad,
Bedford, USA), Novation (Siemens,
Erlangen, Deutschland), Digital
Mammography Systems Manufactured by
Agfa, Instrumentarium, Giotto 106
6.4.3.4 Results from FCR 5000MA (Fujifi lm,
Tokyo, Japan; Siemens, Erlangen,
Deutschland) 106
6.4.4 Soft Copy Reading 106
6.4.1
Technical Prerequisites for Mammography
Screening Exams
Screening for breast cancer by means of mammog-
raphy has been proven to reduce mortality from
breast cancer.
This was only possible by standardisation – the
European guidelines for quality assurance in breast
cancer screening and diagnosis (Commission of
the European Communities 2006).
A prerequisite for a successful screening is that
the mammograms contain sufficient diagnostic
information to be able to detect breast cancer, using
as low a radiation dose as is reasonably achievable
(ALARA). This quality demand holds for every
single mammogram. Quality control (QC) must
therefore ascertain that the equipment performs at
a constant high quality level.
In the framework of “Europe Against Cancer”
(EAC) (Commission of the European Communi-
ties 2003), an European approach for mammog-
raphy screening is chosen to achieve comparable
high quality results for all centres participating in
the mammography screening programme. Within
this programme, quality assurance (QA) takes into
account the medical, organisational and technical
aspects.
The technical prerequisites include the basic test
procedures, dose measurements and their frequen-
cies. The use of these tests and procedures is essen-
tial for ensuring high quality mammography and
enables comparison between centres – a minimum
standard for implementation throughout the EC
Member States.

6.4.5 CAD 106

R. Schulz-Wendtland, MD
6.4.6 Discussion 106 Professor, Radiologisches Institut, Gynäkologische Radiologie,
Universität Erlangen-Nürnberg, Universitätsstrasse 21–23,
References 109 91054 Erlangen, Germany
102 R. Schulz-Wendtland
6.4.1.1
Quality Control (QC)
Mammography screening should only be performed
using modern dedicated X-ray equipment and
appropriate image receptors.
QC of the physical and technical aspects in
mammography screening starts with specification
and purchase of the appropriate equipment, meet-
ing accepted standards of performance. Before the
system is put into clinical use, it must undergo
acceptance testing to ensure that the performance
meets these standards. This holds for the mammog-
raphy X-ray equipment, image receptor, fi lm pro-
cessor, viewing device and QC test equipment. After
acceptance, the performance of all equipment must
be maintained above the minimum level and at the
highest level possible.
The QC of the physical and technical aspects must
guarantee that the following objectives are met:
• The radiologist is provided with images that have
the best possible diagnostic information obtain-
able when the appropriate radiographic technique
is employed. The images should at least contain
the defined acceptable level of information, nec-
essary to detect the smaller lesions.
• The image quality is stable with respect to infor-
mation content and optical density and consis-
tent with that obtained by other participating
screening centres.
• The breast dose is As Low As reasonably Achiev-
able (ALARA) for the mammographic informa-
tion required.
6.4.1.2
QC Measurements and Frequencies
To attain these objectives, QC measurements should
be carried out. Each measurement should follow a
written QC protocol that is adapted to the specific
requirements of local or national QA programmes.
The European protocol for the Quality Control of
the Physical and Technical Aspects of Mammog-
raphy Screening (Commission of the European
Communities 1999) gives guidance on individual
physical, technical and dose measurements, and
their frequencies, that should be performed as part
of mammography screening programmes.
Image quality and breast dose depend on the
equipment used and the radiographic technique
employed. QC should be carried out by monitoring
the physical and technical parameters of the mam-
mographic system and its components. The follow-
ing components and systems parameters should be
monitored:
• X-ray generator and exposure control system
• Bucky and image receptor
• Film processing (for screen-fi lm systems)
• Image processing (for digital systems)
• System properties (including dose)
• Monitors and printers (for digital systems)
• Viewing conditions
The probability of change and the impact of a
change on image quality and on breast dose deter-
mine the frequencies at which the parameters should
be measured. The protocol also gives the acceptable
and achievable limiting values for some QC param-
eters. The acceptable values indicate the minimal
performance limits. The achievable values indicate
the limits that are achievable. Limiting values are
only indicated when consensus on the measurement
method and parameter values has been obtained.
In conclusion: to receive the results in mammog-
raphy screening, the reduction of mortality of 35%
in the group age 50–69 years, it is necessary to have
high level standardisation, especially in view of the
technical prerequisites:
• European Guidelines for Quality Assurance in
Breast Cancer Screening and Diagnosis (Commis-
sion of the European Communities 2006)
• Europe Against Cancer (Commission of the
European Communities 2003)
• European Protocol for the Quality Control of the
Physical and Technical Aspects of Mammogra-
phy Screening (Commission of the European
Communities 1999)
6.4.2
Role of Conventional and Digital
Mammography
For many years, almost all types of diagnostic radi-
ology have had digital imaging technology at their
disposal, but no adequate digital alternative was
available for traditional screen fi lm mammography
(SFM) (Bick 2000; Feig and Yaffe 1998; Grabbe et
al. 2001; Hermann et al. 2002a; Säbel et al. 1999).
Even in “fi lmless” hospitals, mammographies were
performed in the traditional manner. The reason is

that mammography has special requirements vis-à-
vis the quality of images, and digital imaging meth-
ods are not capable of meeting these requirements
just like that. Traditional screen fi lm mammography
is – so far – the only imaging technique that has
led to a reduction in breast cancer mortality when
uses as a regular screening tool (Schreer 2001).
Its advantages include its comparatively low costs,
a high resolution in the high contrast area (up to
20 lp/mm), and easy viewing on a viewbox. In addi-
tion to having to find a compromise between defi-
nition and exposure, the disadvantage of the SFM
imaging system includes its low effective quantum
efficiency (DQE). Owing to the sigmoid gradation
curve of conventional screen fi lm system, each
system can be usefully employed only when radia-
tion dosages are clearly defined.
The information conveyed by a radiograph is
best described with the so-called signal to noise
ratio (SNR). This ratio depends on the radiation
dose and the quantum flow that was used to obtain
the image, but also on the structural attributes of
the imaging system. The DQE is a further impor-
tant measure to gauge the capacity of a mammog-
raphy system by indicating how effectively the SNR
or the information contained in the radiograph
– produced by X-rays that have passed through the
breast – is transferred on to the mammogram. The
ideal is a transfer ratio of 1:1, i.e. a DQE of 100%.
Real equipment, however, is not capable of such
high effectivity, owing to noise and other processes
that reduce the contrast. The resulting quality of the
image is therefore always reduced, and the DQE falls
to less than 100%. The reduction in the SNR results
in an inferior assessment (visualization?) of small
details in the breast, such as microcalcifications.
The DQE is dependent on the radiation dose and
the local frequency. With the same dose, a system
with a high DQE produces images with less noise, or
it produces images of equal quality with a smaller
radiation dose than a system with a lower DQE. The
DQE enables objective comparison between differ-
ent radiographical imaging systems on the basis of
the image quality and dose efficiency. Currently no
standardised procedures exist to determine the DQE
for mammography imaging systems, and especially
not for complete mammography workstations with
a complete set of components, including images
viewers. The DQE values provided by manufactur-
ers of digital mammography systems can therefore
not be compared and can be used only as approxi-
mate information.
Technical Prerequisites: Mammography 103
In digital mammography, conventional screen
film mammography is replaced by an electronic
detector that absorbs the incoming X-rays and pro-
duces an electric signal. This signal is digitalised in
an analogue-to-digital converter and can therefore
be processed and stored on a computer. In conven-
tional film screen mammography, the entire imaging
process is linked to the radiograph, whereas in digi-
tal radiography, the actual imaging is split into three
steps: recording, processing, and reproduction. This
means that each individual step can be optimised,
and in addition an opportunity arises for electronic
imagine transfer in the sense of teleradiology. A digi-
tal mammogram consists of a finite number of pixels,
which are arranged in a two-dimensional image
matrix. The distance between two adjacent pixels is
known as the sampling frequency or, more gener-
ally, as the pixel size. The grey value of each individ-
ual pixel is quantified – i.e., represented by a finite
number of signals. These values range from 0 to 2n–1,
with n equalling the number of bits that are used to
digitalise the variation of the analogue signal in the
detector. Systems than can be used for mammogra-
phy capture the data with a depth of up to 16 bit/pixel,
equalling 216 = 65,536 shades of grey. The greater the
number of pixels and shades of grey, the greater the
storage requirement of an individual mammogram.
The digital mammography systems that are cur-
rently licensed by the US Food and Drug Adminis-
tration achieve a resolution of 5–12.5 lp/mm (max)
to reach the very high resolution of conventional
fi lm screen mammography (of up to 20 lp/mm). Dig-
ital detectors would have to have a maximum pixel
size of 25 µm, which would mean an image matrix of
7200 × 9600 = 69.1 million pixels for a detector area
for 18 × 24 cm2. Nishikawa et al. (1987), however,
found in 1987 that the detection of critical struc-
tures is limited more by an SNR that is too low and
has too little contrast than by the resolution of the
digital imaging system. In spite of this finding, the
quality of resolution and its importance in assessing
a digital mammography system were the centre of
technical discussions for a long time. At an Euro-
pean level, work is being done on an addendum to
the section covering “digital mammography” in the
European protocol for Quality control of the physi-
cal and technical aspects of mammography screen-
ing (EPOQ), to introduce the threshold contrast vis-
ibility as the crucial measure of image quality. The
lower requirements vis-à-vis local contrast visibility
for digital mammography systems are being justi-
fied with the fact that lesions are detected because
104 R. Schulz-Wendtland
of their contrast against their background and that
contrast visibility or other functions of transmission
that use contrast are a more appropriate measure
than the modulation transfer function used by fi lm
screen systems or the threshold frequency of visual
perception that is derived from it (Commission of
the European Communities 2006). The contrast
resolution is determined as the smallest radiologi-
cal contrast that produces a visible difference in the
image for an image detail of a particular size.
Two types of digital mammography systems have
to be distinguished: plate-based (offline) and inte-
grated (online) imaging systems. Off-line systems
include storage devices (plates, etc) that can be used
with any conventional mammography equipment if
the exposure variables are selected accordingly. Inte-
grated imaging systems are installed into each indi-
vidual mammography system and cannot be moved.
Further distinction has to be made between full-field
systems and scanning systems. Full-field detection
are exposed like a film screen system, whereas in
the case of scanning systems, an array of detectors is
moved very slowly across the area that is to be imaged,
and the X-rays are sent through a slot and therefore
limited to the width of the row of detectors.
6.4.2.1
Digital Mammography System with FDA Licence
6.4.2.1.1
Senographe 2000 D
(GE Medical Systems, Waukesha, USA)
The digital mammography system Senographe
2000 D manufactured by GE Medical Systems uses
a flat panel digital detector of 19 × 23 cm2. The detec-
tor is based on a semiconductor layer from amor-
phous silicon (Busch 1999; Neitzel 2003; Schulz
2001) (Table 6.4.1).
6.4.2.1.2
SenoScan (Fischer Imaging, Denver, USA)
The digital mammography system SenoScan man-
ufactured by Fischer Imaging uses a “slot scan”
detector measuring 1 × 22 cm2 and consisting of four
charge coupled devices (CCDs), using a default pixel
size of 54 µm. CCD technology uses a particular
attribute of silicon – namely, it converts incoming
light photons into mobile charge carriers (Busch
1999; Neitzel 2003; Schulz 2001) (Table 6.4.1).
6.4.2.1.3
LDBI (Hologic/Lorad, Bedford, USA)
The Lorad digital Breast Imager (LDBI) works with
a digital image acquisition system, which consists of
12 CCDs that are arranged in the form of a mosaic,
and that are coupled with a large scintillator plate
that is thallium doped caesium iodide. This receptor
covers an area of 18.6 × 24.8 cm2. Hologic is, how-
ever, not planning further marketing of the CCD-
based units but is concentrating its activities on the
flat panel digital detector consisting of amorphous
selenium (Busch 1999; Neitzel 2003; Schulz 2001)
(Table 6.4.1).
6.4.2.1.4
Selenia (Hologic/Lorad, Bedford, USA), Novation
(Siemens, Erlangen, Deutschland), Digital
Mammography Systems Manufactured by Agfa,
Instrumentarium, Giotto
The digital mammography system uses a 24 × 29 cm2
flat panel detector, which, instead of a scintillator,
has a semiconductor layer of amorphous selenium.
Selenium enables the direct conversion of X-rays
into electrical charge (Busch 1999; Neitzel 2003;
Schulz 2001) (Table 6.4.1).
6.4.2.1.5
FCR 5000MA (Fujifilm, Tokyo, Japan;
Siemens, Erlangen, Deutschland)
Fuji’s full-field mammography system FCR 5000MA
includes an image plate reader with a resolution of
50 µm for all mammography formats, with dual-
sided reading technology (Busch 1999; Neitzel
2003; Schulz 2001) (Table 6.4.1).
6.4.3
Results from Clinical Studies
6.4.3.1
Results from Senographe 2000 D
(GE Medical Systems, Waukesha, USA)
Obenauer et al. (2000a,b) and Fischer et al. (2002)
compared digital mammography (GE-System) and
conventional screen fi lm mammography in clinical
and control investigations and found comparable
 Technical Prerequisites: Mammography 105

Table 6.4.1. Digital mammography systems

Senographe 2000D SenoScan LDBI Selenia/Novation FCR 5000MA

Manufacturer GE Medical Systems Fischer Imaging Hologic/Lorad Hologic/Lorad Fujifi lm
Conversion material Scintillator Szintillator Scintillator Photoconductor Phosphor Storage
CsI:Tl CsI:Tl CsI:Tl aSe Screen
Detector material ASi 4 CCD 12 CCD aSi
(slot detector) (mosaic detector)
Pixel size 100 µm 50 µm 40 µm 70 µm 50 µm
(laser width)
Field of view 19 cm × 23 cm 2 21 cm × 29 cm 2 19 cm × 25 cm 2 24 cm × 29 cm 2 24 cm × 30 cm 2
(scan system)
DQE 42 50 55 65 45
a 5 lp/mm 10 lp/mm 12.5 lp/mm 7.1 lp/mm 10 lp/mm
Spatial resolution
Memory depth 14 Bit 12 Bit 14 Bit 12 Bit 10 Bit
FDA approval January 2000 September 2001 March 2002 October 2002 2004
a
The designated spatial resolution is the resulting Nyquist frequency from the given pixel size

results or slight superiority (not significant) of the
digital technique. Grebe et al. (2000) and Schulz-
Wendtland et al. (2002) also found no significant
differences between the two systems. In a com-
parative study of 692 female patients, Venta et al.
2001 found agreement of conventional fi lm screen
mammography and digital mammography in 82%,
part-agreement in 14%, and no agreement in 4% of
results, which they explained with interobserver
variability. Another study by Lewin et al. (2001)
that included 4945 female patients comparing con-
ventional and digital mammography and found a
total of 35 cases of breast cancer – the conventional
system detected 22 cases and the digital system
21 cases. The authors found no significant differ-
ence in the detection rate, but a lower recall rate in
digital mammography than in conventional mam-
mography (11.5% vs 13.8%, respectively). They did
not fi nd a significant difference in the rate of posi-
tive biopsies (19% vs 30%). Lewin et al. (2002) in a
study with 6736 patients whose condition was gen-
erally diagnosed through both imaging modalities,
found 42 malignancies in 181 biopsies, of which
15 were detected exclusively though conventional
mammography and only 9 through digital mam-
mography. They did not fi nd a significant differ-
ence in the detection rate for malignancy, but a
lower recall rate for digital mammography. The
study by Skaane et al. (2003) included 1832 women
who were examined with both techniques (addi-
tionally generally double reading) (Oslo I). The
authors did not fi nd significant differences in the
detection rate but a higher rate of air ingress and
average parenchymal dose for the digital system
than for the conventional system. This study has
met with substantial criticism with regard to dif-
ferent variables, and in addition the results are
diametrically opposed to those of Hermann et al.
(2000, 2002b), who found a dose reduction of 25%
for digital mammography compared with conven-
tional mammography. Skaane and Skjennald
(2004) published a further study (Oslo II) with
10,303 patients examined with conventional and
3985 patients with digital techniques. The detec-
tion rate of cancers was 0.54 and 0.83, respectively
– the results for the digital mammography were
significantly better. Skaane confi rmed this with a
learning curve of the investigators by working every
day with the digital mammography. This confi rms
that adequate training (2–3 months) with digital
mammography is required in order to achieve a
significantly higher accuracy, in contrast to con-
ventional screen fi lm mammography.
6.4.3.2
Results from SenoScan
(Fischer Imaging, Denver, USA) and
LDBI (Hologic/Lorad, Bedford, USA)
Studies with small-field detectors, such as the one
published by Undrill et al. (2000) i.e. full-field
106 R. Schulz-Wendtland
detectors of Schulz-Wendtland et al. (2003a,
2004) found, in phantom studies, significantly better
results in clarity of detail for the CCD technique as
well as fi lm screen mammography and digital sys-
tems with a Se or a Si detector, without significant
interobserver variability. Cole et al. 2004 found no
significant diagnostic differences between CCD and
conventional mammography techniques – a study
with six institutions and eight investigators and the
well known problems of inter- and intraobserver
variability.
6.4.3.3
Results from Selenia (Hologic/Lorad, Bedford,
USA), Novation (Siemens, Erlangen,
Deutschland), Digital Mammography Systems
Manufactured by Agfa, Instrumentarium, Giotto
Investigations with an amorphous selenium detec-
tor (phantom study) resulted in significantly better
results in clarity of detail for the digital system as
compared to conventional screen fi lm mammog-
raphy without significant interobserver variability
(Schulz-Wendtland et al. 2003b).
6.4.3.4
Results from FCR 5000MA (Fujifilm, Tokyo,
Japan; Siemens, Erlangen, Deutschland)
The available studies, among other by Schulz-
Wendtland et al. (2000, 2002b), show equivalence
of luminescence radiography and conventional
fi lm screen mammography and. significantly better
results (Ideguchi et al. 2004) of high resolution
luminescence mammography, respectively.
The results published by the Digital Mammogra-
phy Imaging Screening Trial (DMIST) Investigators
Group under the guidance of E. Pisano online in the
N Engl J Med (16.09.2005) (Pisano et al. 2005), the
only prospective, randomised clinical trial includ-
ing a total of 49,000 women, all examined with both
techniques (conventional screen fi lm mammogra-
phy and digital systems of different manufacturers)
separately evaluated in 11 institutions were: same
detection rate of cancer for all patients with signifi-
cantly better results for the digital mammography
systems in women under 50 years, radiologically
dense breasts and pre- and perimenopausal women,
respectively.
6.4.4
Soft Copy Reading
Soft copy Reading is possible with the same results
as hard copy reading; see European Guidelines
for Quality Assurance in Mammography Screen-
ing (EPOQ) (Commission of the European
Communities 2006).
6.4.5
CAD
CAD is the computer-assisted detection and diagno-
sis in mammography, respectively. The whole process
includes image acquisition, segmentation, post-pro-
cessing and detection. The following systems are on
the market: ImageChecker M 1000 (R2-Technology),
Second Look (CADx Medical Systems), Mammex
TR (Scanis Inc.) and iCad (Fischer) (Table 6.4.2). In
all these systems, conventional mammograms are
secondarily digitized, which is problematic. In the
literature, the detection rate of microcalcifications
is 86%–100% (Birdwell et al. 2001; Freer and
Ullssey 2001; Funovics et al. 2001), for lesions we
have sensitivities of 67%–89% (Freer and Ullssey
2001; Malich et al. 2001), spiculated lesions are
detected with a sensitivity of 100% (Kegelmeyer
et al. 1994). In double reading, CAD systems enable
the sensitivity of the investigators to be increased
by up to 20% (Jiang et al. 2001). Karssemeijer et al.
(2003) found that diagnostic accuracy of radiolo-
gists less experienced in mammography will profit
more from CAD than more experienced mammog-
raphers. In addition, the interobserver variability
has to be considered with 15%–90% (Jiang et al.
2001; Karssemeijer 2000). The problem with CAD
systems is the high number of false-positive markers
up to 95% (Bick 1996; Freer and Ullssey 2001).
6.4.6
Discussion
As of yet, few clinical studies have compared con-
ventional and digital mammography. Phantom and
 Technical Prerequisites: Mammography 107

Table 6.4.2. CAD-system

Imaging checkers Second look Mammex TR iCad

Manufacturer R2-Technology CADx medical Systems Scanis Inc. Fischer Imaging
Resolution 50 µm 43.5 µm No comments No comments
Time of post-processing 6–8 min 6 min No comments No comments
(four fi lms)
Evaluation Special alternator Every viewing station Every viewing station Every viewing station
every viewing station;
monitor
Result PC-monitor Paper PC-monitor/paper PC-monitor
Adaptation to full-field Yes Yes Yes Planned
digital mammography
systems
FDA Approval 1998 2002 No No

clinical studies indicate that luminescence radiog-

raphy with high resolution imaging plates (CR-M)
(Fuji/Siemens), digital full-field mammography (GE)
(using a digital amorphous silicon detector), digital
full-field mammography (Fischer) (digital CCD-
detector) and the digital full-field mammography
(Lorad, Siemens, Agfa, Instrumentarium, Giotto)
(digital amorphous selenium detector) are equal or
slightly superior to conventional film screen system
(Cole et al. 2004; Fischer et al. 2002; Grebe et
al. 2000; Hermann et al. 2000, 2002b; Ideguchi et
al. 2004; Lewin et al. 2001, 2002; Obenauer et al.
2000a,b; Pisano et al. 2005; Schulz-Wendtland a
et al. 2000, 2002a,b, 2003a,b, 2004; Skaane et al.
2003, 2004; Undrill et al. 2000; Venta et al. 2001)
(Figs. 6.4.1–6.4.3).
This will be confirmed by the study of Pisano,
published 16.09.2005 (N Engl. J Med) (Pisano et al.
2005).
Notably, however, both digital mammography
devices manufactured by Lorad (detector from amor-
phous selenium and CCD basis), the digital full-field
mammography system manufactured by Fischer
(digital CCD-detector), the device manufactured by
General Electric (digital amorphous silicon detector),
the digital unit of Siemens, Agfa, Instrumentarium, b
Giotta (digital amorphous selenium detector) and
digital mammography with high resolution lumines- Fig. 6.4.1a,b. Sixty year old postmenopausal client. ACR-
cence (Fuji, Siemens) have been licensed by US FDA Type 3. Isodense, spiculated lesion in no-man’s land/milky
way left at 11.00/10 cm: size 7 × 6 × 6 mm. BI-RADS 5. Histo-
(United States Food and Drug Administration).
logy: tubular breast cancer pT1b pN0 (sn) G1 max. diameter
The future will be digital mammography in com- 6 mm, hormonal receptors positive, Her-2-new negative, R0
bination with CAD and the possibilities of tomo- V0 L0, additional small low-grade DCIS
108 R. Schulz-Wendtland

Fig. 6.4.2. a Fifty four year old premenopausal client. ACR-

Type 4. Group of microcalcifications retromamillary in 8 cm
depth left, size 2 × 2 × 1.6 cm. BI-RADS 4b. Histology: high-
grade DCIS with necrosis of 4.2 cm diameter. b Digital post-
processing of the group of microcalcifications (a)

Fig. 6.4.3. Fifty four year old postmenopausal

client. ACR-Type 1. Two hyperdense, spiculated
lesions left (bifocal) at 12.00/4.0 cm (lesion 1)
and 5.5 cm (lesion 2): largeness 12 × 7 × 6 mm
(lesion 1) and 5 × 4 × 6 mm (lesion 2). BI-RADS 5.
Histology: moderate differentiated invasive-
ductale breast vancer pT1c (2) pN0 (sn) G1 max.
diameter 12 mm and 7 mm, hormonal receptors
positive, Her-2-new negative, R0 V0 L0
 Technical Prerequisites: Mammography 109

Normal Tomosynthesis
mammogram
Fig. 6.4.4. 3D digital mammography, Tomosynthesis (Novation DR TOMO, Sie-

Normal Tomosynthesis
mammogram

(Selenia, Lorad/Hologic)

Fig. 6.4.5. Normal mammogram, Tomosynthesis (Selenia, Lorad/Hologic)

synthesis, contrast-enhancement and dual-energy
(Dieckmann et al. 2005; Jong et al. 2003; Lewin et al.
2003; Niklason et al. 1997; Schulz-Wendtland et al.
2006) (Figs. 6.4.4, 6.4.5), integrated in a PACS (Picture
Archiving and Communication System)-system.
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 Technical Prerequisites: PET-CT 113

Technical Prerequisites 6
6.5 PET–CT
Gerald Antoch and Robert Stahl

CONTENTS part when assessing primary tumors and recurrent

disease. Radiological imaging procedures need
6.5.1 Introduction 113 to include characterization of the primary tumor
and its potential infi ltration into adjacent organs
6.5.2 Technical Aspects of PET and PET/CT 114
(T-staging), detection of local lymph node involve-
6.5.2.1 FDG-PET 114 ment (N-staging) as well as assessment of all pa-
6.5.2.2 PET/CT 116 tients for potential distant metastases (M-stag-
6.5.3 Clinical Aspects of PET and PET/CT ing). For tumor staging on initial diagnosis and
in Oncology 118 when assessing tumor recurrence, morphological
and functional imaging procedures are available.
6.5.3.1 Head and Neck Tumors 118
However, both types of imaging have well-known
6.5.3.2 Lung Tumors 119 limitations in their diagnostic accuracy when as-
6.5.3.3 Breast Cancer 120 sessing malignant disease: CT, MRI, and ultrasound
6.5.3.4 Gastrointestinal Tract 120 provide mainly morphological information on the
tumor and its potential metastases. This lack of
6.5.3.5 Lymphoma 121
functional data has been shown to hamper accu-
6.5.3.6 Further Perspectives 121 rate assessment of local lymph node involvement
References 123 (Haberkorn and Schoenberg 2001; Toloza et al.
2003). In addition, differentiation of focal parenchy-
mal lesions into benign and malignant may be dif-
ficult if based on morphology alone. Functional data
provided by [18F]-2-fluoro-2-deoxy-d-glucose (FDG)
6.5.1 Positron Emission Tomography (PET) are known
Introduction to be more sensitive and specific than morphology
alone when assessing local lymph node involvement
Malignant tumors are the second most common in malignant tumors complementing morphological
cause of death in the western world (Jemal et al. imaging procedures (Adams et al. 1998; Marom et
2003). Based on the assumption that the patients’ al. 1999; van Tinteren et al. 2002). However, le-
prognoses can be improved when applying a stage- sion localization may be difficult on FDG-PET alone
adapted therapy, accurate clinical and radiologi- due to the only limited anatomical data provided
cal tumor staging must be considered an essential (Weber et al. 1999; Diederichs et al. 2000).
To overcome these limitations of morphological
and functional imaging procedures dual-modality
G. Antoch, MD PET/CT imaging was developed and implemented in
Department of Diagnostic and Interventional Radiology and clinical practice. CT and PET data sets are acquired
Neuroradiology, University Hospital Essen, Hufelandstrasse 55, in a single session providing accurately fused images
45122 Essen, Germany
for tumor diagnosis. Different studies evaluating the
R. Stahl, MD
Department of Clinical Radiology, University Hospitals – diagnostic accuracy have shown a benefit of these
Grosshadern, Ludwig-Maximilians-University of Munich, intrinsically fused data sets over either, morphol-
Marchioninistrasse 15, 81377 Munich, Germany ogy or function, alone (Antoch et al. 2003b, 2004d;
114 G. Antoch and R. Stahl
Bar-Shalom et al. 2003; Lardinois et al. 2003). The
following chapter will summarize technical aspects
of PET/CT imaging and discuss its clinical value in
diagnostic imaging of primary tumors and recur-
rent disease.
6.5.2
Technical Aspects of PET and PET/CT
6.5.2.1
FDG-PET
FDG is produced by labelling deoxyglucose with 18F,
a positron emitter with a half-life of 109 min. 18F
decays to the stable 18O by emission of a positron
and a neutrino. The positron (e+) is an antimat-
ter particle of the negatively charged electron (e −).
The positron annihilates an electron releasing two
511-keV gamma rays which travel in opposite direc-
tions (Fig. 6.5.1). These 511-keV gamma rays are de-
tected by two photoluminescent crystals and, based
on their angle of travel of approximately 180°, the
point of origin of these annihilation quanta can be
calculated precisely by a computer. However, be-
fore annihilation occurs the positron may travel for
some millimeters within tissue before the annihila-
tion occurs. Thus the point of origin calculated for
the annihilation differs minimally from the location
of the radiotracer. While this slight inaccuracy is
generally considered insignificant for clinical PET
511 keV
511 keV
180q
Fig. 6.5.1. 18F decays to the stable 18O by emission of a posi-
tron (e+) and a neutrino (ν). The positron is an antimatter
particle of electrons (e-). The positron annihilates with an
electron releasing two 511-keV gamma rays which travel
in the opposite direction. These gamma rays are detected
by two photoluminescent crystals followed by computer-
based calculation of the point of origin of these annihila-
tion quanta
imaging, it contributes to the maximal resolution
of the technique, which is approximately 2 mm for
FDG-PET.
Today most PET-systems and all PET/CT-systems
provide a full-ring PET detector (360° coverage)
which surrounds the patient’s table. The size of each
detector crystal defines the spatial resolution of the
tomograph, whereas the number of detector crystals
installed in series define the axial field-of-view per
bed position. In modern PET and PET/CT the axial
field of view per bed position is approximately 15 cm.
Therefore PET imaging is performed discontinu-
ously for different bed positions. Depending on the
image quality desired, on the type of detector mate-
rial, on the amount of radioactive tracer applied as
well as on the patient`s weight, the acquisition time
for a single bed position may vary. In oncology typi-
cal acquisition times for FDG-PET and FDG-PET/CT
are 2–5 min per bed position.
The PET annihilation quanta are attenuated when
travelling from the point of annihilation to the de-
tectors of the PET scanner. The extent of PET attenu-
ation is dependent on different factors: in adipose
patients, for example, PET annihilation quanta are
attenuated more strongly than in non-adipose pa-
tients. However, the extent of attenuation affects the
tracer quantification on PET. Thus, PET data need
to be attenuation-corrected if quantitative image
analysis is desired. In PET imaging attenuation cor-
rection of the acquired data is performed based on
an additional transmission scan using gallium-68
transmission sources. These transmission sources
are integrated into the PET gantry. The attenuation
of the gallium-68 transmission scan by the patient`s
body is used to calculate the attenuation-coefficients
for PET.
PET data may be analysed both, qualitatively
and quantitatively. While qualitative image evalua-
tion relates to the detection of regions with focally
increased tracer uptake, quantitative image evalu-
ation is based on the measurement of tracer activi-
ties in the lesion and calculation of the standardized
uptake value (SUV). The SUV correlates the activity
concentration within the lesion with the amount of
injected tracer activity and the patient`s body weight
or body surface area:
activity concentration of lesion (MBq/ln)
SUV =
injected activity (MBq) / patient’s weight (g)
The benefit of SUV determination in PET imaging
has, however, been discussed controversially. While
 Technical Prerequisites: PET-CT 115

some authors have tried to define cut-off values for
differentiation of malignant from benign lesions
(Kang et al. 2004; Rasmussen et al. 2004), others
argue that the SUV may not add any relevant infor-
mation to qualitative image evaluation alone (Keyes
1995). Today in most PET and PET/CT centers the
SUV is used as an additional means to support the
diagnosis based on qualitative image evaluation. In
patients undergoing PET to follow up tumor therapy
the SUV serves as an indicator to assess therapy re-
sponse. A decrease in the SUV in a patient undergo-
ing therapy indicates a responding tumor.
Many radioactive tracers are available for PET
imaging worldwide. Most PET examinations in on-
cology are, however, performed using FDG. Based
on its fairly long half-life of approximately 109 min,
even sites which do not have their own cyclotron for
FDG-production are able to have the tracer deliv-
ered. FDG represents glucose radioactively labelled
with 18Fluor which is being taken up by cells accord-
ing to their glucose metabolism. Within the cell FDG
is metabolised to FDG-6-phosphate which is then
trapped (Fig. 6.5.2). The brain and the heart repre-
sent organs with physiologically high glucose metab-
olism; thus FDG-uptake is physiologically intense in
these organs. Malignant tumors often go along with
increased glucose metabolism compared to their
surrounding tissue, which leads to focally increased
FDG-uptake in these tumors. Therefore tumor diag-
nosis on FDG-PET is based on the detection of fo-
cally increased glucose metabolism, and additional
quantitative measurements may support the correct
diagnosis. False positive results may occur in pa-
tients with inflammatory disease. Tissue inflamma-
tion is associated with increased glucose metabolism
as well, and the differentiation of an inflammatory
lesion from a malignant tumor may prove difficult
with FDG-PET and FDG-PET/CT (Fig. 6.5.3).

Fig. 6.5.2. 18Fluor is actively taken

up by cells according to their glucose
metabolism. Within the cell FDG is
metabolised to FDG-6-phosphate
which is metabolically trapped

Fig. 6.5.3. A 57-year-old male with cervical lymphadenopathy. PET/CT detected several lymph-nodes in the left cervical
region with increased glucose metabolism (maximal SUV: 12,5). Lymph node metastases of an unknown primary tumor
were suspected based on the PET/CT examination. Histology later verified lymph node tuberculosis. PET/CT was false-posi-
tive for malignancy
116 G. Antoch and R. Stahl
6.5.2.2
PET/CT
All PET/CT scanners currently available are based
on the same imaging principle (Beyer et al. 2000):
A CT and a PET are installed in series. The patient
is positioned on an examination table, which serves
both, the CT and the PET. First the CT data are ac-
quired followed by acquisition of the PET. Based on
the same position of the patient on the examination
table when acquiring morphological and functional
images both data sets can be fused accurately by
using special fusion software. Differences between
PET/CT vendors can be found for the CT and the PET
designs. For the CT component, currently multi-
detector systems with up to 64 detector rows are
integrated in PET/CT. For PET differences relate to
the type of detector material in use, which may be
bismuth germanate (BGO), lutetium oxyorthosili-
cate (LSO), or gadolinium oxyorthosilicate (GSO).
Compared to a stand-alone PET, transmission scan-
ning for attenuation correction using gallium-68
rod sources is no longer required in PET/CT imag-
ing. The CT data, which represent a transmission
scan as well, are used for calculation of the PET
attenuation coefficients. Obviating the need for ad-
ditional transmission scanning, PET/CT examina-
tion times are approximately 30% shorter than PET
examinations.
One major limitation of currently available PET/
CT systems relates to the principle of image acquisi-
tion. CT data and PET data are generated in series
with different detectors. Patient motion in between
the two scans or motion of movable organs, such as
the bowel, may result in different positions of an or-
gan or a lesion during CT and PET. This may cause
inaccurate image coregistration thus rendering the
correct diagnosis difficult. Manual adjustment of
image fusion may help to solve questionable cases.
Other inaccuracies in image coregistration are
caused by differences in image acquisition with CT
and PET. While CT imaging is performed with con-
tinuous table movement in a short period of time
(imaging times of approximately 20–60 s for a scan
from head to the thigh, depending on the CT system
in operation), PET imaging is performed discon-
tinuously for different bed positions with acquisi-
tion times of 2–5 min per bed position. Thus PET
imaging is performed in shallow breathing, while
CT is commonly imaged in breath-hold technique.
These differences in the breathing-protocol may
cause inaccuracies when fusing morphological and
functional data (Fig. 6.5.4). For most accurate image
fusion with PET, the CT data should be acquired in
an expiration breath-hold (Goerres et al. 2002b;
Beyer et al. 2003). In CT scanners with a limited
number of detector rows a special breathing proto-
col can improve image fusion in the area of the dia-
phragm (Beyer et al. 2003).
The use of CT contrast agents in PET/CT imag-
ing has been discussed controversially. While some
PET/CT users argue that FDG must be considered
the contrast agent for CT in PET/CT imaging , oth-
ers stress the necessity of intravenous and oral CT
contrast agents not only to detect potentially FDG-
PET negative lesions, but also to assure accurate an-
atomical localization of a PET-positive lesion on CT
(Antoch et al. 2004a). Differentiating anatomical
structures of similar attenuation can be difficult on
CT, but correct lesion localization may not only be of
interest for accurate staging, but may also be impor-
tant for lesion characterization. Thus FDG-uptake
may be interpreted as pathological if fused with a
lymph node, whereas it may be called physiological
bowel activity if coregistered with the colon. The au-
thors of this chapter, therefore, believe that intrave-
nous and oral contrast agents should be applied in
PET/CT imaging to not only assure a high-quality
PET but also a diagnostic CT.
As described before, the CT data are used for at-
tenuation correction of PET. However, the CT X-rays
with energies of approximately 70–140 keV are at-
tenuated substantially more strongly by structures
of high density (such as contrast agents or metal
implants) than the PET quanta at 511 keV. This may
lead to an overestimation of the PET attenuation in
the presence of structures with high density if at-
tenuation correction is based on the CT data. This
overestimation of PET attenuation leads to artifacts
which show as areas of apparently increased tracer
uptake in accurate coregistration with the underly-
ing high-attenuating structure on CT (Antoch et al.
2002; Goerres et al. 2002a; Halpern et al. 2004)
(Fig. 6.5.5). To avoid false positive interpretation of
Fig. 6.5.5a–d. High attenuation artefact caused by a port-
catheter. If the CT data are applied for attenuation correc-
tion of PET, the artefact caused by the port catheter system
(arrow in a) will show on PET as an area of apparently in-
creased tracer uptake (arrow in b). When fusing the two
data sets (c) the area of apparently increased tracer uptake
will be found in accurate coregistration with the site of high
attenuation on CT. On non-attenuation-corrected PET im-
ages (d) no artefact will be detectable
 Technical Prerequisites: PET-CT 117

a b c

Fig. 6.5.4 a–c. Breathing-induced artefact on PET. Free breathing during the CT acquisition caused an artefact of the liver
dome on CT (arrow in a). Attenuation correction of PET was based on the CT data which led to translation of the artefact
into the PET (b) and PET/CT images (c)

a b

c d
118 G. Antoch and R. Stahl
these artefacts on PET, non-attenuation-corrected
PET images should be read additionally in question-
able cases. While there are no alternatives to posi-
tive contrast agents for intravenous opacification,
water-equivalent oral contrast agents may be used
for intestinal distension instead of barium or iodine.
These water-equivalent agents do not increase atten-
uation on CT, thus avoiding PET artefacts (Antoch
et al. 2004b). While contrast-associated artefacts
may cause interpretative problems on qualitative
image evaluation, no clinically relevant effect has
been detected on tracer quantification (Dizendorf
et al. 2003; Nakamoto et al. 2003).
Depending on the tracer in use and the amount
of tracer applied, radiation exposure attributable to
the PET component may vary. For FDG-PET a ra-
diation dose of approximately 7 mSv applies. How-
ever, the more relevant part of radiation exposure
is caused by CT, if the CT component of the PET/CT
is acquired in a diagnostic manner (mAs typical for
stand-alone CT acquisition). Scanning the patient
from head to the upper thighs will add approxi-
mately 15 mSv of radiation exposure from the CT
component thus raising the overall dose of the PET/
CT to more than 20 mSv (Brix et al. 2005). The ra-
diation burden set upon the patient may be reduced
if the CT is performed “low-dose” with 40–80 mAs
or even less. Cases in which a diagnostic CT may not
be necessary are, for example, patients undergoing
PET/CT for assessment of therapy response or those
with a diagnostic CT scan performed shortly before
the PET/CT.
6.5.3
Clinical Aspects of PET and PET/CT
in Oncology
The considerable effective radiation dose for a
whole-body examination makes PET-CT inadequate
for preventive screening. It is mainly applied in on-
cological patients for tumor-node-metastasis (TNM)
system staging or to detect tumor recurrence. A rap-
idly expanding body of literature demonstrates that
the interpretation of coregistered PET and CT im-
ages obtained from one examination leads to im-
proved diagnostic performance compared to that
of PET alone, CT alone, and visually correlated PET
and CT images obtained from separate scans. Initial
studies reported that PET/CT is more accurate in
assessing the TNM-stage of different malignant dis-
eases (Bar-Shalom et al. 2003; Antoch et al. 2004c)
which potentially impacts on patient management
in a considerable number of cases.
6.5.3.1
Head and Neck Tumors
In patients with head and neck tumors accurate as-
sessment of the N-stage must be considered cru-
cial to determine further therapeutic steps such
as surgery or radiation therapy. The sensitivity of
FDG-PET to detect lymph node metastases in head
and neck tumors has been reported to reach 90%;
in CT this sensitivity has only been approximately
65% (Kutler et al. 2006). Based on physiologically
increased FDG-uptake in muscles of the neck, in
salivary glands, or in brown fat the interpretation
of PET images may be somewhat challenging. By
providing CT information to PET the number of
equivocal FDG-avid lesions can be reduced on initial
tumor staging both, locally and when assessing po-
tential distant metastases (Syed et al. 2005; Ha et al.
2006). Thus an increase in diagnostic accuracy over
the two imaging modalities alone may be expected.
However, reported sensitivities of PET/CT of up to
100% should be interpreted with caution (Chen et al.
2006). In patients with suspected tumor recurrence
anatomical imaging modalities may be inconclusive
due to tissue alteration by surgery and radiotherapy.
Similarly, on PET alone a persistent FDG uptake
due to sterile inflammation can often be detected
in patients after radiotherapy (Schoder et al. 2004).
PET/CT aids in localizing elevated FDG uptake in
over 90% of cases and may clarify 60% of equivocal
lesions (Goshen et al. 2005).
Cervical nodal metastases from cancers of un-
known primary (CUP-syndrome) account for 1%–
2% of head and neck malignancies. The median
survival for patients with CUP is poor but may be
elevated from 12 to 23 months in cases where an
identified primary site is subsequently treated with
specific therapy (Raber et al. 1991). The detection
of the primary lesion may, therefore, impact patient
management. However, the detection rate of primary
tumor sites has been reported to be low with con-
ventional imaging modalities (including CT). FDG
PET has been reported a valuable diagnostic tool in
patients with cervical CUP with detection rates of up
to one third of patients (Bohuslavizki et al. 2000).
PET/CT does not seem to further increase the detec-

tion rate of primary lesions compared to PET alone
(Freudenberg et al. 2005). As could be expected
from the PET literature, FDG-PET/CT proved more
accurate than CT when defining the primary lesion
in CUP patients. Different hypotheses exist concern-
ing the large number of tumors remaining undetec-
ted even on a PET and PET/CT scan. Some authors
hypothesize that the primary tumor may be small or
may even disappear after seeding. Additional fi nd-
ings may alter patient management when assessing
CUP with FDG-PET/CT. Even without detection of
the primary tumor detection of yet unknown metas-
tases has been reported in over 20% of patients with
FDG-PET/CT, modifying the stage of disease with
potential impact on patient management (Nanni et
al. 2005; Pelosi et al. 2006).
6.5.3.2
Lung Tumors
In patients with suspected lung tumors or lung me-
tastases from other primaries, FDG-PET/CT can give
morphological and functional information on pul-
monary lesions. In a solitary pulmonary nodule po-
tential FDG-uptake may hint at malignancy whereas
FDG-PET negative nodules are more likely to be be-
nign (Reinhardt et al. 2006). However, FDG-PET
is well known to be less sensitive in small pulmo-
nary lesions (below 1 cm) due to breathing-induced
“smearing” of FDG-uptake. Gating of the PET can
compensate for this limitation, however, at the cost
of longer examination times. PET/CT can increase
the sensitivity in patients with small FDG-negative
nodules compared to PET alone by providing the
CT component. However, in recent studies it has
a b
Fig. 6.5.6 a–c. A 63-year-old male with NSCLC of the right upper pulmonary lobe. On CT N2 disease was suspected based
on a pathologically enlarged lymph node in the mediastinum (arrow in a). FDG-PET (b) and FDG-PET/CT (c) demonstrate
homogeneous tracer distribution without focally increased FDG uptake staging this patient as N0. Histopathology verified
an N0 nodal status
Technical Prerequisites: PET-CT 119
been shown that CT acquired in shallow breathing
seems inadequate for comprehensive cancer staging
as small lesions may be missed in over a third of
all patients (Allen-Auerbach et al. 2006; Aquino
et al. 2006). Thus, a CT in breath-hold technique
should be acquired as part of the PET/CT.
FDG-PET is more accurate than CT in the staging
of non-small cell lung cancer (NSCLC) (Fig. 6.5.6)
and the most significant prognostic factor for sur-
vival in these patients (Kramer et al. 2006). Par-
ticularly in NSCLC initial TNM-staging can be fur-
ther improved with PET/CT (Antoch et al. 2003a;
Lardinois et al. 2003; Halpern et al. 2005) mainly
due to the better differentiation between tumor and
adjacent atelectasis. In posttherapeutically distorted
anatomy PET/CT can also improve the localization
of suspicious FDG accumulation if tumor recur-
rence is suspected (Keidar et al. 2004). It has been
shown that a decrease in FDG-uptake and a reduc-
tion of the SUV on PET/CT scans after chemother-
apy correlates with the histopathologic response to
the therapy (Hoekstra et al. 2005; Pottgen et al.
2006) (Fig. 6.5.7).
In the field of image-modulated radiation therapy
(IMRT) the use of PET/CT has some theoretical ad-
vantages. Fusion of function and morphology may
improve the definition of the treatment volume when
compared with morphological imaging alone. Fusion
of metabolic and anatomical information basically
reduces interobserver variability when estimating
the gross tumor volume (GTV) (Ciernik et al. 2003;
van Baardwijk et al. 2006). In the primary lung
tumor integration of functional data often leads to
a decrease of the target volume. The major cause for
this decrease seems to be the ability of PET to differ-
entiate viable tumor areas from adjacent atelectasis
c
120 G. Antoch and R. Stahl
b
Fig. 6.5.7 a,b. NSCLC before and after combined chemotherapy/radiation therapy. CT, FDG-PET, and FDG-PET/CT before initia-
tion of the treatment (a) demonstrate large tumor at the right pulmonary hilum. The follow-up examination (b) demonstrates
good response of the tumor to the combined chemo-irradiation
(Ciernik et al. 2003). On the other hand PET may re-
sult in an increase of the target volume, mainly due
to identification of nodal disease (Ashamalla et al.
2005). This higher accuracy when defining the target
volume will improve therapy results. In the case of
radiotherapy with a curative intent, the dose to non-
tumorous tissue has been shown to be the dose-limit-
ing factor. In patients with NSCLC modelling studies
demonstrated that the use of FDG-PET/CT scanning
information reduces the radiation exposure of the es-
ophagus and lungs thus allowing a substantial radia-
tion dose escalation (De Ruysscher et al. 2005; van
Der Wel et al. 2005). Further studies have to evaluate
if this higher accuracy when defining the radiation
target with PET/CT translates into better patient out-
come (Messa et al. 2005).
6.5.3.3
Breast Cancer
Currently there is little literature available on po-
tential advantages of FDG-PET/CT in breast can-
cer. While PET and PET/CT will not be performed
in patients to assess the primary tumor (T-stage),
it may be of benefit to assess the N-stage and M-
stage. Accurate assessment of the tumor stage will
aid therapy decision and might play an important
role in radiation therapy planning of breast cancer
patients (Zangheri et al. 2004). PET/CT correctly
characterized more malignant lesions than did CT
(Tatsumi et al. 2006). Compared to PET alone, PET/
CT may reduce the number of false-positive findings
by identifying benign areas of mild FDG-uptake in
brown fat (Heiba et al. 2005; Rousseau et al. 2006).
In restaging, an initial study by Fueger et al. did not
detect a statistically significant difference between
PET/CT and PET alone in detecting tumor recur-
rence (Fueger et al. 2005). Theoretically, however,
accurate localization of FDG-uptake after therapy
may improve differentiation of a recurrent tumor
from posttherapeutic tissue alteration.
6.5.3.4
Gastrointestinal Tract
In initial staging of patients with colorectal carci-
noma, FDG PET alone has been reported to be highly
sensitive in the detection of distant metastases. With

the addition of a CT the diagnostic accuracy in initial
tumor staging can be further improved based on ac-
curate localization of areas with potentially increased
FDG-uptake (Cohade et al. 2003; Gearhart et al.
2006). This has been shown to increase the detection
rate of lymph node metastases by 19% (Gearhart et
al. 2006). Veit et al. (2006b) demonstrated the feasi-
bility of a PET/CT staging protocol with integrated
PET/CT colonography. This protocol suggests fur-
ther benefits in primary tumor staging, particularly
in patients with incomplete colonoscopy. However,
the most important indication for FDG-PET/CT in
colorectal tumors is detection of potential tumor re-
currences. Differentiation of scar tissue from tumor
recurrence or residual tumor has been shown to be
challenging when applying morphological imaging
procedures. FDG-PET/CT appears to be very prom-
ising for distinguishing a viable tumor from fibrous
tissue after therapy, thereby avoiding unnecessary
laparotomy (Even-Sapir et al. 2004b; Votrubova
et al. 2006). Particularly in rectal tumors accurate
anatomical localization must be considered an ad-
vantage of PET/CT over FDG-PET. In this setting
fusion of increased FDG-uptake with a lesion on CT
helps differentiating pathological FDG-uptake from
physiological uptake, such as accumulation within
the bladder.
The value of FDG-PET for detection of liver
metastases has been discussed controversially.
While some authors report FDG-PET to be supe-
rior to CT in detecting colorectal liver metasta-
sis (Abdel-Nabi et al. 1998; Rohren et al. 2002;
Arulampalam et al. 2004), others report the op-
posite. The accuracy of PET seems to be depend-
ant on the lesion size within the liver. PET data are
acquired in shallow breathing, thus small lesions
may be missed on FDG-PET due to breathing-as-
sociated smearing of FDG-uptake. This limitation
of PET can be compensated for by adding the CT
component. In this case the examining physician
must specifically focus on the CT protocol as part
of the PET/CT. It has been shown, that if the CT is
performed with intravenous contrast agents more
hepatic lesions can be detected than on non-en-
hanced PET/CT (Setty et al. 2005). PET/CT has
been shown to be able to differentiate between
extrahepatic disease and tumor recurrence in the
liver before and after liver surgery (Delbeke and
Martin 2004; Erturk et al. 2006; Khan et al.
2006); (Selzner et al. 2004). Further applications
of PET/CT in patients with colorectal liver metas-
tases include follow-up-examinations of local liver
Technical Prerequisites: PET-CT 121
therapy. FDG-PET and FDG-PET/CT may be of
benefit over CT alone in depicting recurrent tumor
after radiofrequency ablation (RFA) of liver me-
tastases (Barker et al. 2005; Joosten et al. 2005;
Veit et al. 2006a). Other authors report promis-
ing results when following-up patients with liver
metastases undergoing therapy with application of
90Y microspheres (Lewandowski et al. 2005) or
neoadjuvant therapy (Goshen et al. 2006).
6.5.3.5
Lymphoma
Accurate staging in patients with Hodgkin disease
(HD) and non-Hodgkin lymphoma (NHL) is cru-
cial to assure a stage-adapted therapy. FDG-PET
has been reported to have both higher sensitivity
and specificity for detection of malignant lesions
than CT in lymphoma patients (Hicks et al. 2005).
On the one hand, staging performed with PET and
PET/CT upstages the disease in a third of HD and
NHL patients compared to CT staging alone. On the
other hand the disease may be downstaged in 15% of
HD patients but only in 1% of NHL patients. Thus,
patient management is altered by PET and PET/CT
in approximately a quarter of NHL and a third of
HD patients (Raanani et al. 2006). Therefore PET
and PET/CT have a substantial impact on diagnos-
tic accuracy and patient management (Tatsumi et
al. 2005; Hutchings et al. 2006; Raanani et al.
2006). In addition, the evaluation of treatment re-
sponse with functional data has been reported to be
more sensitive than morphology alone (Metser et
al. 2004; Schaefer et al. 2004). However, compar-
ing FDG-PET with FDG-PET/CT did not reveal a
statistically significant difference in patients with
lymphoma, both, for initial staging and follow-up
in patients undergoing therapy (Hutchings et al.
2006; Freudenberg et al. 2004).
6.5.3.6
Further Perspectives
FDG accumulates in tumors as well as in non-
tumorous pathologic lesions (e.g. inflammation) and
in normal tissue (e.g. brain). New and potentially
effective radioactive tracers for PET are being de-
veloped rapidly and are expected to be more specific
for certain tumors than FDG (Table 6.5.1). Typically
these specific tracers provide fewer anatomical land-
122 G. Antoch and R. Stahl

Table 6.5.1. Overview of newer radiopharmaceuticals for PET and PET/CT

Radiopharmaceutical Principle Cancer entity

11C-acetate Lipid synthesis Prostate (Oyama et al. 2002), hepatoma (Ho et al.
2003), brain (Liu et al. 2006)
11C-choline Lipid synthesis Prostate (Farsad et al. 2005), head and neck (Khan
et al. 2004)
18F-choline Lipid synthesis Prostate (Kwee et al. 2005, 2006; Schmid et al. 2005),
brain (Spaeth et al. 2006)
O-[11C]methyl-l-tyrosine (CMT) Amino acid transport Brain (Ishiwata et al. 2005), general (Tsukada et al.
2006)
(18)F-fluoro-ethyl-l-tyrosine (FET) Amino acid transport Brain (Spaeth et al. 2006)
O-(18)F-fluoromethyl tyrosine Amino acid transport General (Tsukada et al. 2006)
O-(2-[(18)F]fluoroethyl)-l-tyrosine Amino acid transport Head and neck (Pauleit et al. 2006)
(FET)
[(11)C]-metomidate Hormone precursor Adrenal cortical tumours (Eriksson et al. 2005)
6-[(18)F]-fluorodopamine Hormone precursor Phaeochromocytomas (Eriksson et al. 2005)
18F-DOPA Hormone precursor Carcinoid (Hoegerle et al. 2001)
[(11)C]-hydroxyephedrine Hormone precursor Phaeochromocytomas (Eriksson et al. 2005)
[(11)C]-5-hydroxytryptophan Hormone precursor Carcinoid, endocrine pancreatic tumours (Eriksson
et al. 2005)
alpha-[(11)C]-Methyl-l-tryptophan Cell proliferation Brain (Juhasz et al. 2006)
(AMT)
[(11)C]-l-dihydroxyphenylalanine Hormone precursor Carcinoid, endocrine pancreatic tumours (Eriksson
et al. 2005)
18F-thymidine DNA synthesis Breast (Pio et al. 2006), brain (Jacobs et al. 2005)
11C-methionine Amino acid transport Prostate (Toth et al. 2005), brain (Jacobs et al. 2005;
Borbely et al. 2006), lung (Ishimori et al. 2004)
18F-fluoroestradiol Hormone receptor Breast (Van Den Bossche and Van de Wiele 2004)
18F-flurodihydrotestosterone Hormone receptor Prostate (Van Den Bossche and Van de Wiele 2004)
124-Iodine Hormone component Thyroid (Freudenberg et al. 2004)
18F-fluoroide Bone compound Bone (Even-Sapir et al. 2004a)
Gluc-Lys([(18)F]FP)-TOCA Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
[(111)In]DTPA-octreotide Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
[(68)Ga]DOTATOC Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
60Cu-ATSM Tumor hypoxia Cervical (Dehdashti et al. 2003a), lung (Dehdashti
et al. 2003b), head and neck (Chao et al. 2001)
18F-fluoromisonidazole ((18)F- Tumor hypoxia Head and neck (Eschmann et al. 2005; Thorwarth et
FMISO) al. 2005), lung (Gagel et al. 2006)
(18)F-labeled nitroimidazole com- Tumor hypoxia General (Piert et al. 2005)
pound fluoroazomycin arabinoside
((18)F-FAZA)
sigma-Ligands Cellular proliferation General (van Waarde et al. 2006)
18F-Galacto-RGD Angiogenesis Malignant melanoma (Beer et al. 2005)
Labeled monoclonal antibodies To be designed for spe- General
cific binding sites

marks than FDG on the PET image which increases
the need for correlation with morphology, as is pro-
vided by PET/CT. Some of them have already been
applied in PET/CT.
Freudenberg et al. reported the feasibility of PET/
CT with iodine-124 in patients with differentiated
thyroid carcinoma before radio-iodine therapy and in
patients with suspected tumor recurrence and/or me-
tastases. Combined I-124-PET/CT had a substantially
higher lesion detectability compared to established
imaging procedures. On CT alone less local recur-
rences, lymph node metastases, and small metastases
involving the bone were detected. On the other hand,
CT alone seems to be sufficient to detect pulmonary
metastases which may even be missed on PET alone if
iodine-negative (Freudenberg et al. 2004).
Even-Sapir et al. (2004a) applied 18F-fluoride
PET/CT in oncologic patients to evaluate its diag-
nostic accuracy when differentiating malignant
from benign bone lesions. Malignant and benign
lesions had increased 18F-fluoride uptake in most
of the cases, but metastases presented in PET/CT as
sites of increased uptake with corresponding lytic or
sclerotic changes. This resulted in a higher sensitiv-
ity and higher specificity of PET/CT over PET alone
(100% vs 88% and 88% vs 56%, respectively).
Farsad et al. (2005) used (11)C-choline and
Schmid et al. (2005) used 18-F-choline in patients
with prostate cancer. Based on a relatively high
number of false-negative results as well as choline-
uptake in prostate disorders other than cancer the
use of PET/CT with choline cannot be recommended
as a first-line screening procedure for prostate can-
cer. However, it may be useful for detecting local re-
currence and lymph node metastases.
None of these new and specific tracers can cur-
rently replace FDG as the workhorse in oncologic
functional imaging. It is likely that FDG will continue
to be the most widely used tracer for the next years.
However, development and clinical implementation
of new PET-tracers will increase the number of in-
dications for PET and PET/CT. Based on the radia-
tion exposure to the patient, these indications will
not include tumor screening but will focus on tumor
detection and follow-up.
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 Risks of Screening and Preventive Diagnosis 127

Risks of Screening and Preventive Diagnosis 7

Jürgen Griebel, Gunnar Brix, and Harald Kramer

CONTENTS Radiological imaging techniques always pose some

risk of adverse health effects to patients or – in the
7.1 Risks Related to Imaging Procedures case of screening and preventive diagnosis – as-
Using Ionizing Radiation 127 ymptomatic persons. Therefore, this issue has to be
7.1.1 Conceptual Considerations 127 thoroughly evaluated before conducting interven-
7.1.2 Detrimental Health Effects Induced by
tions to promote radiological screening for persons
Ionizing Radiation 128
7.1.3 Dosimetric Quantities and with an increased risk for specific diseases or even
Dose Values for some Relevant the introduction of regular screening programs. In
Diagnostic Procedures 128 this chapter we review health risks related to the use
7.1.4 Assessment of Radiation Risks 1293 of radiography, CT, PET and MRI procedures and
7.1.5 Risk-Benefit Assessment 132
discuss ethical aspects associated with radiological
7.2 Risks Related to screening.
Magnetic Resonance Imaging
Procedures 132
7.2.1 Interaction Mechanisms and
Biological Effects of Magnetic Fields 133
7.2.2 Exposure Limits 133
7.2.3 Contraindications 133
7.1
7.3 Medical Risks and Informed Consent 134
7.3.1 Informed Consent 134 Risks Related to Imaging Procedures
7.3.2 False Positive and Using Ionizing Radiation
False Negative Results 135
References 89 7.1.1 Conceptual Considerations

In the past, health strategies focused on a patient

J. Griebel, MD
G. Brix, PhD, Professor
Federal Office for Radiation Protection, Department of
Medical Radiation, Hygiene and Dosimetry, 85764 Neuher-
berg, Germany
H. Kramer, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
presenting to a medical doctor in a hospital or pri-
vate practice with recognized symptoms. Screening
is a significant departure from this clinical model of
care, because apparently healthy individuals are of-
fered a test. An effective screening detects either risk
factors for developing a disease, or the disease itself
at an early stage where treatment can improve clini-
cal outcome. The aim is to identify those individuals
who are more likely to be helped than harmed by
further diagnostic tests or treatment (BMA 2005).
Screening programs systematically invite all
members of a certain population to take a screening
test. Examples of this are the breast screening pro-
grams in Europe where all women between 50 and 69
routinely receive invitations to have an X-ray mam-
mography. These programs are evidence based and
128 J. Griebel, G. Brix, and H. Kramer
meet stringent quality requirements, taking into ac-
count the need to include all parts of the program.
From these formal screening programs, it is im-
portant to differentiate more informal arrangements
in which clinical guidance and/or patient choice
result in an ad hoc screening. The most prominent
example is whole-body CT screening, which is pro-
moted – especially in the USA – by private providers
in the last years. As long as there is lack of evidence
underpinning the screening tests on offer, this op-
portunistic screening potentially puts individuals
at risk. Furthermore, the service is unlikely to be
properly quality assured or coordinated. Individu-
als are also unlikely to receive sufficient information
to enable them to make an informed decision as to
whether or not to undertake the screening test.
Even for well established screening programs,
the balance between benefits and undesired adverse
health effects is narrow. Due to the typically low
prevalence of serious diseases in an asymptomatic
population, the vast majority of individuals un-
dergoing screening are not affected by the disease.
These individuals do not derive a direct health ef-
fect, but can only be harmed. The adverse effects
most relevant in any screening are false-positive re-
sults and overdiagnosis.
With respect to screening using radiography, CT or
PET examinations, health effects induced by ionizing
radiation have additionally to be taken into account.
While adverse health effects – at least in part – are
difficult to be assessed quantitatively, risk estimates
for detrimental radiation effects are available.
7.1.2
Detrimental Health Effects Induced by
Ionizing Radiation
Detrimental radiation effects, the most significant
being induction of cancer, have been demonstrated
in humans through various epidemiological studies
at intermediate and high doses, i.e. organ or whole-
body doses exceeding 50–100 mGy, delivered acutely
or over a prolonged period. Due to the large size
of the study population (about 80,000 individuals
with reconstructed dose values), the broad age- and
dose-distribution, the long follow-up period (up to
50 years) and the existence of a valid internal con-
trol group (individuals not or only at a minute level
exposed), the so-called Life Span Study (LSS) of the
atomic bomb survivors at Hiroshima and Nagasaki,
who have been acutely exposed to whole-body ir-
radiation, is the most important of these studies.
The LSS provides data with good epidemiologic evi-
dence and, therefore, is generally used for predicting
radiation-induced risks for the general population.
Hereby, risk coefficients (risk per dose) have been
derived using the so-called linear, non-threshold
(LNT) hypothesis, which is based on the assump-
tion that:
1. Any radiation dose – no matter how small – may
cause detrimental health effects.
2. The probability of these effects is directly propor-
tional to the dose absorbed in the tissue.
There is, however, considerable controversy re-
garding low-level radiation, typical for diagnostic ra-
diation exposures, since the risks evaluated at these
dose levels are not based on experimental evidence.
Given this lack of evidence, the risk coefficients,
derived from high doses, have been extrapolated
down to low dose levels by various scientific bod-
ies, including ICRP, UNSCEAR, and BEIR. Although
the risks evaluated at low dose levels are hypotheti-
cal, the proponents of the LNT model argue that it
is conservative to presume that these risks exist,
and that the LNT model represents an upper bound
for them. It is for this reason that current radiation
protection standards as well as risk assessments are
generally based on the LNT hypothesis.
7.1.3
Dosimetric Quantities and Dose Values for
some Relevant Diagnostic Procedures
The fundamental dosimetric quantity is the ab-
sorbed dose expressed in the unit Gray (1 Gy = 1 J/
kg). It is defined as the radiation energy absorbed
in a small volume element of matter divided by its
mass. The absorbed dose averaged over the total
mass of an organ or tissue T is denoted as organ
dose, DT. Whenever an organ is only partially ex-
posed by external radiation, as in the case of an
organ extending over the whole body (e.g., red bone
marrow or skin) or an organ situated at the border
of the irradiated body region, the organ dose may
differ markedly from the absorbed dose at different
positions within that organ.
Tissues and organs are not equally sensitive to
the effects of ionizing radiation. Due to this rea-
son, tissue weighting factors, wT, were provided by
the ICRP (ICRP 1990) for a reference population of
equal numbers of both sexes and a wide range of ages

(Table 7.1). These factors indicate the relative pro-
portion of each organ or tissue to the total health
detriment − in terms of the risk of fatal cancers and
hereditary defects − resulting from a uniform irra-
diation of the whole body. If the body is exposed in
a non-uniform manner, as for example in a person
undergoing a CT or PET examination, the sum of the
products of the organ dose and the corresponding tis-
sue weighting factor determined for each of the vari-
ous organs or tissues exposed has to be computed:
Table 7.1. Tissue weighting factors wT given in ICRP Publi-
cation 60 (ICRP 1990) reflecting the relative susceptibility of
various tissues and organs to ionizing radiation
Tissue or organ wT
Gonads 0.20
Bone marrow, lungs, colon, stomach 0.12
Liver, thyroid, esophagus, breast, bladder 0.05
Bone surface, skin 0.01
Remaining organsa 0.05
a The ‘remaining organs’ consists of a group of additional
organs and tissues with a lower sensitivity for radiation
induced effects for which the average dose must be used: small
intestine, brain, spleen, muscle tissue, adrenals, kidneys, pan-
creas, thymus and uterus
The resulting quantity is denoted as effective
dose, E, and expressed in the unit Sievert (Sv). On
the basis of the effective dose, it is possible to as-
sess and to compare the probability of stochastic
radiation effects resulting from different radiation
exposures – as for example diverse X-ray or nuclear
medicine procedures yielding a different pattern of
dose distribution in the body.
It should be mentioned, however, that the weight-
ing factors provided by the ICRP are generic rather
then individual because age and gender of the per-
son examined are not taken into account. They are
thus not suited for the assessment of radiation risks
to individual persons or sub-groups of the popula-
tion with a distribution of age and gender differing
from that of the general population. Furthermore,
the weighting factors are supposed to be changed
significantly in the next future (ICRP 2005).
Representative effective dose values for various
diagnostic imaging procedures used in clinical rou-
Risks of Screening and Preventive Diagnosis 129
tine as well as for screening and preventive diagnosis
are summarized in Table 7.2. For each examination
considered, radiation exposure to asymptomatic
persons is lower than that to patients, which means
that the scan protocols used for screening are – at
least to some extent – optimized from a radiation-
hygienic point of view. Table 7.2 also gives estimates
of the dose to breast parenchyma of females that are
calculated under the assumption that both breasts
are completely in the imaged body region. The lat-
ter data make it possible to compare the stochastic
risk for breast cancer induced by CT and PET proce-
dures with the corresponding risk of a conventional
screening mammogram.
In practice, neither organ nor effective doses can
be measured directly. In order to overcome this diffi-
culty, operational dose quantities are defined, which
can easily be measured. Examples are the dose-area
product or the entrance-surface dose in radiography,
the computed tomography dose index or dose-length
product in CT scanning, and the activity of a radio-
pharmaceutical administered to a patient in case of
a PET examination. These quantities can not only be
used for comparison of different protocols within a
particular diagnostic modality (e.g., CT or PET) but
also form the basis for the estimation of organ and
effective doses. In the latter case, operational dose
quantities have to be combined with conversion or
dose coefficients computed by Monte-Carlo calcu-
lations for anthropomorphic mathematical models
or by dose measurements in an anthropomorphic
phantom.
7.1.4
Assessment of Radiation Risks
The risk estimates proposed by ICRP and UNSCEAR
(ICRP 1990; UNSCEAR 2000) – for use in radiation
protection – are based on risk coefficients and effec-
tive doses, as mentioned above. They provide simple
and robust estimates for the lifetime excess risk to
die from radiation-induced cancer. But they facili-
tate only an over-all, not an organ-specific estimate
and are aimed at large, age and gender averaged
collectives such as the working population or the
whole population of a country.
An assessment of radiation risks induced by
screening procedures such as X-ray mammography
or CT has to take into account that these procedures
typically are aimed at members of a certain popula-
tion, such as – for example – women between 50 and
130 J. Griebel, G. Brix, and H. Kramer

Table 7.2. Effective dose and dose to breast parenchyma of some radiological examinations

Modality Examination Individuals Effective dose Dose to breast

(mSv) parenchyma (mGy)

X-raya Mammography Patients and asymptomatic 0.2 4

females
CT b Calcium scoring Patients 3.1 r 1.5 18
Asymptomatic persons 3–4
Coronary angiography Patients 10.2 r 3.6 62
Asymptomatic persons 8–11
Lung Patients 5.5 r 2.4 16
Asymptomatic persons 0.4–2.1
Virtual colonoscopy Patients 8.0 r 4.3 –
Asymptomatic personsc 3–5 –
Whole-body Patients 14.5 r 5.5 18
Asymptomatic persons 8–16
d 18F-FDG
PET Patients 7.0 2.5
e
PET/CT Whole-body, Patients 24.8r 1.1 19
18F-FDG

a Representative dose values relate to the examination of both breasts in two views
b Effectivedoses (mean r SD) of multi-slice CT examinations carried out in patients were determined in a nationwide survey
performed in Germany in the year 2002 (Brix et al. 2003). The range of CT doses given for screening examinations are from
a review of recent publications. Representative doses to breast parenchyma are calculated from the CTDIvol values and a dose
coefficient given in Brix et al. (2005)
c Paired examination in supine and prone position
d Dose values given for a representative PET examination using 370 MBq of 18F-labeled fluorodeoxy-glucose are calculated using
the dose coefficients given in ICRP publication 80 (ICRP 1996)
e Dose values (mean r SD) given were determined in a multi-center study performed in Germany in 2004 (Brix et al. 2005). The

body region scanned by CT extended from the symphysis at the lower limit to the thyroid at the upper limit

69 years in breast cancer screening. Furthermore,

with respect to screening, the radiation induced
risk to be diseased with cancer, i.e. the incidence, is
of major concern, not the radiation induced risk to
die from cancer, i.e. the mortality. Finally, screening
procedures using ionizing radiation typically ex-
pose only parts of the body and thus, organ related
absorbed doses and risk estimates are necessary for
a precise assessment.
The standard approaches to generate age, gender
and organ specific risk estimates are based on the
so-called excess absolute risk, ear (e.g. SSK 2002). It
denotes the additional risk, after an exposure at the
age e, to be clinically diseased with a specific radia-
tion-induced cancer at the age a or, more specific,
in the interval [a, a+1]. It is commonly calculated
from:
where D denotes the organ dose and S the gen-
der. ro(a,S) is the normal or baseline risk for a
person of gender S to be diseased with a specific
cancer in the interval [a, a+1]. For a particular
country, normal cancer risks can be received from
the IARC national cancer incidence rates (Ferlay
et al. 1999). The normal risk has to be corrected
for competing risks by the probability P(e,a), i.e.
the probability that a person at the age e survives
beyond the age a. err(e,a,D,S) is the excess relative
risk. For example, an err(e,a,D,S) = 1 means that
the additional, radiation-induced cancer risk for a
person of gender S who was exposed at age e to an
organ dose D and attained age a is as high as his or
her normal cancer risk.
 Risks of Screening and Preventive Diagnosis 131

The excess relative risk, err(e,a,D,S), for specific
organs is usually derived from cancer incidence
data of the LSS, whereby a linear dose dependency
is commonly assumed for solid tumors, while a lin-
ear-quadratic approach provides better results for
leukaemia. Since the LSS data are regularly updated,
a variety of different models can be found in the lit-
erature, reflecting the currently evaluated observa-
tion period. Well established models are applied for
the calculation of probabilities of causation, which
serve the needs of official institutions in adjudicat-
ing cancer claims fi led by persons exposed to radia-
tion (for example, Chmelevsky 1995; HHS 2003).
The excess absolute lifetime risk, EAR, for a per-
son of gender S who was exposed at age e to a or-
gan dose D is easily calculated by summing up all
err(e,a,D,S) values between the age of exposure and
the age of 85 years, commonly used for lifetime risk
estimates:
Please note that the excess relative risk,
err(e,a,D,S), is set to zero in the interval between a=e
and a=e+∆t, where ∆t denotes the minimum latency
period during which radiation induced cancer typi-
cally does not show clinical symptoms. A period of
about 5 years for carcinoma and of about 2 years for
leukaemia is widely applied for incidence data.
For typical CT related screening procedures, age,
gender and organ specific risk estimates for radia-
tion induced cancer have been performed, for ex-
ample, by Brenner (2004), Brenner and Elliston
(2004) and Brenner and Georgsson (2005) using
a somewhat simpler approach as described above.
Furthermore, the risk estimates refer to a popula-
tion with US normal risk rates, which differ from
European countries in some cancer entities, e.g.
breast cancer. The underlying organ dose estimates
result from calculations which essentially take into
account one typical CT scanner, respectively. The
resulting excess absolute lifetime risks, considering
typical screening frequencies and periods – as dis-
cussed in the literature, are summarized in Table 7.3.
In addition, the corresponding data for breast can-
cer screening are provided.
For the CT screening procedures mentioned
above, radiation induced cancer of the lung, female
breast, colon and stomach as well as leukemia is the
dominant cause of detrimental radiation effects.
This is especially valid for whole-body CT, where all
of these organs are involved, being exposed to organ
doses of about 10 mGy and more (Brenner and El-
liston 2004). In CT colonography, colon and stom-
ach are of major concern, being exposed to similar
organ doses (Brenner and Georgsson 2005). In
CT lung cancer screening, major contributors are
lung and female breast. Here, the organ doses are
significantly lower as compared to whole-body CT
(Brenner 2004). Furthermore, it has to be consid-

Table 7.3. Excess absolute lifetime risks for typical screening procedures using X-ray or CT

Excess absolute lifetime risk for cancer incidence [%]

Screening Screening CT: Screening CT: Screening CT:

mammographya lungb colonc whole bodyd

0.01–0.10 0.23 0.15 5.7

(female) (male current smoker) (male)
0.85 0,13
(female current smoker) (female)
a According
to SSK (2002); the estimate refers to a woman who undergoes screening mammogra-
phy every two years between 50 and 69 years of age
b According to Brenner (2004); the estimate refers to a current smoker who undergoes annual

screening CT between 50 and 75 years of age; the lifetime risk is estimated only for radiation-
induced lung-cancer, ignoring radiation-induced breast cancer risk in females
c According to Brenner and Georgsson (2005); the estimate refers to a 50-year-old person who

undergoes one screening CT; it ignores radiation-induced risks to the uterus and the female
gonads
d According to Brenner and Elliston (2004b); the estimate refers to a person who undergoes

annual screening CT between 45 and 75 years of age; in the paper, the lifetime risk of cancer mor-
tality is estimated as about 1.9%. Taking into account that overall cancer incidence is roughly three
132 J. Griebel, G. Brix, and H. Kramer
ered, that estimates of organ doses are highly depen-
dent on the scanner settings. However, up to now, no
standard CT protocols are available for screening.
Furthermore, even for identical CT parameter set-
tings, the dose estimates show significant scanner-
to-scanner variations (Nagel 2002).
Compared to the breast cancer screening pro-
grams, established in various countries, the excess
absolute lifetime risks for screening approaches us-
ing CT are relatively high (see Table 7.3). So, for an-
nual whole-body CT screening between the age of
45 years and 75 years, the lifetime risk to be diseased
with a radiation-induced cancer is about 5%–6%,
while the normal lifetime cancer risk for a 45-year-
old person – concerning the entities outlined above
– is about 25%–30% for the USA (Ferlay et al. 1999).
The corresponding risks for breast cancer screening
by X-ray mammography are < 0.10% and about 10%,
respectively.
As mentioned before, CT protocols used for
screening are by no means standardized at this time.
The same is true for the time schedule, discussed
in the literature for CT screening approaches. CT
protocols, optimized with respect to dose, as well
as prolonged screening intervals and later onset of
screening could significantly reduce dose and, thus,
radiation-induced risk.
7.1.5
Risk-Benefit Assessment
It is important to notice, that at the moment – in con-
trast to screening X-ray mammography – no valid
data from prospective, randomized clinical studies
are available, indicating a significant reduction in
cancer mortality due to CT screening approaches.
Therefore, risk-benefit analyses are not possible, at
least at the moment, for CT based screening ap-
proaches in asymptomatic persons.
In contrast, for breast cancer screening by X-
ray mammography, statistically sufficient data for
a risk-benefit analysis are available from various
randomized trials in Europe and the USA. See IARC
(2002) for a recent reassessment of theses studies.
The IARC expert’s panel concludes that there is suf-
ficient evidence that inviting women 50–69 years of
age to screening reduces their mortality from breast
cancer by about 20%–30%.
Defining the benefit of the screening as the num-
ber of breast cancer deaths prevented in the screen-
ing population and the risk as the number of radia-
tion-induced breast cancer deaths due to the repeated
X-ray mammographies, a risk-benefit analysis has
been performed by SSK (2002) and Nekolla (2005).
Under the assumption that screening reduces breast
cancer mortality by 20%, it is concluded that the
benefit outweighs the risk by a factor of about 12–50,
depending on the epidemiologic models used for the
risk assessment.
7.2
Risks Related to
Magnetic Resonance Imaging Procedures
In MR imaging three variants of magnetic fields
are employed to form cross-sectional images of the
human body: a high static magnetic field generating
a macroscopic nuclear magnetization, rapidly alter-
nating magnetic gradient fields for spatial encoding
of the MR signal, and radio-frequency (RF) electro-
magnetic fields for excitation and preparation of the
spin system. Because no ionizing radiation is used,
MRI is deemed safer than CT in terms of health
risks. Nevertheless, there are possible risks and
health effects associated with the use of diagnostic
MR devices that have to be considered (Ordidge et
al. 2000; Shellock 2001). In this context, a funda-
mental difference between ionizing and non-ioniz-
ing radiation has to be noted: radiation doses related
to diagnostic X-ray or nuclear medicine procedures
result in stochastic effects, whereas biological effects
of magnetic fields are deterministic. A stochastic
process is one in which the exposure determines
the probability of occurrence but not the magni-
tude of the effect. In contrast, deterministic effects
are those for which the magnitude is related to the
level of exposure and a threshold may be defined
(ICNIRP 2002). As a consequence, the probability
of detrimental effects caused, for example, by CT
or PET examinations performed over many years
accumulate, whereas physiological stress induced by
MR procedures is related to the acute exposure levels
of a particular examination and does, to our present
knowledge, not accumulate over the years.

7.2.1
Interaction Mechanisms and
Biological Effects of Magnetic Fields
The basic actions of static magnetic fields are trans-
lation and orientation effects of metallic objects or
macro-molecules, electrodynamic forces on moving
electrolytes, and effects on electron spin states of
chemical reaction intermediates. Until now, most MR
examinations have been performed using static mag-
netic fields up to 3 T, although whole-body MR sys-
tems with static magnetic fields up to 8 T are already
used in clinical tests. The literature does not indicate
any serious adverse health effects from the exposure
of healthy human subjects up to 8 T. However, sensa-
tions of nausea, vertigo, and metallic taste may occur
in magnetic fields above 2 T. The greatest potential
hazard comes from metallic, in particular ferromag-
netic materials (such as scissors, coins, pins, oxygen
cylinders) that are accelerated in the inhomogeneous
magnetic field in the periphery of an MR system and
quickly become dangerous projectiles. This risk can
only be minimised by a strict and careful manage-
ment of both patients and staff (cf. MDA 2002).
Rapidly switched magnetic gradient fields induce
electric fields in the human body, which, if of suf-
ficient magnitude, can produce nerve and muscle
stimulation. The induced electric field is propor-
tional to the time rate of change of the magnetic
field, dB/dt. From a safety standpoint, the primary
concern with regard to time varying magnetic fields
is cardiac fibrillation, because it is a life-threatening
condition. In contrast, peripheral nerve stimulation
is of practical concern because uncomfortable or in-
tolerable stimulations would interfere with the ex-
amination (e.g., due to patient movements) or would
even result in a termination of the examination.
Time-varying electromagnetic fields with frequen-
cies above 10 MHz (RF fields) deposit energy in the hu-
man body that is mainly converted to heat. The param-
eter relevant for the evaluation of biological effects of
RF fields is the increase in tissue temperature, which is
dependent not only on localized power absorption and
the duration of RF exposure, but also on heat transfer
and the activation of thermoregulatory mechanisms
leading to thermal equalization within the body. Since
temperature changes in the various organs and tissues
of the body during an MR procedure are difficult to
measure in clinical routine, RF exposure is usually
characterized by means of the ‘specific absorption rate’
(SAR in W/kg), which is defined as the average energy
dissipated in the body per unit of mass and time.
Risks of Screening and Preventive Diagnosis 133
7.2.2
Exposure Limits
To minimize health hazards and risks to patients
undergoing MR procedures, exposure limits for
the three different magnetic fields used in MRI are
specified in:

The product standard IEC 60601-2-33 provided
by the International Electrotechnical Commission
(IEC 2002) for manufacturers of MR equipment
to follow

The safety recommendation issued by the Inter-
national Commission on Non-Ionizing Radiation
Protection (ICNIRP 2004)
All major manufacturers of MR equipment have
adopted the regulations of the IEC product standard
and ensure compliance with the specified exposure
limits (which are with one exception identical with
those of the ICNIRP recommendation) by integrated
monitor systems.
With respect to the examination of patients in
clinical routine, both the IEC standard and the IC-
NIRP recommendation give exposure limits for two
different modes of operation: In the normal operating
mode none of the outputs have a value that may cause
physiological stress to patients. In the controlled op-
erating mode, on the other hand, one or more outputs
reach a value that may cause physiological stress to
patients. Examinations in the controlled mode thus
require not only a thorough clinical decision balanc-
ing possible side effects against foreseen benefits but
also medical supervision of patients. Up to now, there
are no recommendations published by regulatory
bodies or scientific communities specifying expo-
sure limits to be considered for MR procedures used
to screen asymptomatic persons. In any case, they
should be adapted in relation to the risk-profile of the
individual to be examined.
7.2.3
Contraindications
Pregnant females undergoing MR examinations are
exposed to the combined magnetic and electromag-
netic fields used in MR imaging. The few studies on
pregnancy outcome in humans following MR ex-
aminations have not revealed any adverse effects,
but are very limited because of the small numbers of
patients involved and difficulties in the interpreta-
tion of the results. Pregnancy should be an absolute
134 J. Griebel, G. Brix, and H. Kramer
contraindication for MR screening of asymptomatic
persons. The same holds for persons with electri-
cally, magnetically, or mechanically activated im-
plants (e.g., cardiac pacemakers and defibrillators,
cochlear implants, electronic drug infusion pumps)
as well as for persons with passive implants or other
objects of ferromagnetic or unknown material (e.g.,
aneurysm and haemostatic clips, orthopedic im-
plants, pellets, and bullets). Lists of implants and
materials tested for safety or compatibility in asso-
ciation with MR systems have been published and
updated (e.g., Shellock 2005)
7.3
Medical Risks and Informed Consent
Screening of asymptomatic individuals using im-
aging modalities has become a matter of contro-
versy, both in the scientific community and the
public media. Various providers offer imaging ex-
aminations targeted at early detection of serious
diseases, such as cancer, stroke, myocardial infarc-
tion and dementia. This approach is stimulated by
the increase of incidental detection of early disease
manifestations with modern imaging modalities.
Moreover, MDCT and MRI have the potential to
examine the whole body without compromising
image quality and diagnostic accuracy. Even if this
concept may appear convincing at the fi rst glance,
implementation of a screening program is associ-
ated with important implications and there has to
be clear scientific evidence, that this is beneficial
both for the particular participant of the program
and the society.
Presently, evidence for improvement in survival
and quality of life by screening using an imaging
method is only available for mammographic breast
cancer screening, provided that comprehensive
quality management is guaranteed. Major trials on
coronary calcium assessment and lung cancer de-
tection with CT are currently performed, which will
be completed within the next years and will provide
evidence about the value of these methods applied
in a screening scenario. When imaging methods are
offered outside of official screening programs, it is
mandatory, that legal and ethical considerations are
respected.
In Germany the use of diagnostic methods as-
sociated with ionizing radiation is only permitted
for purposes of patient treatment and diagnosis
when a justification is present which indicates that
the presumable advantage outweighs the hazards
of ionizing radiation. Screening mammography in
asymptomatic female individuals has been intro-
duced in Germany by law and extensive measures
of quality assurance had been taken. Any other im-
aging method employing ionizing radiation needs a
justification based on the personalized analysis of a
particular patient’s clinical symptoms, history, and
risk factors, respectively.
7.3.1
Informed Consent
From the legal point of view, diagnostic methods
without ionizing radiation, such as MRI and ultra-
sound, can be offered also to individuals without
medical justification. Nevertheless, the provider
of such services takes over extensive responsibil-
ity and may become subject to litigation, if adverse
events or complications occur. Even if no court suits
have been published yet, it can be anticipated that
requirements would be even more strict, when as-
ymptomatic individuals are subjected to diagnostic
imaging procedures. As long as no legislation con-
cerning preventive imaging exists and no decisions
by courts are made, the following recommendations
appear useful to us:

Extensive information of the client about the type
of examination to be performed

Potential adverse events and complications asso-
ciated with the method

Strengths and weaknesses of the method to be
employed

Follow-up examinations and further diagnostic
measures, which have to be take in case of patho-
logical, suspicious and ambiguous findings
Despite the high image quality which can be
achieved with modern imaging modalities, even if
large anatomical areas are scanned, e.g. with whole
body MRI, the examination technique can not be
as precise as with dedicated scanning protocols.
Therefore, the client has to be informed, that not
all organs included in the scanning range may be
examined with the same accuracy as in a dedicated
exam. For example, liver tumors may remain un-
detected without RES- and hepatotropic contrast
agents, respectively and prostate cancer without
the use of endorectal coils. Therefore, the patient

has to be informed, that he or she has to consult
a physician, whenever symptoms appear. Estab-
lished methods of disease screening, such as PSA
testing, Pap- smears or colonoscopy do not become
obsolete by whole body MRI. When a patient re-
ports about symptoms or a history of a disease
which requires surveillance, a dedicated exam has
to be performed.
The clients have to be precisely informed about
the nature and technique of the examination and
potential risks have to be mentioned. Before sign-
ing the written consent there has to be time and
opportunity to ask questions and to consider the
decision. For the provider of screening examina-
tions it is important to obtain written consent and
make notes about the verbal communication and
oral consent.
In MRI screening exams it has to be excluded
that the client has any metal implants and devices,
which may result in a risk for his or her health or
may be detrimental to a device. Even if contrast
media in MRI have a low rate of adverse reactions
and most of these allergoid reactions are mild,
moderate and severe reactions can not be excluded.
The client has to be asked, whether Gadolinium
based contrast agents have been applied previously
and whether they were well tolerated or not. In in-
dividuals with other diseases associated with an
increased tendency of allergoid reactions, such as
asthma and urticaria, the rate reactions to contrast
media is also increased.
Nephrogenic systemic fibrosis (NFS) is a recently
described disease entity which results from the ap-
plication of Gadolinium chelates in patients with
renal failure, especially when higher doses are ap-
plied or when more than one Gadolinium enhanced
exam is performed within a short period of time. In
clients with chronic kidney disease (GFR < 30 ml/
min/1.73 m2) special attention has to be paid.
In cardiovascular screening, examination of myo-
cardial perfusion may require applying a pharmaco-
logical stress. Without pharmacological stress only
high-grade coronary artery stenoses are detectable.
Stenoses of less than 80% can only be detected when
pharmacological stress is applied. Adenosine is well
established for stress examinations in perfusion MRI.
It is well tolerated by most patients and adverse reac-
tions can be treated by interrupting the infusion of
adenosine. Nevertheless, the clients have to be in-
formed about the possibility of adverse reactions and
adenosine should be only used in those individuals at
increased risk of coronary artery disease.
Risks of Screening and Preventive Diagnosis 135
7.3.2
False Positive and False Negative Results
Both false positive and false negative results may
have negative consequences for the clients of preven-
tive imaging exams. False positive diagnoses result
in psychological stress due to the diagnosis of po-
tentially serious diseases and the recommendation
of follow up examinations and interventional and
surgical procedures, respectively. Follow up exami-
nations and interventions may also be associated
with complications. It is warranted to inform the
clients prior to the preventive imaging exam about
the possibility of false positive results and about
adequate strategies of clarification and treatment,
if necessary.
Patients should also be informed about the possi-
bility of false negative results. Otherwise they might
underestimate signs and symptoms of a disease be-
cause they trust in the negative result of a previous
preventive whole body exam. This about possible
false negative and false positive results has to be in-
cluded in the written informed consent.
Clients for preventive imaging examinations may
be self referred or referred by a general practitioner
and other medical specialists, respectively. Unless
the client denies, the report of the exam, especially
if there is need for follow up or additional exams
should be sent to the physician who takes care of
the client. He or she should be encouraged to ask
for additional information and interpretation of the
screening report.
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 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging 137

Ethical Aspects of Screening and Preventive 8

Diagnosis with Radiological Imaging
Stella Reiter-Theil and Nicola Stingelin Giles

CONTENTS 8.7.2 Communicating the Screening Test

Result 143
8.7.2.1 Information Elements 143
8.1 Introduction: Ethical Issues in Radiology. 8.7.2.2 Counselling Elements 143
How Advanced is the Debate? 8.7.2.3 Elements of Relationship 144
What are the Issues? 137
8.8 Open Questions Put to Discussion 144
8.2 Defi nition of Screening and Public 8.8.1 How to Deal with Questionable Diagnoses
Health 138 Resulting from Screening Studies? 144
8.8.2 Should a Patient be Treated on the Basis of
8.3 Ethical Difficulties with Relevant Medical the Results of a Screening Exam Although
Knowledge as Such 138 He or She is A-Symptomatic? 145

8.4 Moving Towards Identifying General References 146

Ethical Aspects of Screening and
Preventive Diagnosis 139

8.5 Identifying More Specific Ethical Aspects:

Structure and Stages of a Screening
Program 140
8.5.1 The Planning of the Screening Process 140
8.5.2 The Implementing of the Screening
Process 141
8.1
8.6 Informed Consent (I.C.) as a Normative Introduction: Ethical Issues in Radiology.
Ethical Framework for Identifying How Advanced is the Debate?
Relevant Aspects of Implementing a What are the Issues?
Screening Program 141

8.7 Application of the Enriched Informed Ethical issues have been addressed in diagnostic
Consent Model 142 and in therapeutic fields of radiology especially in
8.7.1 Invitation to Participate in a Screening Anglo-American publications. Barron and Kim
Program 142 (2003) articulate doubts if American radiologists,
8.7.1.1 Threshold Elements 142
8.7.1.2 Information Elements 142 when faced with increasing technological oppor-
8.7.1.3 Counselling Elements 142 tunities of imaging, adequately apply the Ethics
8.7.1.4 Elements of Relationship 142 Code of the American College of Radiology in
8.7.1.5 Consent Elements 143 their doctor-patient relationship. The radiology
ethics debate in the U.S. includes concerns regard-
ing research and its regulation; patient rights;
S. Reiter-Theil, PhD informed consent and funding sources (Cooper
Professor and Director, Institute for Applied Ethics and 2005a,b). The European ethical debate in radiol-
Medical Ethics, University of Basel, Missionsstrasse 21a ogy, especially in the German speaking area, is
4055 Basel, Switzerland
N. Stingelin Giles, MA
still developing with some pilot work or educa-
Institute for Applied Ethics and Medical Ethics, University tional activities (Reiter-Theil and Hiddemann
of Basel, Missionsstrasse 21a, 4055 Basel, Switzerland 2000). Ethical issues here are mostly studied from
138 S. Reiter-Theil and N. Stingelin Giles
the physicians’ perspective (Schafer and Herbst
2003) such as patient information, an issue that
receives great attention. Institutional or politi-
cal aspects such as resource allocation are also
discussed (Schafer et al. 2005). A pilot survey of
Schafer et al. (2005) gives evidence of profound
disagreement among radio-oncologists regarding
the question whether waiting lists should be han-
dled differently for patient groups with palliative
vs curative treatment goals. The study revealed
ethical uncertainty about fair distribution of
limited services, ethical justification for waiting
lists, and about patient information on waiting
lists. This evidence of ethical difficulties corre-
sponds to the results of a representative investi-
gation in four European countries (Switzerland,
Italy, Norway and Great Britain) on physicians’
concerns about the practice of bedside rationing
both in diagnostic and therapeutic care (Hurst
et al. 2006; Hurst et al. 2007, accepted for pub-
lication 2008). The political European develop-
ment is stimulating ethical discourse because of
the need for harmonization, as illustrated by the
Euratom recommendations concerning referral
criteria for medical exposure and its necessary
implementation into national laws of EU member
states (Kainberger et al. 2002). Kainberger and
his co-authors from Austria discuss the role, the
achievements and the limitations of guidelines,
e.g. on standardization of referral criteria in diag-
nostic radiology. Corrao et al. (2004) refer to
significant events in contemporary history such
as the 1947 Nuremberg Code, and the US radia-
tion experiments of the 1950s and 1960s, which
raised serious ethical debate because they violated
principles of the Nuremberg Code. The radiation
experiments on American soldiers carried out
without informed consent are a paradigm case
for the discussion of the relation between ethical
principles or guidelines and their impact on court
cases and jurisdiction (Winslade and Krause
1998). Whereas some of the ethical concerns men-
tioned above concern severe misuse of technology
and research or a threat for patients, the ethical
dimension of radiological screening or preventive
diagnosis seems to be of a more subtle nature: they
centre around patient rights for information, ade-
quate counselling and an adequate risk-benefit
balance. Often they are implicit and need special
attention and analysis. This applies particularly
when we study the ethical issues going beyond the
individual patient.
8.2
Definition of Screening and Public Health
„Screening is a public health service in which
members of a defi ned population, who do not
necessarily perceive they are at risk of, or are
already affected by a disease or its complications,
are asked a question or offered a test, to iden-
tify those individuals who are more likely to be
helped than harmed by further tests or treatment
to reduce the risk of a disease or its complications“
(UK National Screening Committee 2000).
This defi nition makes clear that ethical aspects of
screening programs include both medical ethics
with an individual patient focus, and a societal,
public health perspective. The Institute of Medi-
cine defi nes “public health is what we, as a society,
do collectively to assure the conditions in which
people can be healthy” (Institute of Medicine
1988). Leading from the WHO defi nition of health
as being a state of complete physical, mental and
social well-being and not merely the absence of dis-
ease or infi rmity (which may be criticized for being
too broad), public health focuses on the societal
aspects of the determinants of health.
8.3
Ethical Difficulties with Relevant Medical
Knowledge as Such
Noting the variety of radiological imaging tech-
nologies available, e.g. MRI, X-ray, CAT scan, etc.,
the question must be asked if any medical risks
are associated with any procedure. Obtaining
such medical information requires interdisciplin-
ary cooperation. Problematic are areas in which
medical opinions vary as to whether physical risks
of a procedure are present, and if present, whether
the risks are significant. A further ethically rel-
evant medical-scientific fact is the predictive value
of various types of radiological imaging. Do any
of the procedures have only a limited predictive
value, so that a screening test will not necessarily
result in a fi rm and certain diagnosis being pos-
sible? Accepting that this is likely to be the case, we
may well have a continuum of the predictive value
or certainty of radiological imaging test results
ranging from:
 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging
• True positive: a disease being diagnosed that has
already manifested symptoms.
• True positive: a disease being diagnosed in its a-
symptomatic phase.
• A grey area of various probabilities that a disease
is present.
• A predisposition being identified that a disease
will develop (with predisposition being defined
as being a susceptibility to develop a disease,
noting that an increase or decrease in suscepti-
bility can result from environmental influences,
and life-style choices of the individual).
• True negative: a disease is not present, nor could
any predisposition be identified.
Each band of classification of predictive value of
a given test result along the continuum of firm test
positive-firm test negative has a specific set of ethi-
cal issues.
8.4
Moving Towards Identifying General
Ethical Aspects of Screening and
Preventive Diagnosis
In order to identify ethical aspects of screening
and preventive diagnosis, we need a framework
of relevant ethical concepts and normative prin-
ciples. The Belmont Report (1979) has been a
cornerstone in the modern codification of ethi-
cal principles for research on human subjects
(Tröhler and Reiter-Theil 1998); it proposed
that the basic medical ethical principles are respect
for persons, beneficence, and justice. The concept
of self-determination is derived from the principle
of respect for persons that is expressed in the
doctrine of informed consent (“IC”); other rules
derived from respect for persons are the right to
privacy and confidentiality, and the duty to pro-
tect the vulnerable. In the same year as the Bel-
mont Report appeared, Beauchamp and Childress
established a framework comprising the ethical
principles of respect for autonomy, beneficence,
non-maleficence and justice (Beauchamp and
Childress 2001). This set of four principles have
been widely appreciated and debated in medical
ethics and beyond. Each of the four principles is
139
a prima facie moral commitment. “Prima facie” is
a term introduced by the English philosopher W.
D. Ross (Ross 1930); it means that the principle
is binding unless it conflicts with another moral
principle. If it does, we have to choose between
them. The four-principle approach is neither an
algorithm nor a pre-fixed hierarchy of values to
be applied like a simple recipe, but “is a common
set of moral commitments, a common moral lan-
guage, and a common set of moral issues” (Gillon
1994). The particular ethical challenges of screen-
ing go beyond the individualistic orientation of
much medical ethics, and reach into the dimen-
sion of public health ethics. The “general moral
considerations” that apply to the population when
ethically evaluating public health interventions
can be seen as being the following (Childress
et al. 2002):
• Producing benefits
• Avoiding, preventing, and removing harms
• Producing the maximal balance of benefits over
harms and other costs
• Distributing benefits and burdens fairly (distrib-
utive justice) and ensuring public participation,
including the participation of affected parties
(procedural justice)
• Respecting autonomous choices and actions,
including liberty of action
• Protecting privacy and confidentiality
• Keeping promises and commitments
• Disclosing information as well as speaking hon-
estly and truthfully (often grouped under trans-
parency)
• Building and maintaining trust
Just as with medical ethics, public health benefits
and harm should include not only physical, but also
mental and social well-being. To these principles
should be added expressing and promoting solidar-
ity with the population. Some of these moral con-
siderations, especially benefiting others, preventing
and removing harm, will justify many activities
aimed at improving public health (Childress et al.
2002). It seems at first glance that most of the listed
topics are also convincing candidates for an individ-
ualized ethics. However sometimes a society cannot
simultaneously realize its obligations to promote
public health and at the same time respect the rights
due to individuals, such as autonomy, privacy and
confidentiality.
140 S. Reiter-Theil and N. Stingelin Giles
8.5
Identifying More Specific Ethical Aspects:
Structure and Stages of a Screening Program
Now that a group of ethical principles, criteria and
considerations have been suggested, the next step
is to reflect on the structure and stages of a screen-
ing program; to identify where ethical difficulties
could arise, and reflect on which ethical principles
should guide decisions and actions. Although this
text focuses on the physician and adult examinee or
patient perspective, a more differentiated analysis of
the ethical aspects of preventive diagnostic screen-
ing would require other perspectives to be consid-
ered, including individuals without the capacity to
make autonomous decisions, and the perspective of
the family.
8.5.1
The Planning of the Screening Process
The structure of the screening process can be divided
into two stages: the planning and the execution.
The various steps in the planning stage will now be
considered. The first step is the decision for which
disease a program will be made. This involves issues
of a just and fair allocation of resources. It must
then be decided if a program will be voluntary or
compulsory. Compulsory health measures can only
be ethically justified in cases of danger to the popu-
lation, usually regarding infectious disease such as
HIV or SARS. Compulsory public health measures
require a careful ethical analysis and weighing-up
the damage regarding ethical principles such as
respect for autonomy and privacy, vs the responsi-
bility of the state and medical community towards
the population.
The following comments focus on voluntary
programs. The WHO has developed criteria for
appraising the validity of screening programmes.
The following list is based on a 1968 World Health
Organization document:
1. The condition being screened for should be an
important health problem.
2. The natural history of the condition should be
well understood.
3. There should be a detectable early stage of the
disease.
4. Treatment at an early stage should be of more
benefit than at a later stage.
5. A suitable test should be devised for the early
stage.
6. The test should be acceptable to the population.
7. Intervals for repeating the test should be deter-
mined.
8. Adequate health service provision should be
made for the extra clinical workload resulting
from screening.
9. The risks, both physical and psychological,
should be less than the benefits.
10. The costs should be balanced against the benefits
(Wilson and Jungner 1968).
This list contains primarily medical and scien-
tific criteria, although ethical criteria are implic-
itly inherent, especially in criteria 4, 6, 9, and 10.
Criterion 4 focuses on the individual benefit com-
pared to burden – the principle of beneficence or
non-maleficence; criterion 6 regards a civil rights
perspective, both general and individual; and
criteria 9 and 10 have ethical implications due to
their utilitarian approach at a societal level. The
screening program design must defi ne the pro-
gram selection criteria. The criteria will vary
according to whether the program is a research
project, or a health intervention. Selection crite-
ria for a research project will be concerned that
the sample is representative of the population to
ensure scientific integrity of the research. For a
health intervention screening program, the selec-
tion criteria for participation are likely to be based
on characteristics of the population perceived
by medical professionals as indicating that they
are at risk. Ethically relevant is in both cases to
ensure that selection is based on reasonable medi-
cal facts, is not discriminatory, and is compatible
with the principle of justice. A well known exam-
ple for challenging these principles is the fact that
“orphan diseases” exist that are not promising in
the (career) interest of researchers or in the (eco-
nomic) preferences of pharmaceutical companies.
The public health aspects of a screening program
require that a transparent communications strat-
egy and campaign be designed. The information
campaign should build trust; avoid any stigma
being attached to the screened public; generate
solidarity, and thereby help improve acceptance of
the program and the level of participation. Steps
must be undertaken to ensure quality control of
the program. This should include an error report-
ing system as well as an orientation at guidelines
(Hart 2005).
 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging
8.5.2
The Implementing of the Screening Process
The steps include: communicating to selected groups
that they are invited to participate; the decision
making process of the invitee whether to participate
or not; the radiological imaging procedure itself;
communicating the results, and taking any neces-
sary decisions that follow there from. The doctrine
of IC provides extensive guidance for these activi-
ties, and will now be addressed in detail.
8.6
Informed Consent (I.C.) as a Normative
Ethical Framework for Identifying Relevant
Aspects of Implementing a Screening
Program
The doctrine of I.C. is well established and legally
regulated in many modern societies, but still being
developed and debated. In its „pure“ form it is a
strictly respect-for-autonomy based concept opposed
to (medical) paternalism; it has been criticized for
not acknowledging important aspects of care-ori-
ented ethics. An interesting debate has taken place
in human genetics and genetic counselling (Reiter-
Theil 1998a; Nuffield Council on Bioethics 2002)
where the rule of non-directivity was taken as an
implicit substitute for an ethical respect-for-auton-
omy orientation towards the client neglecting any
need for advice and recommendations from the health
care professional. Particularly in the light of concerns
regarding eugenics and paternalism, counselling has
often been propagated as best being non-directive
(Nuffield Council on Bioethics 2002). In exag-
gerated interpretations this meant that no directions
should be given to the patient, although leaving the
patient alone with the decision is ethically question-
able. A more balanced understanding of non-direc-
tivity is that advice should not be given in a manner
which would limit or dissuade the clients from form-
ing their own decision. Adopting non-directivity
as an interpretation of the right to autonomy risks
neglecting the principles of beneficence and non-
maleficence (Reiter-Theil 1998a,b). For screening
and preventive diagnostic procedures we can assume
a similar problem structure and apply this analysis.
Therefore instead of a “purist” approach, a combined
“respect and protection model” is suggested.
141
Self-determination (autonomy) should be
respected in combination with support and protec-
tion being offered to clients and patients according
to their needs. Having rights as a patient should not
mean being left alone with the privilege and risk of
making critical and difficult choices. Informed con-
sent is a necessary, but not a sufficient ethical orien-
tation for the whole enterprise of good counselling.
Beauchamp and Childress (2001) formulated
their model of Informed Consent around three ele-
ments:
1. Threshold elements (competence, voluntariness)
2. Information elements (clarification of medical
facts, information on current status diagnosis,
prognosis, recommendation, understanding)
3. Consent elements (decision making, authoriza-
tion)
Especially for practical instruction and a more
comprehensive ethical orientation including
aspects of care and support for clients and patients,
an enriched version of this model was suggested
(Reiter-Theil 1998c; 2003). The resulting enriched
model has two additional components, the elements
of Counselling and the elements of Relationship.
They are suggested for all health care professionals
involved in patient care or screening and preventive
programs, whereas classical Informed Consent has
been a privilege and an obligation to physicians.
The Enriched Model of Informed Consent accord-
ing to Reiter-Theil (1998c; 2003) is as follows:
1. Threshold elements
• Competence
• Voluntariness
2. Information elements
• Clarification of medical facts
• Information on current status diagnosis, prog-
nosis
• Recommendation
• Understanding
3. Counselling elements
• Encourage a dialogue
• Time, patience
• Contextualize information
4. Elements of relationship
• Involve trusted people
• Show respect for individual and support their
sense of their own responsibility
• Care
5. Consent elements
• Decision making
• Authorization
142 S. Reiter-Theil and N. Stingelin Giles
8.7
Application of the Enriched Informed
Consent Model
Critical ethical aspects of the implementation of a
screening program using this I.C. model will now
be identified. The following should not be seen as
a comprehensive review of all aspects of the I.C.
process, but should rather serve as an introduction
to elements of I.C. particularly critical to screening
procedures.
8.7.1
Invitation to Participate in a Screening Program
8.7.1.1
Threshold Elements
The voluntary nature of the screening process, and
that withdrawing from the screening process is pos-
sible at any stage, should be stated in writing in
the invitation to participate, and regularly repeated
during the screening process, assuming that the
candidate is competent to decide.
8.7.1.2
Information Elements
Persons being screened are entitled to receive suf-
ficient information in a way that they can under-
stand what is proposed. They must be made aware
of medical, psychological and social risks as well as
benefits. Clarification of the following medical facts
should be given:
• Information on the disease being tested for
• Why an individual was selected
• The benefits of screening
• Any risks of the screening procedure itself
• Full details of the screening procedure
The following further non-medical information
should also be supplied:
• Information on how and when individuals will be
informed of the individuals results
• What the next steps would be should the result
be positive
• The fact that consent to screening does not imply
consent to any therapy
Information on current diagnosis and prognosis
should be provided:
• Reasons for the individual being selected for
screening
• The risk of the individual developing the disease
• Facts on the therapeutic options available
• Information on the reliability of the screening
test, i.e. the rate of false positives and false nega-
tives; the chance of the predictive value being less
than 100%
8.7.1.3
Counselling Elements
The key ethical principles of counselling are dialogue
and communication; both should ensure that the indi-
vidual offered screening understands the purpose of
the test, and any risk of harms and benefits. Counsel-
ling should be available to help the examinee decide
to participate or not. Often the information given is
initially plausible for the client, but upon reflection
does not make sense to him and his everyday life.
An important remedy here may be to contextualize
the given information with reference to the person‘s
situation. An extra effort towards good counselling
may consume time initially, but may help to save
time in the long run avoiding repetitive clarification
of misunderstandings.
8.7.1.4
Elements of Relationship
The health care professional should understand that
he or she has to offer a relationship, not only for
the time a treatment lasts, but already during an
I.C. procedure. This relationship cannot only rely
on cognitive information. It has to take into account
existential aspects of the patient‘s life as well. Here,
a central message of the model becomes most evi-
dent: respect and support or protection have to be
integrated in good counselling and the relationship
between the health care professional and client.
Entering a screening programme and staying in
it may be one of those challenges creating anxiet-
ies about one‘s condition of health and the future.
This may require assistance; it may be helpful to
involve trusted family members of the client. The
relationship should be based on an assurance of con-
fidentiality, e.g., in the handling of the results, thus
improving patient trust in the program.
 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging
8.7.1.5
Consent Elements
The decision made by the client should be respected,
even if it is „no“. It may be difficult for staff to accept
a later withdrawal of the participant, but the right
of a person to change his or her mind also has to
be respected. A valid authorization is necessary to
justify that the screening procedure is carried out
in the client. An explicit consent may prevent mis-
understandings.
8.7.2
Communicating the Screening Test Result
The above outlined ethically critical aspects regard
the decision to participate in a screening program.
Communicating the result should likewise follow
the enriched model of I.C., and best be done in
conjunction with a personal consultation, with the
information being backed up in writing.
8.7.2.1
Information Elements
Medical ethics has widely accepted the validity of
a patient’s right to know; once established it has
taken additional time to enforce the patient‘s right
not to know details of his or her medical status.
After undergoing screening, an individual should
normally in line with the principle of the right to
know be fully informed of the results, both positive
(i.e. abnormal) for the disorder being screened for,
or negative (i.e. no defect is found), or if the test was
inconclusive – and why. Even if an individual has
voluntarily and knowingly agreed to take part in a
screening, they should be free to exercise after test-
ing the right not to know. Exceptions to this prin-
ciple could be in the event of a contagious disease,
e.g. TB or if family members are affected in their
lives by a potential genetic disposition.
Medical facts should be clarified. These facts
should include the following:
1. The risk of the individual developing the disease
in the light of the results
2. The reliability of the screening test diagnosis i.e.
the rate of false positives and false negatives; the
chance of the predictive value being less than
100%
• Clarification will be especially difficult if the
test result failed to make a firm diagnosis, but
143
indicated a likelihood or a predisposition; the
medical professions have a duty to generate
and act on reliable scientific grounds as far as
possible;
• When a fi rm diagnosis is not possible, health
care professionals must communicate the pre-
dictive nature of the test result.
3. Facts on the therapeutic options available: their
benefits and risks, possible variations in response
/ non-response to therapies
4. Information on current status, diagnosis, prog-
nosis; the prognosis should be explained under
both the condition that available therapy is com-
menced, or is rejected by the patient
5. Reasons should be given why a screening would
be indicated and for which purposes and whose
benefits
6. Recommendation: making a medical recommen-
dation does not mean to behave in an authoritar-
ian (“directive”) way and breaking the principle
of respect (see Section 8.7.2.2)
• The medical contents of the recommenda-
tion will vary according to the screening test
result interpretation; regarding uncertain test
results and the location of a predisposition,
the recommendations may include preventive
medications, life style changes that will reduce
risk of disease developing, and regular further
check-ups.
8.7.2.2
Counselling Elements
The elements of the optimal counselling process
in communicating the screening test result should
include encouraging a dialogue; taking time; exer-
cising patience, and contextualizing the infor-
mation for a particular individual. An underly-
ing belief in justifying a screening program may
be that a potential benefit lies in ‘knowledge’ as
a prerequisite for planning one’s life, for exercis-
ing autonomy, and for being able to take respon-
sibility for one’s life. However with knowledge
can come social risks, confl icts in the family or at
work, and insurance problems. Some fi ndings have
serious medical, social or fi nancial consequences
for individuals and their family, and will require
that decisions be taken. How knowledge is dealt
with will be a function of an individual’s prefer-
ences, history, personal situation, and will also be
influenced by their personal social network, and
the wider ‘ethical resources’ in place in a society
144 S. Reiter-Theil and N. Stingelin Giles
(Reiter-Theil 2003). A particularity of the screen-
ing process is that a-symptomatic individuals may
enter a program believing themselves to be well,
and be diagnosed as either having a condition, or
having a likelihood or predisposition for a disease
developing. This differs from a clinical setting more
familiar to patients in which persons seek medical
advice when they are already symptomatic. Fur-
thermore an uncertain screening diagnosis can be a
distress for an individual and their family; knowing
that one has a likelihood or predisposition can be
benefit or burden. It can therefore be argued that
having counselling available is not only desirable,
but should be part of a good program.
Bearing all this in mind, for some individuals in
some situations the burden of exercising autonomy
and independently deciding what action to take can
be a strain. Can or should counsellors offer such a
recommendation, or should they remain ‘neutral’?
Indeed one can argue that the right to autonomy is
best expressed by counsellors offering their profes-
sional advice and recommendation, based on facts
fully and understandably explained, and based on
their understanding of the individual’s situation,
trusting the client to be able to absorb and consider
this input when making their own deliberations
and arriving at their autonomous decision. Further
arguments for counsellors making a recommenda-
tion are that counsellors are likely to have specific
knowledge and expertise that they are obliged to
share with the client, and have an obligation to help
those seeking advice. However any recommenda-
tion should be laid on the table for discussion, and
not communicated as being a directive. There is an
important difference between offering advice, and
being paternalistic or coercive, even an effort to per-
suade may collide with the respect-component of
the approach. A health care professional will need
good reasons and a robust evidence of patient ben-
efit to try to persuade him or her to do something
he or she is not yet convinced of. An adequate rec-
ommendation should contextualize the information
for a particular individual in order to link cognitive
bits of information with emotional significance and
practical experience.
8.7.2.3
Elements of Relationship
The principle of confidentiality of medical informa-
tion is an established part of the traditional medi-
cal ethos as well as of modern medical ethics, and
any departure from this principle (without consent
of the patients) requires substantial justification. In
the event that a genetic test result is of importance
for the health of family members, and the patient
does not wish to communicate the results, opinions
vary in the field of medical ethics as to what extent
health care professionals are justified in seeking to
persuade the patient to disclose, or in some cases
to interpret the right to privacy as being a quali-
fied right that should be overridden by substan-
tial grounds, e.g., for reasons of preventing severe
damage of others. It should be reflected whether or
not a screening test could at all play a similar role as
a genetic test result for third parties and next of kin.
Regarding the possible abuse of screening results
by insurance or employers confidentiality should be
assured. However in cases where due to the nature
of the employment pursued by an individual others
could be put at risk of harm should the disease
develop, keeping the health status confidential is
ethically problematic. Thus we see very clearly that
the freedom of the individual and respecting his or
her rights to confidentiality meets their limits when
respecting these rights interferes with the rights of
others, especially when the others are in a dependent
position (such as children).
8.8
Open Questions Put to Discussion
8.8.1
How to Deal with Questionable Diagnoses
Resulting from Screening Studies?
Although any test with a low predictive value that
has accordingly a significant risk of false diagno-
sis being made should not be used in screening
programs, many radiological procedures may have
sufficient predictive value across the board to jus-
tify a program, whilst not precluding that some test
results will not allow a conclusive diagnosis to be
made. A questionable diagnosis, being a diagno-
sis with less than certain predictive value, brings
with it special ethical considerations from a health
care professional perspective. The doctrine of I.C.
and „Shared Decision Making“ informs that han-
dling such situations must be a joint undertaking
between the individual, health care profession-
als or counsellors. Assuming that the individual
 Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging
indicates that they desire to know the test result,
an individual should in line with the principle of
the right to know be fully informed of the results,
including if the test was inconclusive, and why it
was inconclusive. Optimally a screening candidate
will have been fully informed before entering the
screening program of the reliability of the screen-
ing test, i.e. the rate of false positives and false
negatives and the chance of the predictive value
of the result being less than 100%. One must be
aware, however, that concepts such as reliability or
probability are not easily understood by lay people
(and not even by all health care professionals as we
learn from cognitive psychological studies show-
ing that severe errors occur in interpreting risk
ratios). The health care professional should make a
balanced recommendation based on medical facts
(such as the severity of the disease, and the rapidity
of progress of the disease in question), contextual-
ized factors specific to the individual, and by reflec-
tion and analysis using as an ethical framework
the enriched model of Informed Consent and the
principles of respect for autonomy, beneficence,
non-maleficence and justice. The contextualized
recommendations can include monitoring health
and repeating the screening procedure after some
time has elapsed, or to commence any preventive
or curative therapy available assuming a worst case
scenario of the inconclusive results. Recommenda-
tions may include preventive medications, life style
changes that will reduce risk of disease developing,
and regular further check-ups. An ethical point of
view does not reduce empirical uncertainty, but
it may contribute to a responsible attitude and
practice.
8.8.2
Should a Patient be Treated on the Basis of the
Results of a Screening Exam Although He or She
is A-Symptomatic?
It is ethically relevant to differentiate between a dis-
ease being firmly diagnosed in its a-symptomatic
phase, and a result that suggests a predisposition or
a probability that a disease will develop. The ethical
responsibilities of the health care professionals in
formulating a sound recommendation can be anal-
ysed using the framework of their having a duty of
beneficence, a duty to prevent harm, and a duty of
justice. Regarding a firm diagnosis, it is prima facie
in accordance with the duty of beneficence to offer
145
and recommend treatment. As identified above, the
doctrine of I.C. requires however acknowledging
that the fact that an individual who consented to
screening did not automatically consent to ther-
apy, and that the decision as to whether and how a
patient should be treated must respect the patient’s
right to self-determination (respect for autonomy).
Although the recommendation based on medical
factors for an a-symptomatic true positive result
may essentially be to proceed with treatment, the
following components should guide the physician-
patient communication:
• Full and transparent information on the reliabil-
ity of the screening test result must be given.
• Facts on the therapeutic options available: their
benefits and risks (side effects) must be given.
• Variations in response or non-response to thera-
pies should be outlined.
• The speed of progression of the disease should be
stated.
• How the disease will manifest itself in its various
stages must be outlined.
Regarding a predisposition or probability that a
disease will develop, or whether treatment should
be recommended from a medical point of view may
depend on weighing up a number of factors. These
include:
• The predictive value of the diagnosis of a predis-
position
• The time scale of the possible progression (if it
occurs at all) of the disease
• The gravity of early symptoms and their revers-
ibility
• If resources are available to offer to repeat the
screening procedure
• Whether the predisposition can be reduced by
non-medical intervention changes in life-style,
noting that some predispositions can be stimu-
lated and worsened by environmental factors
outside the control of the medical profession or
the individual
For both a diagnosis of a disease being present
in its a-symptomatic phase, and the identification of
a predisposition, in making a recommendation and
arriving together with the patient at a decision as to
how to proceed, not only medical harms and ben-
efits but also social and psychological elements as
outlined above from the patients perspective need
to be contextualized and included in the decision
making process.
146 S. Reiter-Theil and N. Stingelin Giles
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 Cardiovascular Diseases: MRI 147

Part 2:
Organ-Related Examinations

Screening in Unselected Populations

 Cardiovascular Diseases: MRI 149

Cardiovascular Diseases 9
9.1 MRI
Susanne Ladd and Harald Kramer

CONTENTS Principally, screening efforts for early detection of

9.1.1 A Screening Protocol for Atherosclerosis 101
9.1.2 Preparation of Cardiovascular Screening
MRI Examinations 106
9.1.2.1 The Client 106
9.1.2.2 Predictive Value of
Cardiovascular Screening with MRI 106
9.1.3 Documentation of Results 106
9.1.4 Results of
Cardiovascular Screening Programs 107
9.1.5 Conclusion 108
References 108
9.1.1
A Screening Protocol for Atherosclerosis
Cardiovascular disease is the leading cause of mor-
tality and an important economic factor in western
societies (Anderson et al. 1991). While the known
risk factors are readily identifiable by a combination
of physical exam, laboratory analysis and patient
history, magnetic resonance (MR) imaging theo-
retically offers a unique opportunity to assess what
damage if any has already been infl icted onto the
cardiovascular system before the disease becomes
symptomatic.
S. Ladd, MD
Department of Diagnostic and Interventional Radiology and
Neuroradiology, University Hospital Essen, Hufelandstrasse 55,
45122 Essen, Germany
H. Kramer, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
atherosclerosis seem to be reasonable: due to the high
prevalence in the general population, due to the fact
that many risk factors are well known, which allows for
effective preselection of patients, and due to the good
therapeutic results in case of early treatment or even
change of lifestyle. Not only are cerebral and myocar-
dial infarctions often underdiagnosed (Lundblad
and Eliasson 2003), but also peripheral arterial dis-
ease (PAD), which clinically is relatively easy to diag-
nose, is often not known to patients or their physicians
(Hirsch et al. 2001). However, if these atherosclerotic
changes progress untreated they cause serious conse-
quences like non-healing ulcers and amputations.
The systemic nature of atherosclerosis requires
a dedicated screening protocol for highly accurate
detection of vascular pathologies in more than one
area of the body. This includes:

The cerebrovascular system with its extra- and
intracerebral arteries as well as the dependent
parenchymal structures in the brain (Fig. 9.1.1).
Early recognition of cerebrovascular disease
(CVD) is all the more important as this disease
is difficult to predict; many patients will only be
diagnosed with CVD when they become symptom-
atic (McDaniel and Cronenwett 1989). MR of
the brain has become an indispensible tool for the
detection of hemorrhagic and non-hemorrhagic
insults, malformations and strokes. The detection
of microangiopathic changes is equally important,
as these can be regarded as a predictor of hem-
orrhagic and lacunar infarctions (Imaitsumi et
al. 2004). MRI’s high soft tissue contrast and sen-
sitivity to flow and susceptibility make it also a
valuable tool for the detection of early changes of
cerebral blood supply (Fiehler et al. 2005).

Assessment of the aorta with its visceral branches
and of the peripheral arteries is the second scope
of a comprehensive atherosclerosis screening pro-
gram. With the introduction of contrast-enhanced
150 S. Ladd and H. Kramer
3D sequences (Prince 1994), MR angiography
(MRA) has experienced a noteworthy expansion.
Today it is possible to image the whole peripheral
arterial tree from the carotids to the ankles with
high contrast to the surrounding structures within
a short time in a single examination (Goyen et al.
2002) (Fig. 9.1.2, Table 9.1.1). Comparative stud-
ies have demonstrated the high accuracy of MRA,
with sensitivities and specificities for the presence
of stenoses and occlusions of more than 94% in
PAD (Meaney et al. 1999; Goyen et al. 2002)
and especially in internal carotid artery stenoses
(Borisch et al. 2003). Moreover, MRA produces
recordable images and renders an interobserver-
agreement which is higher than that for digital
subtraction angiography (DSA) (Schoenberg et
al. 2002). Certainly other radiological modalities
such as digital subtraction angiography (DSA) or
computed tomography angiography (CTA) pro-
vide higher spatial resolution than MRA, and DSA
additionally offers dynamic information. But both
modalities have to deal with the disadvantage of
ionizing radiation and potentially nephrotoxic
contrast agents (CA). DSA additionally implies
other well known risks from arterial puncture and
catheterization. Thus, neither mentioned modali-
ties can be used for imaging healthy individu-
als participating in a screening exam. The pos-
sibility to image all these vessels within a single
short whole-body MR angiography examination
has already changed the diagnostic procedure in
many radiological departments.

Finally, the heart must be assessed. Ischemic heart
disease can be imaged to advantage with MRI (van
der Wall et al. 1997). Fast cine-imaging for the
evaluation of global and regional contractility as
Fig. 9.1.1. TOF MRA of the intracranial vessels as well as pre- and post-contrast agent admin-
istration morphologic imaging of the brain to detect intracerebral vessel abnormalities, e.g.
aneurysms, and intracranial masses
well as late-enhancement studies for the detection
of myocardial scars have already entered clinical
routine (Barkhausen et al. 2001; Hunold et al.
2002) (Fig. 9.1.3). MRI of the heart has evolved as the
gold standard for the evaluation of filling volumes
(Rajappan et al. 2002). The important structures
for diagnosing coronary heart disease (CHD) are
the coronary arteries; however, coronary imaging is
not yet ready for being implemented into a routine
cardiac MRI protocol. But even when “only” cin-
ematic studies and late enhancement studies for the
depiction of myocardial infarctions are performed,
this renders important information, as the rate of
CHD in general and particularly unknown previ-
ous myocardial infarctions are not to be neglected
(Lundblad and Eliasson 2003). Additionally, per-
fusion imaging of the left ventricular myocardium
can also be performed. There are two options for
performing perfusion imaging. The first option is
perfusion imaging at rest. In this case only non-
perfused myocardial areas or areas distal to a high
grade coronary artery stenosis can be detected by
means of a perfusion defect. The likelihood of an
unknown myocardial infarction or a high grade
coronary artery stenosis detected by perfusion
imaging at rest in non-symptomatic individuals is
very low. Thus, if perfusion imaging of the myo-
cardium is performed in screening individuals, it
should be performed at stress. This second method
for performing perfusion imaging requires the
pharmacological induction of stress, which allows
one to detect also coronary artery stenoses of less
than 80%. This raises the question whether it is
medically and legally justifiable to perform phar-
macological induced stress perfusion imaging in
check-up clients.
 Cardiovascular Diseases: MRI 151

Based on a whole-body MR angiography ap- Fig. 9.1.2. Whole-body MRA

proach (Goyen et al. 2002), a fairly comprehensive performed in four steps all
with a spatial resolution of
combined protocol can be developed, which accom-
less than 1.6 × 1.0 × 1.5 mm3
plishes the depiction of brain, heart and peripheral within a total imaging time
arteries, as described in Goehde et al. (2002) (Ta- of 88 s. Spatial resolution of
ble 9.1.2). This protocol optimises the logistic of the cervical and lower leg ves-
intravenous contrast agent administration, which sels is 1.0 × 1.0 × 1.0 mm3.
is not trivial at all, if several different MRI exami- Different strategies to per-
nations shall be combined within the same single form whole-body MRA are
described in Fig. 9.1.4
setting. This protocol offers the high image quality
known from clinical routine, but can be performed
in less than 60 min (Table 9.1.2):

The head is imaged according to clinical standards
and includes T2-weighted images as well as T1-
weighted images pre and post CA administration,
diffusion-weighted sequences and a multi-slab 3D
time of flight angiography. After termination of
all subsequent sequences, for which intravenous
contrast agent has been administered, a final T1-
weighted gradient-echo sequence is applied. This
increases the sensitivity for potential intracranial
tumors.

Table 9.1.1. Injection scheme of whole-body MRA when using a dedicated whole-body MR sys-
tem equipped with a matrix coil system and wide table movement

CA dose @ flowrate Acquisition time Spatial resolution

Carotid arteries 12 ml @ 1.5 ml/s 21 s 1 × 1 × 1 mm3

Calf and feet 37 s 1.2 × 1 × 1 mm3
Abdominal aorta 20 ml @ 1.5 ml/s 15 s 1.6 × 1 × 1.5 mm3
Thigh 15 s 1.6 × 1 × 1.5 mm3

Fig. 9.1.3. Cine imaging of the left ventricular myocardium with up to 11 short axis slices in one breathhold. Additionally
two and four chamber view series can be acquired. To calculate functional parameters high temporal resolution is very
important. If it is less than 50 ms, end systolic volume is over- and ejection fraction under-estimated
152 S. Ladd and H. Kramer
Table 9.1.2. Flow chart of an atherosclerosis screening MR protocol
Examination Sequence
Cranial MR 1. T1w SE axial
2. T2w TSE axial
3. 2D inversion recovery FLAIR head axial
4. Diffusion weighted echo planar
imaging axial
Whole-body 1. 5 3D stations spoiled GRE coronal
MR angiography
Cardiac MR 1. 2D HASTE axial
2. 2D trueFISP/balanced FFE/FIESTA
short axis (“shared phases”), long axes
3. 2D inversion-recovery GRE
(“late enhancement”) long axes
4. 3D inversion-recovery GRE
(“late enhancement”) short axis
Cranial MR 1. Contrast-enhanced GRE axial

As a second step, whole-body MR angiography
is performed. Meanwhile, a variety of different
MRA methods exists, primarily depending on
the MRI system used. The MRI technique usually
employed consists of the consecutive acquisition
of contrast-enhanced three-dimensional data sets
of 4–5 stations of the body. When utilizing a stan-
dard MRI system without dedicated platforms
and with restricted table movement of 150 mm
maximum, whole-body MRA is performed in two
parts. In part one, the patient is positioned head
first in the magnet, and MRA of the thoracic aorta
and the cervical arteries is acquired. The second
part consists of MRA of the abdominal aorta and
the arteries of the lower extremity. For this pur-
pose, the patient is repositioned feet first in the
magnet, and four consecutive MRA slabs from the
abdominal aorta to the feet are acquired. When
using a dedicated rolling platform like the Angio-
SURF system, whole-body MRA can be performed
without repositioning the patient. The patient is
placed on the rolling platform and is manually
pulled from one station to the next. Five consecu-
tive MRA slabs are acquired from the scull base
down to the feet (Fig. 9.1.4a). A problem that can
occur with both methods is venous contamination
in the lower legs. When using a dedicated whole-
body MRI system with both a large range of table
Comments
Native
–
–
–
Individual bolus timing in ascending aorta
Double dose intravenous paramagnetic contrast agent
Heart and lungs
Functional imaging, valve pathologies
Makes use of contrast agent applied for
MR angiography
–
Makes use of contrast agent applied for
MR angiography
movement and a large field of view, venous con-
tamination can be eliminated in nearly all cases
by use of an optimised imaging protocol. In this
protocol the patient is positioned head first in
the magnet during the whole MRI exam. MRA
datasets are acquired in two steps with two CA
injections. The first step consists of imaging of
the thoracic aorta and cervical vessels as well as
imaging of the lower legs and feet. The possibility
to move the table from the cervical station down
to the lower legs offers the chance to “overtake”
the CA bolus after the cervical vessels have been
imaged, and to perform MRA of lower legs and
feet without venous contamination. The second
step with a second injection of CA covers the
abdominal aorta and thigh vessels in two consecu-
tive MRA blocks (Fig. 9.1.4b). Another option is
the so-called “venous compression” (Herborn et
al, 2003). With this technique, the venous return
of the contrast agent is delayed by use of a mid-
femorally positioned thigh cuff with a pressure of
60 mm Hg.

Cardiac imaging consists of a T2-weighted axial
“dark blood” sequence for a gross morphologic
survey of the heart; this sequence can be extended
cranio-caudally to additionally cover the entire
lung; this technique has shown to be quite sensi-
tive for the detection of lung nodules (Vogt et al.
 Cardiovascular Diseases: MRI 153

2004). Cardiac functional imaging with ultrafast
gradients (optimal image quality can be reached
with T2/T1-contrasts) as well as “late enhance-
ment” studies with preparing inversion pulses
for optimal contrast of myocardium vs scar is
performed in short and long axes. Here, the late
enhancement imaging makes use of the previ-
ously administered contrast agent (for MR angi-
ography); a re-administration of contrast agents is
not required. Cine imaging of the left-ventricular
myocardium not only depicts potential wall move-
ment dysfunction as indicator of CHD, but it also
allows to calculate functional parameters such as
enddiastolic and systolic volumes, ejection frac-
tion and myocardial mass normalized to patient’s
body surface. Cardiac imaging can be comple-
mented by perfusion imaging to detect perfusion
defects and thus to assess the status of the coro-
nary arteries. When performing perfusion imag-
ing at rest, only coronary artery stenoses of more
than ~80% or vessel occlusions can be detected. If
perfusion imaging is performed using pharmaco-
logically induced stress, even lower grade stenoses
can be detected.

Fig. 9.1.4. a AngioSURF system: the images show the patient outside the magnet to demonstrate the five fi xed table positions.
The rolling platform is pulled manually through the magnet. To increase contrast an integrated spine array as well as an an-
terior positioned body array is used. Lower images show five consecutive acquired MRA steps from the skull-base down to the
feet. b Coil setup for whole-body MRI when using a matrix coil system in combination with a dedicated whole-body MR system.
Before starting the exam all necessary coils are placed at the patient, whilst the exam they can be selected individually
154 S. Ladd and H. Kramer
9.1.2
Preparation of
Cardiovascular Screening MRI Examinations
9.1.2.1
The Client
To ensure a safe, meaningful MRI screening exami-
nation and a satisfied client, various aspects have to
be considered:

The screening exam has to be targeted at individu-
als at risk of diseases which can be detected with
a particular exam.

Is the client self motivated and willing to undergo
therapy and follow recommendations of life style
modification, if pathological findings are detected?

The client has to be extensively informed about
the examination and the potential consequences
of positive ore suspicious findings.

Is the client willing to undergo additional diag-
nostic or interventional procedures in case of
positive or questionable findings?

The clients have to be aware of potential adverse
reactions and risks of the examination (allergic
contrast media reactions, stress test).

Whole body MRI is not able to detect each pathol-
ogy, even if the respective part of the body is im-
aged. Established methods of early disease detec-
tion, such as PSA testing, Pap smears, colonoscopy
and mammography must not be abandoned.

The selection of clients for cardivascular screen-
ing examinations has to take the risk profile into
account.

Atherosclerosis is most likely to become evident
and treatable at the age of 40 years. In individuals
older than 70 years the probability of asymptom-
atic cardiovascular manifestations of atheroscle-
rosis is low. Therefore, we recommend to perform
screening for cardiovascular diseases within this
age range.

Individuals suffering from symptoms indicative of
cardiovascular diseases should not be included in
a screening examination but rather subjected to
an examination tailored to their specific clinical
situation. If they are self- referred contact with a
medical specialist is required in order to guide the
further diagnostic and therapeutic measures.

Before the exam, the diagnostic accuracy of the
whole body MRI exam concerning different pa-
thologies has to be discussed with the client. The
cardiovascular screening protocol described in
this chapter enables to precisely assess the arte-
rial vasculature and the heart. Other organs and
organ systems, such as the skeletal system, the
bone-marrow, abdominal organs and bowel are
included in the scan range. However, minor pa-
thologies may escape detection.

For the clients it may be difficult to understand
the significance of follow-up examinations and
non-invasive and invasive diagnostic methods
necessary for clarification of suspicious results.
Therefore, a general practitioner, internist or oth-
er surgeon of confidence should be asked for who
would also receive a report about the result of the
screening exam.
9.1.2.2
Predictive Value of
Cardiovascular Screening with MRI
In various studies the accuracy of whole body MR-
angiography and cardiac MRI has been analyzed.
Limited patient populations were included in these
trials and correlated with a variety of reference
methods. However, no studies are available yet on
the predictive value of the screening protocol in low
pretest probability populations. There are also no
data available concerning the outcome of patients
with MRI based cardiovascular screening as com-
pared to other types of risk assessment in terms
of survival, quality of life, rate of stroke, myocar-
dial infarction and other major cardiac events and
amputation, respectively. The clients have to be in-
formed about of this lack of evidence concerning
the value of cardiovascular screening with MRI. In
order to elucidate this issue it is most important to
collect follow up data and to perform large scale
clinical trials
9.1.3
Documentation of Results
The report about the cardiovascular screening exam
has to contain all relevant findings which may be
important for the patient. It has to be clearly ex-
pressed whether a particular finding requires fol-
low-up, additional examinations or invasive pro-
cedures. Information which might help to achieve
better estimation of cardiovascular risk should also

be included – great care should be taken not to alarm
the client unnecessarily on the one hand and not to
understate relevant findings on the other hand:

Stenoses and occlusions of the arteries including
the precise location and degree of the vessel ob-
struction. Variants of the vascular anatomy should
also be mentioned.

Previous infarctions and signs of chronic ischemia
of the brain and myocardium.

Vascular malformations, aneurysms, valvular ste-
noses and regurgitation, hypertrophy, scarring
and inflammation within the myocardium.

Incidental findings which are not primarily in the
focus of the cardiovascular screening exam have
also to be mentioned. Additional diagnostic im-
aging might be required in order to clarify these
findings.
It is definitely not enough just to write a report.
The radiologist performing screening exams has a
great responsibility. He or she must ensure that the
client really understands the result of the exam and
that the adequate measures are taken. This is true
both for the findings related to the cardiovascular
system but also for incidental fi ndings, which may
have even greater importance, such as lesions suspi-
cious of malignant neoplasms. First results on pre-
dominantly asymptomatic subjects actually show
that the number of incidental findings can exceed
the number of relevant atherosclerotic target lesions
(Goehde et al. 2005).
It may be useful to contact the physician of the
client directly or to recommend a specialist.
9.1.4
Results of
Cardiovascular Screening Programs
Published results of MRI based cardiovascular
screening programs are limited by small collectives
and inhomogeneous study populations. Most pub-
lications deal with technical aspects and results in
small collectives. Therefore, prospective random-
ized trials are needed before cardiovascular screen-
ing with MRI can be recommended as an effective
method.
In a group of nearly 200 mainly healthy, execu-
tive individuals (mean age 50 years, otherwise non-
selected), the prevalence of relevant atherosclerotic
Cardiovascular Diseases: MRI 155
pathologies was quite low (Goehde et al. 2005) (my-
ocardial infarctions 0.3%, cerebral infarctions 0.6%,
significant internal carotid artery stenoses 1%, sig-
nificant renal artery stenoses 0.3%, significant lower
extremity artery stenoses 1%). Altogether, mani-
festations of atherosclerosis were detected in 7%.
In one client a renal cell cancer was detected. Two
subjects had previously undiagnosed intracerebral
aneurysms. The total number of clinically relevant
incidental findings was 5%–9%.
Another study evaluated 200 individuals partici-
pating in a healthcare program of their company.
In these subjective healthy individuals, 19 cardiac
pathologies (like wall motion abnormalities or per-
fusion defects) as well as 42 vascular pathologies
(like hemodynamically significant stenoses or ves-
sel occlusions) were found (Kramer 2006).
The low prevalence in manifestations of athero-
sclerosis in a non-selected group of asymptomatic
individuals may indicate that it might be more ef-
ficient to include only those patients who have a
higher risk, e.g. diabetics or patients with manifes-
tations of atherosclerosis in one vascular territory
such as coronary heart disease, stroke or lower ex-
tremity ischemia. This approach, however, would no
longer constitute a screening test in the strict sense
but rather a new algorithm in the management of
diseases which are due to atherosclerosis in differ-
ent vascular territories. One example of a disease as-
sociated with vascular disease is diabetes mellitus.
Weckbach 2006 showed that the presence of vascu-
lar pathologies in a risk group like that is much more
frequent than in subjective healthy individuals.
Does MR imaging find the same pathologies as
detected by conventional exams like chest X-ray,
ECG at rest and at stress, Doppler-ultrasound of the
vessels, ultrasound of the abdomen, etc.? A feasibil-
ity study for MRI as a screening exam for atheroscle-
rotic disease showed good correlation between MRI
and conventional exams. Individuals included in
this study were participants of companies´ health-
care programs and yearly underwent “check-up” ex-
ams looking for atherosclerotic as well as malignant
disease. Results of the conventional exams were not
accessible before the MR exam and were correlated
to the MR findings after the exam. The only pathol-
ogy not detected by MRI was thickening of the ar-
terial wall as diagnosed by ultrasound. The vessel
wall is not accessible by contrast enhanced MRA as
good as it is with ultrasound because MRA renders
only a luminogram. Thus, the correlation between
conventional exams and MRI concerning the find-
156 S. Ladd and H. Kramer
ings from conventional exams was excellent. On the
other hand, numerous relevant additional patholo-
gies were detected by MRI. Peripheral vessel sten-
oses or occlusions as well as internal carotid artery
stenoses and restriction of myocardial function
were not detected by conventional exams. Another
important advantage of MRI is the reproducibility
and the good inter reader agreement. In this study
all MR exams were read by two radiologists blinded
to each other and the results correlated thereafter.
Kappa values of 0.66–0.90 stand for a good to excel-
lent inter reader agreement.
Does the performance of an atherosclerosis
screening MR improve one’s future health status?
For this purpose, a prospective randomized study
was started in 2003. This study consists of two
groups of subjects (55–75 years old) without known
CHD, who are followed up for 3–6 years. One group
is examined by an initial atherosclerosis screen-
ing MR; the other only gets blood tests. With yearly
questionnaires and a follow up MR for either group
the physical and mental health status is assessed and
can be compared for the two groups. Will one of the
groups suffer from cerebral or cardiac infarctions
more frequently? Or have potential earlier therapeu-
tic efforts lead to a reduction in disease progression?
Preliminary results of this study show relatively low
rates of malignancies or vascular pathologies, com-
parable to the results of the “manager study”. The
study will also answer the question if people with
positive findings for atherosclerosis actually change
their lifestyles and follow the radiologists’ recom-
mendations for further diagnostic or therapeutic
work up.
At the same time, as a secondary effect, informa-
tion will be gained concerning false positive and
false negative results of relevant and potentially ma-
lignant side findings, as also late contrast enhanced
axial imaging is added at the end of the MR exam;
this was added to eliminate the need for subsequent
additional MR visits due to potentially dimly visible
side findings in the arteriograms.
9.1.5
Conclusion
Due to major advances in technology, whole-body
MRI without compromise in image quality has re-
cently become feasible. This allows one to assess
manifestations of various systemic or multifocal
diseases, which may result in lesion findings in
the whole body or multiple sites. Promising results
have been reported in individuals with malignant
tumors, inflammatory joint diseases and diseases of
the skeletal muscle. The combination of whole body
MR-angiography with a comprehensive examina-
tion of the heart and imaging of various target or-
gans opens the opportunity to detect manifestations
of atherosclerosis in all vascular territories. This
approach may also be used for early diagnosis and
prevention. This type of atherosclerosis screening
can be performed within acceptable examination
times and great diagnostic accuracy is achieved,
if high performance equipment and sophisticated
imaging techniques are employed. Further studies
are required to explore suitable populations at risk
and to assess effectiveness and outcome of such an
approach.
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Cardiovascular Diseases
9.2 CT
Christoph R. Becker
CONTENTS
9.2.1 Pathogenesis of
Coronary Artery Disease 159
9.2.2 Estimation of Cardiac Event Risk
9.2.3 Clinical Value of Coronary Calcium
9.2.4 Future Perspective 162
References 162
9.2.1
Pathogenesis of Coronary Artery Disease
Coronary atherosclerosis begins as early as in the
first decade of life with endothelia dysfunction, pro-
liferation of smooth muscle cells and deposition of
fatty streaks in the coronary artery wall (Stary et
al. 1994). At the later stage of the still clinically si-
lent disease, these lesions may further accumulate
cholesterol within the intima and media coronary
artery wall layer with a fibrous cap separating the
lipid pool from the coronary artery lumen (Stary
et al. 1995). Inflammatory processes with invasion
of macrophages and activation of matrix-metallo-
C. R. Becker, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
Cardiovascular Diseases: CT 159
9
proteases may cause consecutive weakening of the
fibrous cap (Pasterkamp et al. 2000).
Such vulnerable plaques may rupture when ex-
posed to shear stress and the thrombogenic lipid
159 material may enter the bloodstream. In the most
unfortunate event, thrombus progression may
161
turn the vulnerable plaques into culprit lesions
that occlude the coronary vessels, leading to myo-
cardial ischemia, ventricular fibrillation and death
(Virmani et al. 2000). Plaque erosions with con-
secutive thrombus formation may be responsible
for approximately 40% of cases of sudden coronary
death (Farb et al. 1996). Plaque erosions are more
commonly seen in young women and men, 50 years
of age and are associated with smoking, especially in
pre-menopausal women.
In the early stage of atherosclerosis, the coronary
vessel widens at the location of the atherosclerotic
plaques. This phenomenon is called “positive re-
modeling” and explains why such plaques may not
be detected by cardiac catheter (Glagov et al. 1987).
Non-fatal plaque rupture or erosion at end stage
may heal, organize and subsequently calcify. Fibro-
calcified lesions may reduce vessel lumen diameter
(negative remodeling) with consecutive reduction of
blood flow and myocardial ischemia.
9.2.2
Estimation of Cardiac Event Risk
In many patients unheralded myocardial infarction
associated with a mortality of approximately 20% is
the first sign of coronary artery disease (CAD). The
risk of an event strongly depends on risk factors,
such as hypertension, hyper-cholesteremia, smok-
ing habits, family history, age and gender. Based of
these risk factors, algorithms such as the Framing-
160 C. R. Becker
ham (Wilson et al. 1998), PROCAM (Assmann et
al. 2002) and SCORE (Conroy et al. 2003) provide
an estimation of the mid-term (10 years) risk for
an individual subject to experience a cardiac event
(Fig. 9.2.1). According to most of the international
guidelines, subjects with a mid-term risk of < 10%
are considered to be at low risk and usually only
require advice for a healthy lifestyle but no specific
therapy. Subjects with a mid-term risk of > 20% are
considered to be at high risk and therefore may also
be regarded as subjects with a CAD equivalent. Simi-
lar to patients with established CAD, these asymp-
tomatic subjects may require intensive intervention
for risk reduction such as lifestyle changes and life-
time medial treatment.
Approximately 40% of the population is con-
sidered to have a moderate (10%–20%) mid-term
a b
c ing
risk. All of the currently available risk stratification
schemes suffer from the lack of accuracy to deter-
mine correctly the risk and also uncertainty exists
of how to treat subjects who have been identified
to be at intermediate risk. Further tools providing
information about the necessity to either reassure
or to treat these subjects are warranted. Currently,
besides testing for myocardial ischemia, e.g. by
treadmill testing, assessment of the atherosclerotic
plaque burden is considered to provide valid infor-
mation for further risk stratification in this cohort
(Greenland et al. 2000).
Tests for myocardial ischemia such as ECG stress
testing are better suited to investigate patients with
ischemic CAD than to assess clinically silent ath-
erosclerosis in the coronary arteries. Determina-
tion of the intima-media thickness (IMT) and ankle
Fig. 9.2.1 a–c. A 57-year-old female with family history
and hypercholesteremia. Coronary calcium CT scan dem-
onstrates extensive calcifications expressing an advanced
stage of atherosclerosis. a Extensive calcifications along the
left anterior descending coronary artery. b Extensive calci-
fications along the right coronary artery. c Summary report
with a total score value far above the 90th percentile accord-
ing to her age and gender. The absolute mass of calcium is
better suited to track the progression of her atherosclerosis).
This fi nding should initiate intensive medical therapy and
assessment of ischemic heart disease by, e.g. treadmill test-

brachial index (ABI) by ultrasound and Doppler are
focusing on the assessment of the atherosclerotic
plaque burden in the carotid and peripheral arter-
ies, respectively. However, only CT and MRI may
have the ability to assess non-invasively the extent
of the atherosclerotic plaque burden in the coronary
arteries. MRI is superior to CT in terms of soft tis-
sue differentiation (Fayad et al. 2000). However, CT
is currently superior to MRI in terms of spatial and
temporal resolution to image the small and con-
stantly fast moving structures such as the coronary
arteries. Therefore, CT is the only reliable and prac-
ticable tool to investigate the entire coronary artery
tree and to quantify the atherosclerotic plaque bur-
den non-invasively (Nikolaou et al. 2003).
9.2.3
Clinical Value of Coronary Calcium
Coronary calcium is a specific marker for coronary
atherosclerosis. Initially, such calcifications were
detected by fluoroscopy or conventional chest ra-
diography. EBCT (electron beam computed tom-
ography) allowed to detect coronary calcifications
more sensitively than fluoroscopy. In a cohort of
584 patients coronary calcium could be detected in
52% and 90% by fluoroscopy and EBCT, respectively.
However, only 109 patients within this entire cohort
had proven CAD, so detection of coronary calcium
by EBCT is not appropriate to discriminate between
patients with and without CAD (Agatston et al.
1990).
Arad et al. (1996) were the first to report the at-
tempt to predict cardiac events with coronary cal-
cium as detected by the EBCT. In their cohort of 1173
patients they observed 26 soft (PTCA and bypass
grafting) and hard (myocardial infarction and death)
events within a follow-up period of 19 months. If the
Agatston score was above 160 the odds ratio for an
event was 20 to 35.4. Raggi et al. (Raggi et al. 2000)
used age and gender specific percentiles derived
from nearly 10,000 patients to identify patients at
increased risk for an event. Of patients with an un-
heralded myocardial infarction (n = 172), 70% were
above the 75th percentile with their calcium score as
compared to an asymptomatic cohort (n = 632).
All currently advocated strategies provide two
different values for the risk estimation, one by the
conventional risk assessment and another by the
Cardiovascular Diseases: CT 161
amount of coronary calcium. It has recently been
hypothesized that the combined use of the Framing-
ham risk assessment and the calcium measurement
is superior to the selected use of the Framingham
risk assessment alone (Greenland et al. 2004). In
the Framingham risk algorithm, higher age be-
comes the predominant factor above all others.
This assumption certainly doesn’t fit all subjects.
Therefore, Grundy (2001) has proposed an alterna-
tive scheme in which the age score in Framingham
is replaced by a scheme which takes the coronary
calcium percentiles into account. If the amount of
coronary calcium is in between the 25th and 75th
percentile the Framingham risk score remains un-
changed. If the amount of calcium is below the 25th
or above the 75th percentile the score is the same
as for subjects approximately 10 years younger or
older, respectively (Table 9.2.1).
The progression of coronary calcium in subjects
with hypercholesteremia may depend on the in-
tensity of the statine therapy. In asymptomatic hy-
percholesteremic persons without therapy, statins
and > 120 mg/dL and < 120 mg/dL cholesterol, the
annual progression rate of coronary calcium was
52% ± 36%, 25% ± 22% and −7% ± 23%, respec-
tively (Callister et al. 1998). However, a regression
of coronary calcium appears very unlikely from the
patho-physiological point of view. The reproduc-
ibility in the measurement of coronary calcium by
CT is in the range of 10%, and therefore a regression
below this value may be very difficult to determine.
Furthermore, it has not yet been proven, that the
progression of coronary calcium really results in an
increased risk for a cardiac event.
Table 9.2.1. Summary of coronary calcium score values be-
tween the 25th and 75th percentile depending on age and
gender according to Schmermund et al. (2006). Any score
value below and above will reduce or increase the estimate
cardiovascular risk according to the conventional risk fac-
tors by approximately 10 years, respectively
Age Male Female
45–49 0–45 0–3
50–54 0–70 0–3
55–59 4–166 0–11
60–64 8–236 0–22
65–69 13–249 0–41
70–75 36–671 0–205
162 C. R. Becker
9.2.4
Future Perspective
Several clinical studies found a predictive value
that was superior to conventional risk factors
(Greenland et al. 2004). Clinically, the use of
coronary calcification assessment may therefore be
beneficial in patients who, based on traditional risk
factors, seem to be at “intermediate risk” for coro-
nary events (10-year event risk 10%–20%) in order
to decide on the aggressiveness of risk factor modi-
fication. The role of coronary calcium quantification
to monitor the progression of disease has not been
clarified yet. Large, ongoing trials will provide fur-
ther data as to the relative merit of coronary calcium
assessment for risk stratification and will help to
more clearly define its clinical role. The relationship
between coronary calcium and coronary stenoses
is more complex. While the absence of coronary
calcifications makes significant coronary stenoses
unlikely, even large amounts of coronary calcium
do not necessarily indicate the presence of coronary
artery stenoses (Sangiorgi et al. 1998). Pronounced
coronary calcification as an isolated finding should
therefore not be the motivation for invasive diag-
nostic procedures in the absence of other evidence
of ischemic heart disease (Achenbach et al. 2003).
Particularly in women, estrogen was found to mod-
ify the calcium content of atherosclerotic plaques
and to slow down the progression (Christian et
al. 2002). However, the clinical significance of this
finding is as yet unknown.
Currently ongoing prospective cohort studies
such as the PACC (O’Malley et al. 1999), RECALL
(Schmermund et al. 2002) and MESA (NHLBI
2000) study will determine the predictive value of
coronary calcium for cardiac events. If the results,
expected by the end of this decade, are positive,
coronary calcium percentile ranking in combi-
nation with conventional risk assessment as dis-
cussed above may be incorporated in future pre-
vention guidelines.
As one of the first results from the MESA study
conducted in 6814 patients, electron beam CT and
multi-detector-row CT demonstrated comparable
sensitivity and reproducibility in detecting coro-
nary calcium. Calcium volume measurements had
a slightly higher reproducibility than score values.
Reproducibility was reduced in CT scans suffering
from motion artifacts or misregistration (Detrano
et al. 2005). In particular for score values ranging
between 11 and 400 score points, MDCT and EBCT
appeared to be well comparable (Stanford et al.
2004). The use of calibration phantoms may further
improve the comparability between score values
derived from different CT scanners (Nelson et al.
2005). However, only MDCT has the potential to im-
prove the sensitivity for the detection of coronary
calcium by the use of thinner slices (Horiguchi
et al. 2005). Introducing calcium mass quantifica-
tion instead of score values may allow standardiza-
tion and wide spread use of the coronary calcium
screening over different CT scanners (Hoffmann et
al. 2006).
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Christian RC, Harrington S, Edwards WD, Oberg AL, Fitz-
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Conroy RM, Pyorala K, Fitzgerald AP et al. (2003) Estimation
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Detrano RC, Anderson M, Nelson J et al. (2005) Coronary
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Farb A, Burke AP, Tang AL et al. (1996) Coronary plaque ero-
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Fayad Z, Fuster V, Fallon J et al. (2000) Noninvasive in vivo
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black-blood magnetic resonance imaging. Circulation
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Glagov S, Weisenberg E, Zarins C, Stankunavicius R, Kolettis
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Greenland P, Abrams J, Aurigemma GP et al. (2000) Pre-
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Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC
(2004) Coronary artery calcium score combined with
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Grundy SM (2001) Coronary plaque as a replacement for age
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Hoffmann U, Siebert U, Bull-Stewart A et al. (2006) Evidence
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 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries...
Cardiovascular Diseases
9.3 Duplex Ultrasound of the Carotid Arteries:
Practical Aspects and Results of Screening for Carotid Disease
Norbert Weiss and Ulrich Hoffmann
CONTENTS
9.3.1 Duplex Ultrasound of the Carotid Arteries
– Technical Prerequisites 156
9.3.1.1 Principles of Vascular Ultrasound 165
9.3.1.2 Examination Technique for Carotid Artery
Ultrasound 166
9.3.2 Detection of Early Atherosclerosis in
Carotid Arteries 168
9.3.2.1 Measurement of
Intima-Media-Thickness 168
9.3.2.1.1 Defi nition of
Intima-Media-Thickness 168
9.3.2.1.2 Standardized Measurement of
Intima-Media-Thickness 1695
9.3.2.2 Implications of Intima-Media-Thickness
Measurement for Cardiovascular Risk
Assessment 169
9.3.3 Duplex Ultrasound for Diagnosis,
Treatment, and Follow-Up Monitoring of
Carotid Artery Stenosis 170
9.3.3.1 The Clinical Problem 170
9.3.3.2 Grading of Internal Carotid Artery
Stenosis 171
9.3.3.3 Characterization of the Carotid Plaque 9.3-9
9.3.3.3.1 Visual Characterization of the Carotid
Plaque 173
9.3.3.3.2 Visual Plaque Classification and Degree
of Stenosis as Predictors of Ipsilateral
Hemispheric Events 173
9.3.3.3.3 Computerized Evaluation of Plaque
Echogenicity: Gray-Scale Median 175
9.3.3.4 Efficiency and Cost-Effectiveness of
Screening for Carotid Artery Disease 176
9.3.3.4.1 Symptomatic Patients 176
9.3.3.4.2 Asymptomatic Patients 177
References 178
N. Weiss, MD
PD, Department of Vascular Medicine, Medical Policlinic,
University Hospitals Munich, Ludwig-Maximilians-University
of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany
U. Hoffmann, MD
Professor and Division Head Vascular Medicine,
Department of Internal Medicine, University Hospital,
Ludwig-Maximilians-University of Munich, Pettenkofer-
strasse 8a, 80336 Munich, Germany
165
9
9.3.1
Duplex Ultrasound of the Carotid Arteries
– Technical Prerequisites
9.3.1.1
Principles of Vascular Ultrasound
Ultrasound is the use of sound waves with frequen-
cies above those heard by the human ear. Ultrasound
units used for imaging in medicine generate fre-
quencies of 2–15 million cycles per second (MHz).
In these systems, electronic voltage is transmitted
to an oscillator within an ultrasound transducer, a
crystal in the oscillator vibrates and emits an ultra-
sound beam with a defined frequency. The ultra-
sound beam hits various targets in its path (i.e., soft
tissue, bone, and flowing blood) and is reflected back
to the crystal.
The ultrasound units available today use B-mode
(“brightness”) technology to provide a real-time,
gray-scale image. In the case of vascular ultra-
sound, B-mode provides the operator with a “live”
image of the blood vessel that is updated several
times per second. High-frequency transducers (i.e.,
10–15 MHz) provide excellent image resolution of
superficial structures; however, the beam attenu-
ates rapidly as depth increases. Such high-frequency
transducers are used to image extracranial carotid
arteries, in arterial and venous mapping studies,
and to clearly delineate plaque morphology. Low-
frequency transducers (i.e., 2–4 MHz) are better
able to visualize deeper structures while sacrificing
image resolution. Low-frequency transducers are
used for abdominal imaging such as the renal arter-
ies, abdominal aorta, and mesenteric arteries and
veins.
The term “duplex” ultrasound refers to B-mode
real-time imaging and pulsed Doppler analysis
of the velocity of flowing blood in arteries and
veins. Christian Doppler described the physics
166 N. Weiss and U. Hoffmann
of ultrasound by identifying the Doppler shift
(Bollinger and Partsch 2003). Color flow sonog-
raphy provides a “road map” for the identification
of the carotid vessels and flow within them. Using
this technique, flow velocities within the vessel are
color-coded. The intensity of color is a function of
the velocity. Flow towards or away from the trans-
ducer is coded either as red or blue. There is general
agreement that blood flow towards the transducer
is coded in red and away from the probe is coded
in blue. Areas of stenosis are depicted as a reduced
lumen with a red to blue shift due to “aliasing”,
a Doppler artifact occurring when velocities are
higher than the pulse repetition frequency. Post-
stenotic areas may have a mosaic color Doppler
pattern due to multiple velocities and flow rever-
sal in a boundary separation zone. In the face of a
nearly occluded lumen, a narrow hairline string of
color through the plaque called the “string sign”
may be seen.
Exact qualitative and quantitative analysis of
blood flow in vessels is obtained by spectral analysis
of Doppler signals and recording of flow velocities.
The velocity of blood in vessels can be measured
using the variables of velocity of flowing blood,
velocity of sound in tissue, the difference between
frequency of transmitted and reflected sound, and
the cosine of the angle of the ultrasound beam to
the direction of flowing blood. This is the basis for
all vascular ultrasonography, thus allowing quanti-
fication of degree of stenosis; as an artery narrows,
blood flow velocity increases.
9.3.1.2
Examination Technique for Carotid Artery
Ultrasound
Duplex ultrasound of the carotids should be per-
formed with a high-resolution linear array trans-
ducer (7.5 MHz, or broad spectrum 5–12 MHz).
Three modalities must be used: (1) B-mode gray
scale imaging, (2) color flow Doppler, on both on
transverse and longitudinal planes, and (3) spectral
Doppler velocity analysis on longitudinal planes.
For ultrasound examination of the neck vessels,
the patient is placed in supine position with the head
slightly extended. The examiner can either sit on
the patient’s right side, or behind the patient’s head.
The patient is instructed not to speak and swallow to
prevent artifacts due to the motion of the laryngeal
bones and soft tissues.
Examination begins in the B-mode after optimiz-
ing the gray scale image. Imaging starts from caudal
to cranial in transverse sections, beginning with the
common carotid artery, and continuing upwards to
the carotid bifurcation and the external and internal
carotid artery in transverse sections. This allows a
rapid orientation of the anatomy, of surrounding soft
tissues, and of the diameters of the carotid arteries.
In adults, normal diameters of the common carotid
artery are in the range of 6–7 mm (up to 7.5 mm in the
carotid bifurcation). The internal and external carotid
artery measure 4–5 mm each. Furthermore, these
cross sections may give an impression on the filling of
the internal jugular vein and whether it can be com-
pressed or not (due to jugular vein thrombosis).
Then the extracranial carotid arteries are iden-
tified in longitudinal images. Relevant diagnostic
images will simultaneously visualize the outer and
inner contours of the vessel walls, as well as the per-
fused lumen (Fig. 9.3.1). Most lesions can already
be identified in the transverse survey, whereby ves-
sels are better defined in the longitudinal sections.
Furthermore, B-mode imaging of the vessel wall is
used for quantitation of the intima-media-thickness
(IMT) and plaque morphology (see below).
After optimization of the B-mode (gray scale)
image, the PRF and color gain is adjusted in a way
that the color pixels completely fi ll the vessel of
interest, at least during systole. Extraluminal color
bleed should be avoided. The flow image in non-
stenotic vessel sections should be free of aliasing,
i.e. no red to blue color shift (Fig. 9.3.2). The exam-
iner monitors the color flow pattern for evidence of
abnormalities.
Afterwards, Doppler spectra are recorded in the
longitudinal scan plane. Analysis of angle-corrected
Doppler spectral wave forms are used for quantita-
tion of flow or of degree of stenosis (see below). Fur-
thermore, they are used for distinguishing the inter-
nal carotid artery from the external carotid artery.
The internal carotid artery shows a typical mono-
phasic (antegrade diastolic) flow with low pulsatility
(Fig. 9.3.3).
Flow in the external carotid artery is more pul-
satile, with low diastolic flow velocities. Temporal
tapping is positive in the external carotid artery,
whereas it is negative in the internal carotid artery
(Fig. 9.3.4).
The common carotid artery exhibits a mixed pic-
ture between both flow patterns (Fig. 9.3.5).
An exact angle correction is a prerequisite for the
reliable measurement of flow velocities and quanti-
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries...
Fig. 9.3.1. Longitudinal section of a normal common carotid
artery with simultaneous visualization of the outer and in-
ner vessel wall contour, including the intima-media thick-
ness, and the perfused lumen
Fig. 9.3.2. Longitudinal section of a normal common carot-
id artery with color Doppler imaging showing homogenous
monochrome color flow of the vessel lumen
Fig. 9.3.3. Spectral analysis of Doppler flow of the internal
carotid artery showing a typical monophasic (antegrade
diastolic) flow with low pulsatility
167
Fig. 9.3.4. Spectral analysis of Doppler flow of the external
carotid artery showing a pulsatile flow with a low diastolic
flow velocity and positive temporal tapping
Fig. 9.3.5. Spectral analysis of Doppler flow of the common
carotid artery
tation of flow velocities or stenosis. To reduce mea-
surement errors below 10%, the angle between the
Doppler beam and the longitudinal axis of the vessel
must be d60q in relation to the longitudinal axis of
the vessel. For reproducibility and comparability
of measurements, the input angle should always be
adjusted to 50–60q.
Because of their smaller calibers and their less
favorable course for ultrasound imaging, the ver-
tebral arteries are imaged in longitudinal sections
only.
At a minimum, documentation of the findings
should include:
● Longitudinal image, Doppler spectrum, and
velocity measurements in the common carotid
artery on either side
168 N. Weiss and U. Hoffmann
● Longitudinal image and transverse image of the
carotid bifurcation on either side
● Longitudinal image, Doppler spectrum, and
maximum velocity measurements of the exter-
nal and internal carotid arteries and the vertebral
artery on either side
● If pathological findings are noted: longitudinal
image with Doppler spectrum analysis of the
respective lesion
9.3.2
Detection of Early Atherosclerosis in
Carotid Arteries
9.3.2.1
Measurement of Intima-Media-Thickness
Silent arterial wall alterations may precede advanced
atherosclerotic disease resulting in cardiovascular
clinical events by decades. The first morphological
abnormalities of arterial walls can be imaged by
high-resolution B-mode ultrasonography. This non-
invasive technique is one of the best methods for
detection of early stages of atherosclerotic disease:
it is easily applicable, readily available, and dem-
onstrates the wall structure with better resolution
than magnetic resonance imaging or conventional
angiography.
Accordingly, ultrasound has been used in a
number of studies to monitor the intima-media
thickness (IMT) of the carotid arteries, a measure-
ment, which has consequently been shown to be
associated with cardiovascular risk factors and the
incidence of cardiovascular disease.
However, there are diverse approaches for mea-
suring IMT, which affect comparisons of results.
Moreover, there are no unified criteria for distin-
guishing atherosclerosis as seen in early plaque
formation from thickening of the intimal-medial
complex. This is because IMT reflects not only
early atherosclerosis, but also nonatherosclerotic
intimal reactions such as intimal hyperplasia and
intimal fibrocellular hypertrophy. This differen-
tiation is important because epidemiological stud-
ies have shown that wall thickening as depicted by
ultrasonographic measurements of IMT is different
from atherosclerotic plaque regarding localization,
risk factors and predictive value on cardiovascular
events.
9.3.2.1.1
Definition of Intima-Media-Thickness
In the absence of atherosclerotic plaques, B-mode
ultrasound displays the vascular wall as a regular
pattern that correlates with anatomical layers. The
intima-media portion of this pattern is represented
by the area of tissue starting at the luminal edge
of the artery and ending at the boundary between
the media and the adventitia. This interface is well
depicted by ultrasound. With increasing age, this
pattern has been shown to thicken in a uniform
way in straight arterial segments. Thickening of
the intima-media is accelerated and enhanced in
the presence of risk factors of atherosclerosis, par-
ticularly high blood pressure. As a mirror of these
processes, IMT was identified as a tool to investigate
normal aging and preclinical atherosclerosis. Later
stages of atherosclerosis (plaque, stenosis, occlu-
sion) can also be identified by ultrasound imaging
either in the absence of or coincident with increas-
ing IMT. However, there are intermediate stages
between increased IMT and atherosclerotic plaque
formation that are impossible to differentiate even
on histological examination. Such conditions are
common at the bifurcation and the origin of the
internal carotid artery, but occur only occasionally
in the common carotid artery. Epidemiological and
intervention studies have shown that although both
share some common atherosclerosis risk factors, the
natural history, patterns of risk factors and the pre-
diction of cardiac and cerebral events are different
for IMT and plaque.
Based on these findings, a recent consensus state-
ment recommended the following definitions for
ultrasound characterization of IMT and atheroscle-
rotic plaque (Touboul et al. 2004):
1. IMT is a double-line pattern visualized by echoto-
mography on both walls of the common carotid
arteries in a longitudinal image. It is formed by two
parallel lines, which consist of the leading edges of
two anatomical boundaries: the lumen-intima and
media-adventitia interfaces (Fig. 9.3.6).
2. Plaque is a focal structure encroaching into the
arterial lumen of at least 0.5 mm or 50% of the sur-
rounding IMT value or demonstrates a thickness
of t1.5 mm as measured from the media-adventi-
tia interface to the intima-lumen interface.
These definitions will allow classification of the
great majority of the carotid lesions observed with
ultrasound.
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries...
Fig. 9.3.6. Normal intima-media thickness in the common
carotid artery
9.3.2.1.2
Standardized Measurement of
Intima-Media-Thickness
For using IMT values in clinical studies, a stan-
dardized imaging technique should be used. The
common carotid artery can be assessed in nearly
every patient. In contrast, successful examination
of the internal carotid artery and of the carotid bulb
depends both upon the anatomical situation of the
particular patient and on the sonographer´s exper-
tise.
1. Measurement of IMT is most simply performed
in a region free of plaque where the double-line
pattern is well observed. This has the advantage
that measurements are easier, more accurate,
reproducible and can be standardized by com-
puterized analyses.
2. IMT can be measured in the common carotid
artery, at the bulb and the origin of the internal
carotid artery.
3. The arterial wall segments is assessed in a lon-
gitudinal view, perpendicular to the ultrasound
beam using a lateral probe incidence. Both walls
should be visualized.
4. IMT should be measured preferably on the far wall
because IMT values from the near wall depend in
part on gain settings and are less reliable.
5. Along a minimum of 10 mm length of an arte-
rial segment, a high-quality image acquisition is
required for serial reproducible measurements.
(a) Edge detection systems that are properly
calibrated provide accurate measurements of
IMT. Observations made by readers are not less
169
valid, but they need to be controlled, and they
are time consuming compared to automated
systems, which can provide the mean maximal
value of 150 measurements performed on 10 mm
of common carotid artery in a very short time
(< 0.1 s). (b) Interadventitial and lumen diameter
measurements must be obtained as IMT is sig-
nificantly correlated with the arterial diameter.
6. Intraclass correlation coefficient should be eval-
uated for intra- and interobserver variability in
each ultrasound lab, both for IMT and plaque
measurements.
Nevertheless, under standardized conditions, the
technique of measurement carotid IMT offers good
reproducibility. This makes it suitable for applica-
tion in relatively small, comparative studies investi-
gating vascular pathophysiology, as well as in large,
multicenter clinical trials.
9.3.2.2
Implications of Intima-Media-Thickness
Measurement for Cardiovascular Risk Assessment
Arterial wall thickness is a continuous variable that
increases from childhood to old age, in patients as
well as in healthy controls (Blankenhorn and
Hodis 1994).
Numerous clinical studies have shown a strong
correlation between IMT and cardiovascular risk
factors such as elevated low-density lipoprotein cho-
lesterol (Wittekoek et al. 1999; Kastelein et al.
2004; Wiegman et al. 2004a), low high-density lipo-
protein cholesterol (van Dam et al. 2002; Hovingh
et al. 2004), blood pressure (Terpstra et al. 2003;
Zakopoulos et al. 2005), diabetes and glycemic
control in diabetes (Selvin et al. 2005), as well as
smoking (Gerli et al. 2005). These findings indicate
that carotid IMT might serve as a marker for the sus-
ceptibility of the vessel wall to atherosclerotic risk
factor exposure.
Whether or not this translates into clinical end-
points and whether or not carotid IMT might there-
fore be used as a surrogate marker for cardiovascu-
lar disease risk had been examined in three large
observational studies, the Atherosclerosis Risk in
Communities study (n = 12,841) (Chambless et al.
1997), the Cardiovascular Health study (n = 5,858)
(O’Leary et al. 1999), and the Rotterdam study
(n = 8,000) (Bots et al. 1997). In all three studies,
increased common carotid artery IMT was associ-
170 N. Weiss and U. Hoffmann
ated with future cerebrovascular and cardiovascu-
lar events. This association persisted even after cor-
rection for several cardiovascular risk factors.
In addition, statin-intervention trials such as
ASAP (Smilde et al. 2001), REGRESS (de Groot et
al. 1995, 1998) and ARBITER-I (Taylor et al. 2002),
have underscored the value of carotid artery IMT
as an efficient parameter to assess efficacy of lipid-
lowering treatment. Both ASAP and ARBITER-I
showed that aggressive lipid lowering with 80 mg
of atorvastatin was associated with a decrease in
carotid artery IMT as opposed to no change or pro-
gression in the comparative low-dose-statin arms.
Additional intervention studies that confirmed that
lowering cholesterol levels reduces carotid artery
IMT have been recently reviewed (Kastelein et al.
2004; Wiegman et al. 2004b).
Taken together, carotid IMT has proven to be a
well-standardized and validated surrogate marker
for cardiovascular disease burden and is particularly
closely correlated with the incidence and extent of
coronary artery disease and the incidence of cardio-
vascular events such as acute coronary syndrome,
myocardial infarction and stroke (Bots et al. 1997;
Hodis et al. 1998; O’Leary et al. 1999; Chambless et
al. 2000; Demircan et al. 2005). However, it does not
fulfi l the characteristics of an accepted risk factor
(Touboul et al. 2004). In contrast, carotid IMT has
not been shown to be associated with restenosis
after femoropopliteal percutaneous transluminal
angioplasty (van der Loo et al. 2005) or secondary
cardiovascular events after coronary bypass surgery
(Aboyans et al. 2005). Standardized measurements
of carotid IMT may therefore be useful in epide-
miological and interventional trials dealing with
vascular diseases to improve characterization of the
population investigated.
In contrast to predicting cardiovascular risk
in large populations, carotid IMT is not useful in
predicting individual risk, since it is a continu-
ous variable without a threshold value. Data from
the Rotterdam Study showed that adding common
carotid IMT to a risk function with established risk
factors has no additional value to predict the coro-
nary heart disease and cerebrovascular disease risk
(del Sol et al. 2001). Therefore a recent consensus
statement concluded that there is no need to treat
IMT values nor to monitor IMT values in individual
patients apart from few exceptions (Redberg et al.
2002; Touboul et al. 2004). These exceptions may
include patients with familial hypercholesterolemia
(Wittekoek et al. 1999; Wiegman et al. 2004a), in
which at least in children IMT values may guide
decision to start treatment to targets early.
9.3.3
Duplex Ultrasound for Diagnosis,
Treatment, and Follow-Up Monitoring of
Carotid Artery Stenosis
9.3.3.1
The Clinical Problem
Stroke is one of the leading causes of death in west-
ern countries. One third of strokes are fatal, and
survivors usually have prolonged or irreversible
disabilities. Four out of five strokes are ischemic
events, half of them are caused by atherosclerotic
disease of the carotid or intracranial arteries. Of
these obstructions, 50%–60% are localized in the
carotid bifurcation and/or the internal carotid
artery, and another 5%–10% in the common carotid
artery (Landwehr et al. 2001). Atherosclerotic ste-
noses of the carotid artery therefore are a leading
cause of all strokes, accounting for around 30% of
all events. The risk of ipsilateral stroke gradually
increases with the grade of stenosis and is higher
in patients with previous ipsilateral transient focal
neurological symptoms compared to asymptomatic
patients (Fig. 9.3.7) (Inzitari et al. 2000).
Consequently, the effect of correcting a carotid
artery stenosis by endarterectomy in regard to stroke
risk has been studied during the last 20 years. First
results were obtained in patients with prior focal
neurological symptoms related to the brain hemi-
sphere dependent on a stenotic carotid artery. Two
randomized studies in symptomatic patients, the
North American Symptomatic Carotid Endarterec-
tomy Trial (NASCET) (Anonymous 1991a; Gasecki
et al. 1995; Ferguson et al. 1999) and the European
Carotid Surgery Trial (ECST) (Anonymous 1991b,
1996) both showed that patients with high-grade
(t70%) internal carotid artery stenosis based on the
angiographic estimation of the degree of stenosis
did clearly benefit from carotid surgery compared
with the group receiving conservative treatment.
Published data have generally reported a 1%–3%
incidence of perioperative mortality and a 2%–10%
incidence of perioperative stroke. In pooled data
from both large studies, surgery reduced the 5-year
risk of any stroke or death by 21.2% in patients with
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 171

70%–99% stenosis. These benefits were maintained 30.0

Symptoms 27.1

Risk of Ipsilateral Stroke at 5 Yr (%)

No symptoms 25.8
at the 10-year follow-up (Fig. 9.3.2) (Rothwell et 25.0
al. 2003). Based on these data, carotid endarterec- 20.2
20.0 18.7 18.5
tomy nowadays is the standard treatment for symp- 17.2
tomatic high-grade internal carotid artery stenosis 15.0 12.9
14.8 14.7

with excellent long-term results (Cunningham et

10.0 9.4
al. 2002). Patients with near occlusion of the carotid 7.8

artery, or with a less severe degree of stenosis do not 5.0

4.6

benefit from carotid endarterectomy.

0.0
In asymptomatic patients with carotid artery

n
0%

9%

4%

4%

9%
e

io
as

<5

−5

−7

−9

−9

s
se

clu
stenosis the risk of ipsilateral stroke is significantly

Di

50

60

75

95

lower than in symptomatic patients (Fig. 9.3.7). The
effect of carotid endarterectomy in asymptomatic
has been studied in two large scaled trials, the asymp-
tomatic carotid surgery trial (ACST) conducted
mainly in Europe (Halliday et al. 1994, 2004),
and the asymptomatic carotid atherosclerosis trial
(ACAS) conducted in North America (Anonymous
1995). In patients younger than 75 years of age with
carotid diameter reduction about 70% or more on
ultrasound (many of whom were on aspirin, anti-
hypertensive, and, in recent years, statin therapy),
immediate carotid endarterectomy halved the net 5-
year stroke risk from about 12% to about 6% (includ-
ing the 3% perioperative hazard). Half of this 5-year
benefit involved disabling or fatal strokes. Subgroups
analysis, however, showed, that the beneficial effect
was restricted to men, but did not occur in women,
and was restricted to younger patients below the age
of 75 (Chambers and Donnan 2005). Outside trials,
inappropriate selection of patients or poor surgery
could even obviate these benefits (Halliday et al.
2004).
Carotid artery stenting has evolved as an alterna-
tive to carotid endarterectomy during the last decade
(Dieter and Laird 2005). Data from registries and
unrandomized studies indicated that carotid artery
stenting is not less safe than carotid endarterec-
tomy in the hands of experienced interventionalists
(Yadav et al. 2004; Anonymous 2005). The carotid
revascularization using endarterectomy or stenting
systems (CaRESS) phase I study, a multicenter, pro-
spective, nonrandomized trial designed to address
the question of whether carotid stenting (CAS) with
cerebral protection, is comparable to carotid end-
arterectomy (CEA) in patients with symptomatic
and asymptomatic carotid stenosis, showed that the
30-days and 1-year risk of death, stroke, or MI with
carotid artery stenting is equivalent to that with
carotid endarterectomy (Anonymous 2005). Fur-
thermore, registry data, like the ELOCAS and CAS
registries (Bosiers et al. 2005; Zahn et al. 2005)
Oc
No
Degree of Stenosis on Angiography
Fig. 9.3.7. Risk of ipsilateral stroke during 5 years of follow
up depending on the degree of stenosis on angiography in
asymptomatic and symptomatic patients. From Inzitari et
al. (2002): The causes and risk of stroke in patients with as-
ymptomatic internal-carotid-artery stenosis. North Ameri-
can Symptomatic Carotid Endarterectomy Trial Collabora-
tors. N Engl J Med 342:1693–1700
and series in high-volume centers (Bergeron et al.
2005) indicate that long-term results up to five years
are comparable to carotid endarterectomy. How-
ever, as stenting with protection does not appear
to be inferior to carotid endarterectomy, this is not
a license for the widespread use of stenting, but it
should indicate that patients, before stenting, need
to be assessed as thoroughly and appropriately as
those being considered for endarterectomy to define
which patient might profit from any intervention at
the carotid arteries.
9.3.3.2
Grading of Internal Carotid Artery Stenosis
Using color Doppler sonography, areas of stenosis
are depicted as a reduced lumen with a red to blue
shift due to “aliasing”. The latter phenomenon is
a Doppler artifact that occurs when velocities are
higher than the pulse repetition frequency. Postste-
notic areas may be detectable by a mosaic turbu-
lent color Doppler pattern due to multiple veloci-
ties and flow reversal in a boundary separation
zone (Middleton et al. 1988; Hallam et al. 1989;
Steinke et al. 1998). In a nearly occluded lumen,
a narrow hairline string of color through the plaque
may be seen. In this case power Doppler sonography
may be helpful to visualize the residual lumen as this
mode is more sensitive to lower velocities (Steinke
et al. 1997; Koga et al. 2001).
172 N. Weiss and U. Hoffmann
Flow velocity is the main parameter for evaluat-
ing the degree of a carotid artery stenosis. This is
achieved by obtaining a B-mode gray scale image
of the vessel and placing the sample volume in the
center of the presumed stenosis. An angle of 60q
should be kept between the Doppler beam and the
longitudinal axis of the vessel. Doppler spectrum
of the carotid flow is then displayed. Flow velocity
must be sampled through the whole area of the pre-
sumed stenosis up to the distal end of the plaque.
This ensures that the site of the highest velocity has
been detected (Grant et al. 2003) (Fig. 9.3.8).
Fig. 9.3.8. High grade internal carotid artery stenosis iden-
tified by a turbulent flow, an intrastenotic peak systolic ve-
locity > 300 cm/s, and an enddiastolic velocity of 150 cm/s
Various studies that related Doppler sonographic
velocity recording to angiographic assessment of
stenosis showed a considerable spread of values,
which affects sensitivity and specificity as well as
the positive and negative predictive values of the
sonographic tests (Sabeti et al. 2004; Jahromi
et al. 2005). Furthermore, depending on whether
the patients are asymptomatic or symptomatic
and related to the risk of subsequent stroke and
the anticipated benefit from carotid artery revas-
cularization, some authors suggest adjustment
of the interpretation to reflect these relative risk
(Moneta et al. 1993, 1995). Based on the determi-
nation of intrastenotic peak systolic velocity (PSV)
and end-diastolic velocity (EDV) in the internal
carotid artery (ICA), and on the ratio of PSV in
the ICA/common carotid artery (CCA), several
classifications of the degree of carotid artery ste-
nosis degree had been proposed (Robinson et al.
1988; Moneta et al. 1993, 1995; Nicolaides et al.
1996; AbuRhama et al. 1998; Elgersma et al. 1998;
Filis et al. 2002; Hwang et al. 2002; Nederkoorn
et al. 2002; Staikov et al. 2002; Strandness 2002;
Thomas et al. 2002).
To summarize these different classification sys-
tems, a multidisciplinary panel under the auspices
of the Society of Radiologists in Ultrasound drew
up and published a consensus statement on the
performance of Doppler sonography for the diag-
nosis of ICA stenosis (Grant et al. 2003). Based on
these recommendations, degree of stenosis in the
ICA can be classified into five categories based on
two primary parameters, the ICA PSV and plaque
size, and on two secondary parameters, ICA/CCA
PSV ratio and ICA EDV (Table 9.3.1). The ICA/CCA
PSV ratio is especially helpful when flow changes
are induced by severe bilateral stenoses of the ICA,
or by proximal CCA stenosis or occlusion. Further-
more it is helpful when high or low ICA velocities
are registered. This might occur in hyperdynamic
states such as in young patients, or vice versa, in
hypodynamic states such as in patients with low
cardiac output that will have proportionally lower
PSV for a given degree of stenosis. Hemodynami-
cally relevant stenosis starts at a diameter reduc-
tion equal or greater than 50%. In clinical terms,
identification of a 70%–99% stenosis is most
relevant.
Comparing different flow velocity criteria for the
quantification of ICA stenosis with duplex sonog-
raphy compared to angiography calculated by the
NASCET method, a PSV t200 cm/s has a sensitiv-
ity of 90% (95% CI, 84%–94%) and a specificity of
94% (95% CI, 88%–97%), and an ICA/CCA ratio t4
is associated with an 80% sensitivity (95% CI, 70%–
90%) and 88% specificity (95% CI, 83%–93%) for
diagnosis of a stenosis t70% (Jahromi et al. 2005).
Using the above-mentioned criteria, Doppler sonog-
raphy and angiography have shown agreement in
at least 90% of the cases in the grading of stenosis
(Alexandrov et al. 1997; Chen et al. 1998).
Taken together, color Doppler sonographic grad-
ing of carotid artery stenosis offers a non-invasive,
reproducible and accurate tool for initial evaluation
and follow-up of patients with suspected or known
carotid artery stenosis. As long as technically appro-
priate measurements are obtained, this method
allows stratification of patients with carotid artery
stenosis that may or may not benefit from carotid
artery revascularization, and therefore should be
used as the initial imaging modality.
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries...
Table 9.3.1. Spectral Doppler velocities and plaque estimate correlated with degree of internal carotid artery
stenosis diameter. Modified from Moneta et al. (1995); Grant et al. (2003)
Stenosis Plaque estimate (%) ICA PSV (cm/s)
Normal NA < 125
< 50% < 50 < 125
50–69% > 50 125–230
> 70% > 50 > 230
Near occlusion Visible High/low/undetectable Variable
Total occlusion Visible, no detectable lumen NA
NA indicates not applicable
9.3.3.3
Characterization of the Carotid Plaque
9.3.3.3.1
Visual Characterization of the Carotid Plaque
Apart from the degree of stenosis, plaque morphol-
ogy has emerged in recent years as an important con-
tributory factor in stroke risk. The main mechanism
of stroke related to pathology of the carotid artery is
thought to be embolism from a fissured or ruptured
plaque. Recent pathological studies of postmortem
and arterectomy specimens have shown that plaque
vulnerability is related to the size of the athero-
matous core, the thickness of the fibrous cap, and
to inflammation within the cap (Bassiouny et al.
1997). Unstable plaques prone to rupture have a thin
fibrous cap with a necrotic core near to the surface.
Rupture of the plaque exposes the thrombogenic
atheroma to circulating blood. This initiates throm-
bus formation which may lead to thromboembolism
into the brain and subsequent ischemic stroke.
As discussed above, recent multicenter trials have
established the benefit of carotid endarterectomy or
stenting in symptomatic and asymptomatic patients
with high-grade stenosis of the ICA. A remarkable
portion of patients on medical treatment alone,
however, remained free of symptoms during the
follow-up period. In addition, in some rare cases,
patients with more moderate degrees of stenosis
also developed neurological events. This indicates
that the degree of stenosis alone does not completely
predict stroke risk.
Therefore high resolution ultrasound has been
used for characterization of carotid plaque morphol-
ogy based on visual analysis of plaque echogenicity,
texture and surface. Morphological appearance of
173
ICA/CCA PSV ratio ICA EDV (cm/s)
<2 < 40
<2 < 40
2–4 40–99
>4 > 100
Variable
NA NA
the plaque has been correlated to the risk or devel-
oping neurological symptoms.
9.3.3.3.1.1
Plaque Echogenicity
Plaque echogenicity varies from anechogenic (dark
on ultrasound) through mixed forms to hyperecho-
genic (bright on ultrasound) plaques. According to a
recent consensus meeting on plaque characterization
(De Bray et al. 1996), echogenicity should be stan-
dardized against flowing blood for anechogenicity,
sternocleidomastoid muscle for isoechogenicity,
and the adjacent transverse apophysis of the cervi-
cal vertebrae for hyperechogenicity. According to
Geroulakos et al. (1993), plaques may be grouped
into five types, as outlined in Figure 9.3.9.
9.3.3.3.1.2
Plaque Texture
Plaque texture reflects the distribution of the gray-
scale levels in a given area of the plaque and may be
either homogenous or heterogenous irrespective of
their echogenicity. Heterogenous plaques therefore
contain both hypoechogenic and hyperechogenic
areas with either a smooth or an irregular surface.
Homogenous plaques have a uniform texture with a
smooth and regular surface (Reilly et al. 1983).
9.3.3.3.1.3
Plaque Surface
The surface of a plaque is either defined as smooth
and regular, mildly irregular, or ulcerated. Mildly
irregular plaques show height variations between
0.4 and 2 mm on the contour of the plaque. Ulcer-
174 N. Weiss and U. Hoffmann

Fig. 9.3.9. Grading of plaque chogenicity. Type 1: uniformly anechogenic with an echogenic fibrous cap. Type 2: predomi-
nantly anechogenic but with echogenic areas representing less than 25% of the plaque. Type 3: predominantly hyperecho-
genic but with anechogenic areas representing less than 25% of the plaque. Type 4: uniformly echogenic plaque. Type 5:
unclassified plaque reflecting calcified plaques with may have zones of acoustic shadowing which obscure the deeper part
of the arterial wall as well as the vessel lumen. Adapted from Sztajzel (2005)

ations correspond to an irregularity or break in the
surface of the plaque that must be visualized on
two different planes, must be at least 2 mm deep
and 2 mm long, must have a well defined wall at
its base, and must exhibit an area of reversed flow
(Sztajzel 2005).
9.3.3.3.2
Visual Plaque Classification and Degree of Stenosis
as Predictors of Ipsilateral Hemispheric Events
Most studies on ultrasonographic plaque morphol-
ogy and risk of subsequent neurological symptoms
performed so far agreed that anechogenic or heter-
ogenous plaques carry a higher risk compared with
echogenic or homogenous plaques.
In 293 asymptomatic patients with more than
75% stenosis of the carotid bifurcation, the inci-
dence of transitory ischemic attacks and stroke
during 5 years of follow-up was 100% in the group of
patients with soft plaques compared of only 60% of
those with dense plaques (O’Holleran et al. 1987).
Several other studies could not reproduce this very
high incidence of neurological events in patients
with carotid artery stenosis, but also showed that
echolucent plaques were associated with a signifi-
cantly (approximately twofold) higher event rate
than echogenic plaques (Langsfeld et al. 1989;
Mathiesen et al. 2001; Grogan et al. 2005). In
addition, data from the Tromso study, a prospective
study of more than 200 subjects each with carotid
stenosis or controls matched for age and gender,
showed that the presence of echolucent plaques at
baseline was associated with an increased risk of
ischemic cerebrovascular events independent of the
degree of stenosis and other cardiovascular risk fac-
tors. As many ischemic events in this study occurred
in a vascular territory different from that supplied
by the artery with the echolucent plaque, this addi-
tionally suggests that plaque echolucency may be
rather a marker of a higher stroke risk than a direct
cause of the cerebrovascular event (Mathiesen et
al. 2001).
Three studies that evaluated the association
between plaque texture and risk for subsequent neu-
rological events uniformly have shown that in both
symptomatic and asymptomatic patients heterog-
enous plaques compared to homogenous plaques
were significantly associated with an increased risk
of stroke or transient ischemic attacks (Sterpetti
et al. 1988; O’Farrell and FitzGerald 1993;
AbuRhama et al. 2002).
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 175

Interpretation and generalization of the results of
all these studies that rely on operator dependent and
subjective methods of plaque characterization, how-
ever, are significantly restricted by several facts.
Although the majority of studies conducted so far
to correlate ultrasound plaque morphology with his-
tological findings indicate that anechogenic plaques
represent either necrotic or hemorrhagic lesions,
and echogenic plaques rather a fibrotic tissue, these
studies cannot be reliably interpreted or compared
because of incomparable or poorly reported histol-
ogy methods (Lovett et al. 2005). The few studies
that documented inter- and intraobserver agreement
on visual plaque characterization have shown that
reproducible grading of ultrasound images is not
consistently achievable using a visual grading system,
even among experienced observers, and that within-
observer agreement may vary with time. Therefore
visual ultrasound characterization of carotid plaque
morphology used in clinical trials so far may be asso-
ciated with unacceptable low levels of reproducibility
(De Bray et al. 1998; Arnold et al. 1999).
ing method, and the GSM value of the adventitia
to 185–195. After these normalizations, the plaque
is outlined and its overall brightness evaluated by
using GSM with a gray-scale rate ranging from 0
(black) to 255 (white) (Fig. 9.3.10) (El-Barghouty
et al. 1995).
An initial case-control study analyzed 148
plaques producing more than 50% ICA stenosis in
87 patients. Sixty-nine plaques were in asymptom-
atic patients, the remaining in patients with amau-
rosis fugax, transient ischemic attacks or stroke.
Fifty-three plaques were associated with ipsilateral
brain infarction detected by computed tomogra-
phy. Plaques with a GSM higher than 32 (echogenic
plaques) were significantly less associated with
bran infarction (11%) compared to plaques with
a GSM below or equal to 32 (echolucent plaques,
55% incidence of brain infarction) (El-Barghouty
et al. 1995). These finding could be reproduced by
the same group of investigators in a larger patient
sample (El-Barghouty et al. 1996a), as well as by
others (Biasi et al. 1999).

9.3.3.3.3
Computerized Evaluation of Plaque Echogenicity:
Gray-Scale Median

As visual plaque characterization is a highly opera-

tor-dependent and subjective method, a new method
has been developed that uses computer-aided ana-
lysis of plaque echostructure. This may provide a
more quantitative, more objective, and more opera-
tor independent methodology.
On longitudinal sections, the luminal plaque
margins are identified using color images, and the
B-mode image superimposed with the color Dop-
pler signal are transferred form the ultrasound
unit to a personal computer. Further analysis
is performed offline on the computer using the
Adobe Photoshop “ image analysis software. The
plaque margins are first identified using the color
image as a guide, the color is then switched off
automatically. Echogenicity of the plaque is then
assessed quantitatively by the gray-scale median
(GSM) of the frequency distribution of gray values
of the pixels within the plaque. To be able to com-
pare GSM values obtained with different ultra-
sound units and instrument settings, gray scales
of the B-mode images are normalized using digi-
tal image processing based on blood and adventi-
tia as two references. The GSM value of the vessel Fig. 9.3.10. Carotid plaque with gray-scale median of 41 as
lumen (blood) is adjusted to 0–5 by a linear scal- analyzed by computer. From: El-Barghouty et al. (1995)
176 N. Weiss and U. Hoffmann
A prospective study included 111 asymptomatic
and 135 symptomatic patients with > 50% ICA ste-
nosis that were followed for 4.4 years. In symptom-
atic patients, the relative risk of ipsilateral stroke for
echolucent vs echorich plaques was 3.1. In this study
the degree of ICA stenosis in symptomatic patients
(relative risk for ipsilateral stroke in patients with
80%–99% ICA stenosis vs 50%–79% stenosis 1.4) was
less predictive than plaque echolucency. The high-
est stroke risk was observed in patient with echo-
lucent high grade (> 80%) ICA stenosis. This asso-
ciation was not observed in asymptomatic patients
(Gronholdt et al. 2001).
Whether or not computer-assisted GSM analysis
of plaque echolucency is superior to visual char-
acterization of the plaque has not been systemati-
cally studied so far. In the hands of an experienced
examiner visual plaque characterization may be
comparable to the more time-consuming com-
puter-assisted GSM analysis and therefore more
suitable for clinical practice (Mayor et al. 2003).
Furthermore, whether or not fi ndings obtained by
GSM plaque analysis should influence the selection
of patients with moderate carotid artery stenosis
but echolucent plaques for carotid endarterectomy
is still under debate.
Although plaque echolucency by computer-
assisted imaging correlated with clinical symp-
toms in the above-mentioned studies, confl icting
results have been obtained regarding histological
studies (El-Barghouty et al. 1996b; Matsagas
et al. 2000; Tegos et al. 2000; Gronholdt et al.
2002; Denzel et al. 2003). Analysis of the median
brightness of the plaque by GSM analysis did not
consistently correlate with histological classifica-
tion of plaque composition. As this analysis repre-
sents a median value of the whole atherosclerotic
area it may not necessarily reflect the presence of
particular regional components. A more detailed
approach that uses a stratified GSM assessment,
analyzing each millimeter from the surface to the
bottom of the plaque can generate a profi le of the
regional GSM as a function of distance from the
plaque surface. This methodology may allow to
identify a necrotic core relative to the plaque sur-
face, and may allow to determine the thickness of
the fibrous cap. A fi rst study showed a good cor-
relation of stratified GSM measurements with vari-
ous histopathological components of the plaque.
This virtual histology of the plaque has the poten-
tial to identify determinants of plaque instability
(Sztajzel et al. 2005).
9.3.3.4
Efficiency and Cost-Effectiveness of Screening
for Carotid Artery Disease
Patients in whom screening for carotid artery dis-
ease should be considered include those with focal
neurological symptoms and asymptomatic patients
at high risk for significant carotid artery disease.
9.3.3.4.1
Symptomatic Patients
The results of several large randomized trials have
shown that patients with symptomatic carotid artery
stenosis presenting with transient ischemic attacks
or minor strokes may benefit from carotid artery
revascularisation, as outlined above. The benefit of
carotid endarterectomy in such patients ranges from
0.35 quality adjusted life years (QALYs) at a cost of
$4,100 per QALY to 0.93 QALYs at a cost of $434
per QALY (Benade and Warlow 2002). Therefore,
the American Heart Association/American Stroke
Association Council on Stroke recommends carotid
endarterectomy for patients with recent TIA or isch-
emic stroke within the last 6 months and ipsilateral
severe (70%–99%) carotid artery stenosis, if carotid
endarterectomy is performed by a surgeon with
a perioperative morbidity and mortality of < 6%
(Class I, Level of Evidence A) (Sacco et al. 2006).
As the results of all large intervention trials on
carotid endarterectomy are based on invasive imag-
ing of carotid stenosis by angiography, noninva-
sive imaging techniques for decision making in
patients with symptomatic carotid stenosis had to
be reevaluated on this background. A recent multi-
center blinded consecutive cohort study performed
in the Netherlands (Buskens et al. 2004) examined
the efficiency and cost-effectiveness of noninvasive
imaging strategies. The sensitivity and specificity of
vascular ultrasonography and magnetic resonance
angiography were tested against digital subtrac-
tion angiography as the reference standard in 350
symptomatic patients. Duplex ultrasound had 88%
sensitivity and 76% specificity for the detection of
high-grade carotid artery stenosis (70%–99%) using
conventional cutoff criteria. MR angiography had
comparable values, the combination of both meth-
ods showed superior diagnostic performance (96%
sensitivity and 80% specificity). Duplex ultrasound
alone was the most efficient strategy. In a 55-year-
old symptomatic male patient vascular ultrasound
based decision making for carotid endarterectomy
 Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries...
and performing carotid endarterectomy would,
on average, yield 11.33 QALYs at a cost of $30,400.
Duplex ultrasound was both less expensive and
more effective than all other strategies, including
digital subtraction angiography. Adding MR angi-
ography to duplex ultrasound results in increased
sensitivity and specificity, and in a slight benefit
in terms of clinical outcome, but at extremely high
costs (cost-effectiveness ratio > $1,665,000 per QALY
gained). Therefore, the authors conclude that duplex
ultrasound performed without additional imaging is
the most cost-effective strategy to select symptom-
atic patients suitable for endarterectomy. Additional
imaging strategies therefore should be restricted to
patients with difficult to interpret or inconsistent
duplex ultrasound findings.
9.3.3.4.2
Asymptomatic Patients
Carotid endarterectomy in asymptomatic patients
with high grade stenosis is associated with sig-
nificantly higher costs per QALY up to $52,700 per
QALY compared to symptomatic patients (Benade
and Warlow 2002). Therefore carotid duplex ultra-
sound performed as a screening test for carotid
artery stenosis currently is not recommend in
the general population and is not reimbursed by
Medicare in the U.S. As the pretest probability of
detecting high-grade carotid artery stenosis signifi-
cantly influences the cost-effectiveness of screening
and treatment strategies, patients population have
to be defined which most likely may benefit from
screening and preventive treatment. These popu-
lations may include patients with established ath-
erosclerotic vascular disease in other vascular ter-
ritories like patients with coronary artery disease,
peripheral arterial occlusive disease, and abdominal
aortic aneurysms, patients with carotid bruits, and
patients after radiation therapy for head and neck
cancers, but not patients with atherosclerotic risk
factors alone.
9.3.3.4.2.1
Patients with Known Heart Disease
In community-based stroke screening programs,
carotid artery stenosis was the most commonly
diagnosed treatable cause of potential stroke, and
patients with known heart disease have a more than
doubled risk to have carotid artery stenosis than
those without heart disease. The risk is further
177
increased in those with arterial hypertension and
coronary or hypertensive heart disease. More than
one of every five patients in this specific popula-
tion was found to have occult carotid artery ste-
nosis, compared to 8% in an age-matched popu-
lation (Rockman et al. 2004). Therefore screening
for occult carotid artery stenosis may be useful in
patients with known coronary or hypertensive heart
disease. However, studies on the efficiency of screen-
ing programs in this population are still missing.
9.3.3.4.2.2
Patients with Peripheral Arterial Occlusive Disease
The prevalence of significant carotid artery steno-
sis is increased as much as 50% in patients with
peripheral arterial disease, as shown in the SMART
study (Simons et al. 1999). In addition, a number of
reports on smaller screening programs suggested
that male patients with symptomatic lower extrem-
ity atherosclerosis (de Virgilio et al. 1997; Cheng
et al. 1999a), elder patients with cardiovascular risk
factors (Ahn et al. 1991), and patients with ankle-
brachial index less than 0.7 (Marek et al. 1996) may
qualify for screening.
9.3.3.4.2.3
Patients with Abdominal Aortic Aneurysms
Several studies have shown that patients with
abdominal aortic aneurysms have an increased
incidence of carotid artery stenosis. The incidence
of high-grade carotid artery stenosis (> 70%) ranges
from 2.9%–18% (Deville et al. 1997; Cheng et al.
1999b; Axelrod et al. 2002). There is no evidence,
however, that carotid endarterectomy performed
prior to aneurysm repair reduces the risk of peri-
operative stroke. A recent cost-effectiveness analy-
sis of screening for carotid disease in patients with
abdominal aortic aneurysms showed that most
patients with advanced carotid artery stenosis (71%
of 206 patients screened) had clinical evidence of the
disease including transient ischemic attacks, amau-
rosis fugax, a complete stroke, or a history of prior
carotid surgery. The absence of clinical evidence of
the disease had a negative predictive value of 99%.
Routine screening for carotid artery disease would
result in additional costs of $5,445 per case, whereas
screening for advanced carotid stenosis in patients
with an appropriate history or symptoms would
reduce costs to one fifth. From the data available,
routine diagnostic screening for the identification
178 N. Weiss and U. Hoffmann
of asymptomatic carotid artery stenosis in patients
with abdominal aortic aneurysms may not be justi-
fied, and should be restricted to those with clinical
symptoms of the disease.
9.3.3.4.2.4
Patients after Contralateral Carotid Endarterectomy
Progression of contralateral carotid artery stenosis
after carotid endarterectomy is relatively common
(Raman et al. 2004). A recent study identified an
8.3% annual rate of progression of contralateral
carotid artery stenosis and a 4.4% annual rate of
progression to severe stenosis or occlusion. Clinical
and demographic factors did not predict the risk
of progression. Therefore, routine follow-up of the
contralateral carotid artery in patients after carotid
endarterectomy may be useful, although cost effec-
tiveness analysis of duplex scanning in this popula-
tion have not been performed so far.
9.3.3.4.2.5
Patients Scheduled for Elective Coronary Artery
Bypass Surgery
Extracranial internal carotid artery stenosis is a risk
factor for perioperative stroke in coronary artery
bypass surgery. Although both selective and non-
selective methods of preoperative carotid screening
have been advocated, it is unclear which approach
is most clinically efficacious. A recent study com-
pared selective screening in patients with either an
age of more than 65, carotid bruit, or a history of
cerebrovascular disease with routine screening in
all patients, followed by carotid endarterectomy
under local anesthesia in those with critical carotid
stenosis (De Feo et al. 2005). Routine screening vs
selective screening for carotid stenosis significantly
reduced the rate of postoperative stroke (0.26% vs
3.82), hospital mortality for stroke (0% vs 1.91%),
and the incidence of non-fatal stroke (0.26% vs
1.91%). These data suggest that preoperative duplex
scanning in all cases of scheduled coronary bypass
surgery would reduce the incidence of postoperative
stroke, at least when carotid endarterectomy is per-
formed under local anesthesia. In addition, a recent
clinical series showed that patients with significant
carotid artery stenosis scheduled for open heart sur-
gery had fewer adverse events when carotid stenting
compared to carotid endarterectomy was used for
preoperative carotid revascularization (Ziada et al.
2005). Based on these findings it may be recom-
mended to routinely screen all patients undergoing
open elective heart surgery for atherosclerotic coro-
nary artery disease and performing carotid revascu-
larization either operatively under local anesthesia
or by carotid artery stenting.
9.3.3.4.2.6
Patients with Carotid Bruits
Carotid auscultation is thought to be a useful screen-
ing procedure for the detection of carotid stenosis
or occlusion. In a series of 145 patients, the negative
predictive value of a normal auscultation was found
to be 97%. The sensitivity of carotid auscultation for
the detection of a 70%–99% stenosis of the common
or extracranial internal carotid artery was 56% and
specificity was 91%. The positive predictive value
of a bruit found during carotid auscultation, how-
ever, was only 27% (Magyar et al. 2002). These data
suggest that the clinical finding of a carotid bruit
requires confirmation by carotid ultrasound.
9.3.3.4.2.7
Patients after Radiation Therapy for Head and Neck
Cancer
Cervical radiation for head and neck cancer is asso-
ciated with an increased incidence of carotid artery
stenosis. During the 10 years following radiation
treatment up to 40% of patients develop significant
carotid artery stenosis (Steele et al. 2004). Whether
or not focused screening of this high-risk population
may be effective and medically beneficial is cur-
rently under investigation.
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 Oncological Disease: Breast Cancer 183

Oncological Disease 10
10.1 Breast Cancer
Karin Hellerhoff, Claudia Perlet, and Thomas Schlossbauer

CONTENTS 10.1.1
Physical and Technical Quality Control

10.1.1 Physical and Technical Quality Successful mammography screening has to keep
Control 183 the radiation exposure as low as reasonably achiev-
10.1.2 Radiographical Performance 184 able (ALARA) to obtain high quality images with
10.1.2.1 Mammographic Examination 184 sufficient diagnostic information. Quality control
10.1.2.2 Image Quality 184 in screening units has to cover all parts of the
imaging chain like X-ray generation, Bucky and
10.1.3 Radiological Performance 184
image receptor, fi lm processing and viewing con-
10.1.3.1 Viewing Conditions 186
10.1.3.2 Reporting System 186 ditions. A nominated radiographer of the screen-
ing unit should be responsible for consistency tests
10.1.4 Radiological Assessment 187 which have to be performed daily and weekly (see
10.1.4.1 Additional Mammography Views 187 Table 10.1). More complex measurements have to be
10.1.4.2 Ultrasound 188
10.1.4.3 MRI 188 undertaken either at acceptance, yearly or every six
months covering the X-ray source (focal spot size,
10.1.5 Image Guided Sampling source to image distance, alignment of X-ray field,
Techniques 189 radiation leakage), tube voltage reproducibility and
10.1.5.1 Fine Needle Aspiration Cytology 190
beam quality (Half Value Layer), automatic expo-
10.1.5.2 Needle Core Biopsy 190
10.1.5.3 Vacuum Assisted Needle Core sure control (reproducibility and security cut-off),
Biopsy 190 tube voltage compensation, dosimetry and exposure
time (Perry et al. 2006). Performance indicators are
10.1.6 Perspectives 191 listed in Table 10.2.
References 191
Table 10.1. Physical and technical quality control parameter

Daily X-ray machine Automatic exposure control

reproducibility
Film processing Sensitometry
Cassettes Screen inspection and
cleaning
Daily or Film processor Cleaning
weekly X-ray machine Automatic exposure control
repeatability
AEC changing thickness
Image quality (spatial reso-
K. Hellerhoff, MD lution, contrast)
C. Perlet, MD Yearly Cassettes Film-screen contact
T. Schlossbauer, MD Sensitivity and radiation
Department of Clinical Radiology, University Hospitals – absorption
Grosshadern, Ludwig-Maximilians-University of Munich, Illuminators Output
Marchioninistrasse 15, 81373 Munich, Germany
184 K. Hellerhoff, C. Perlet, and T. Schlossbauer

Table 10.2. Performance indicators for physical aspects and radiographical performance (European Guidelines, 4th edn)

Performance indicator Acceptable level Desirable level

Target optical density 1.4–1.9 OD 1.4–1.9 OD
Spatial resolution > 12 lp/mm > 12 lp/mm
Glandular Dose – PMMA thickness at 4.5 cm < 2,5 mGy < 2 mGy
Proportion of women with radiographically 97% > 97%
acceptable screening examination
Proportion of women undergoing a technical < 3% < 1%
repeat screening examination

toral muscle of the woman for obtaining oblique

10.1.2
Radiographical Performance
Since high quality screening demands high qual-
ity mammograms carried out in an acceptable
manner, radiographers play a key role in screening
programmes aiming at a significant reduction of
breast cancer mortality.
Radiographers are responsible for:
 Technical quality control (see above)
 Mammographic examination
 Producing the mammogram in a manner accept-
able to the women and therefore encouraging
future attendance
10.1.2.1
Mammographic Examination
The examination should start with an introduc-
tory talk explaining the procedure including the
number of views to be taken and the positioning.
The importance of compression should be empha-
sized. A pleasant and trustful ambience should be
created.
Positioning of the woman is the most important
part of the examination. The chamber of the auto-
matic exposure device should be completely covered
by breast tissue and be positioned under the anterior
part of the breast. The equipment should allow ergo-
nomic and easy handling. To allow the use of both
hands when positioning the breast, the equipment
should provide foot-pedal-operated compression.
Compression should be applied slowly and carefully
but not exceed the necessary degree. It should be
released immediately after the exposure. The angle
used has to be well adjusted to the angle of the pec-
views. The height of the fi lm support table has to be
well adjusted to the woman’s height for obtaining
cranio-caudal views.
Two-view examination should be standard, since
a detection rate increase of 24% and a decrease of
recall rates of 15% by adding cranio-caudal view
could be demonstrated (Wald et al. 1995).
10.1.2.2
Image Quality
All images should be assessed for the following cri-
teria in daily routine:
 Correct identifications
 Correct exposure
 Appropriate compression
 Absence of skin folds or overlying artefacts
 No movement artefacts
 Correct development techniques
 Absence of scratches etc.
The quality of the images is classified using the
PGMI system (see Table 10.3): P = perfect, G = good,
M = moderate, I = inadequate.
More than 97% of the mammograms should be of
acceptable image quality. Less than 3% of the women
should have to undergo a technical repeat.
10.1.3
Radiological Performance
The responsibilities of the radiologist are to ensure
all mechanisms of quality control in order to pro-
 Oncological Disease: Breast Cancer 185

Table 10.3. Quality criteria for mammograms

PGMI criteria for mediolateral oblique view PGMI criteria for cranio-caudal view

All the breast tissue clearly shown As much as possible of the lateral part of the breast is shown
Pectoral muscle to nipple level If possible, the pectoral muscle is shown at the posterior edge of the
mammogram
Symmetrical images Symmetrical images
Nipple in profi le Nipple in profi le
Inframammary angle clearly visible Medial border is visible

Table 10.4. Performance and impact indicators of screening mammography (European Guidelines, 4th edn)

Performance indicator Acceptable level Desirable level

Attendance rate > 70% > 75%

Proportion of women reinvited in the specified screening interval > 95% 100%
Time delay between screening mammography and result 15 wd 10 wd
Time delay between abnormal mammography and result 5 wd –
Recall rate for further assessment
Initial screens < 7% < 5%
Subsequent screens < 5% < 3%
Breast cancer detection rate, as a multiple of the underlying,
expected incidence rate (IR) in the absence of screening
Initial screens 3 × IR > 3 × IR
Subsequent screens 1.5 × IR 1.5 × IR
Interval cancer rate, proportion of symptomatic breast cancers
after a screening examination
Within 12 months after screening mammography 30% < 30%
Within 24 months after screening mammography 50% < 50%
Proportion of invasive screen-detected cancers 90% 80%–90%
Proportion of screen-detected cancers stage II+
Initial screens – < 30%
Subsequent screens 25% < 25%
Proportion of screen-detected, node-negative cancers
Initial screens – > 25%
Subsequent screens > 25% > 30%
Proportion of screen-detected cancers that are < 10 mm in size
Initial screens – > 25%
Subsequent screens > 25% > 30%
Proportion of screen-detected cancers that are < 15 mm in size 50% < 50%

vide high quality images, to read mammograms
with optimal sensitivity and specificity meeting the
targets of the given performance and impact param-
eter and to take care of the timely follow-up assess-
ment for women with abnormal mammograms.
Performance standards representing the sensitivity
and specificity of the reader are the detection rate of
initial and subsequent screens related to the back-
ground incidence of the population, the proportion
of screen-detected small invasive cancers < 10 mm
and screen-detected DCIS as a proportion of all
screen-detected cancers (see Table 10.4).
186 K. Hellerhoff, C. Perlet, and T. Schlossbauer
The radiologist should be involved with symp-
tomatic breast assessment and be experienced in
all biopsy techniques including ultrasonography,
ultrasound guided core biopsy, stereotactic guided
vacuum biopsy and preoperative localisation pro-
cedures such as wire placement. Radiologists per-
forming histologic assessments should attend mul-
tidisciplinary review boards to be involved in the
preoperative and postoperative therapy decisions.
Interval carcinoma is defined as breast cancer
becoming symptomatic after attending mammogra-
phy and before the next subsequent screen. Although
interval carcinoma are inevitable, the rate should
be kept low. Monitoring and reviewing of interval
cancer is essential for further improvement of radio-
logical skills. If any interval cancer is observed it
should be evaluated whether it is due to failures in
the reading of mammograms or in further assess-
ment procedures. True interval carcinoma with
negative screening fi lm should be differentiated
from occult carcinoma remaining without mam-
mographic manifestations and cases of minimal
mammographic signs retrospectively detectable in
screening mammograms.
10.1.3.1
Viewing Conditions
The luminance of viewing boxes should be well
related to the ambient light level. Generally it should
be in the range of 3000–6000 cd/m2.
Collimation should be provided as well as the use
of magnifying glasses. To prevent inhomogeneities
of the permeating light as a result of dust, the boxes
should be cleaned regularly. The ambient light in
the viewing room should not exceed 50 lux. Viewing
conditions have to be controlled yearly.
Digital full field mammograms should be read as
soft copies. The work station must provide at least
two high resolution monitors (2.5 × 2 K). Since the
luminance of these monitors is lower than the aver-
age luminance of viewing boxes, the ambient light
should be diminished as far as possible.
Previous mammograms should be displayed at
the time of screen reading if ever possible. Double
reading should be performed routinely, since the
detection rate increases by 15% compared to single
reading (Thurfjell et al. 1994). If double reading is
performed, the second reader should be experienced
with a minimum of 5000 mammograms per year. If
the mammogram is considered to be abnormal by
one or two radiologists it should be reviewed by an
expert radiologist who is able to arbitrate.
10.1.3.2
Reporting System
Reporting screening mammograms should use stan-
dardized terminology to describe mammographic
lesions and give standardized recommendations for
the further assessment. Inconsistencies and confu-
sions among the radiologists being involved in the
further follow-up of a woman have to be avoided.
A simple five-point classification system is used
widely in European screening programmes:
R1 Normal/benign
R2 A lesion having benign characteristics
R3 Abnormality of indeterminate significance
R4 Features suspicious of malignancy
R5 Malignant features
The increasingly used BI-RADS system allows a
more precise classification including recommenda-
tions for the need of further follow-up (ACR 2003).
The breast density is included into the report,
because it has an important impact on the accuracy
of mammography. The sensitivity of 80% in women
with fatty breast tissue (ACR 1) decreases to 30% in
women with very high density (ACR 4) (Mandelson
et al. 2000). Screening mammograms of women with
dense breast tissue were 30% more likely to have
lesion-assigned discordant assessments and recom-
mendations compared with those of women with
fatty tissue (Lehman et al. 2002).
Breast tissue density according to the BI-RADS
system is classified as follows:
ACR Mammographic appearance
1 Mostly fatty
2 Fibroglandular tissue
3 Heterogeneously dense
4 Completely dense
Mammographic lesions are differentiated as fol-
lows.
Mass: a mass is a lesion which can be seen in two
different views (otherwise it should be described as
density). It should be described by its shape (round,
oval, lobular, irregular), its margin (well-defined
and smooth, microlobulated, obscured by surround-
ing tissue, indistinct and spiculated) and its density
(higher, lower or equivalent) compared to the sur-
rounding glandular tissue.

Calcifications: these are classified for different
appearances and distributions. A monomorphic
and smoothly shaped appearance indicates typical
benign calcification. Amorphous or pleomorphic
calcifications are of indeterminate character. Linear
or branching calcifications indicate ductal origin
with higher suspicion of malignancy. The distribu-
tion is described as diffuse, clustered or linear and
segmental, the latter indicating higher suspicion of
malignancy.
Architectural distortion: the regular tissue archi-
tecture is disturbed without a recognizable definite
mass.
Lesions should be correctly described for their
location including the side (left, right), the involved
quadrant (I–X), the location according to the face
of the clock and the location related to the nipple
(nipple-lesion distance, subareolar, central, prepec-
toral).
The size should be evaluated using two views.
Associated mammographic findings like skin retrac-
tion or thickening, nipple retraction and axillary
adenopathy should also be described. Whenever
possible, previous examinations should be available
to compare previous and current status in order to
evaluate changes of appearance or size of a lesion.
Moreover, previous screens enable the recognition
of anatomical variants like asymmetric breast tissue
or intramammary lymph nodes.
BI-RADS definitions of mammographic lesions
and concordant recommendations for further
assessment are listed in Table 10.5.
The concordance of assessments and recom-
mendations assigned to screening mammograms
Table 10.5. BI-RADS classification system
BI-RADS category Defi nition
0 Additional imaging needed
1 Negative
2 Benign fi nding
3 Probably benign
4 Suspicious abnormality
5 Highly suggestive of malignancy
6 Histologically proven malignancy
Oncological Disease: Breast Cancer 187
among 18 community radiologists was determined
by Lehman et al. (2002). The assessment with the
highest rate of discordance between BI-RADS
assessments and recommendations (53.5%) was
the BI-RADS 3 category “probably benign finding”.
Although the overall discordance between the BI-
RADS assessments was low (3%), further improve-
ment was observed over a period of 4 years with
exception of the high discordance rates of the BI-
RADS 3 category persisting across all of the study
years.
The European Guidelines for quality assur-
ance therefore recommend that for screening pur-
poses “BI-RADS category 3 should be avoided or
restricted to a minimum of < 1% of women”, since
early recall is associated with low predictive value
but creates uncertainty and anxiety. Breast cancer
detected by early recall is defi ned as interval cancer
by some programmes, because the diagnosis is
delayed.
10.1.4
Radiological Assessment
10.1.4.1
Additional Mammography Views
Additional views are helpful to visualize mammo-
graphic lesions in two orientations allowing correct
localization of a lesion. Commonly used additional
views are listed in Table 10.6.
Recommendation
Special mammographic views, spot compression,
magnification, ultrasound
Normal interval follow-up
Normal interval follow-up
Short-term follow-up
Biopsy should be considered
Histological assessment using core biopsy, surgical
biopsy
188 K. Hellerhoff, C. Perlet, and T. Schlossbauer

Table 10.6. Imaging assessment: commonly used additional mammographic views

Additional view Indication

Mediolateral view Preoperative localization and biopsy planning with perpendicular views
Visualization of “tea-cup” appearance of microcalcifications of mastopathic origin
Lateromedial view Visualization of medially localized lesion in cc view
XCC view Visualization of lesions seen in oblique view and suspected to be localized laterally
Cleavage view Visualization of dorsally and medially located lesions
Torquated cc view Localization of lesions seen in cc view but not in oblique view. Lateral movement of
the breast will induce a lateral shift of lesions located in the upper quadrants and
induce a medial shift of lesions located in the lower quadrants of the breast
Paddle compression spot views To improve the visualization of distortion and possible mass
To resolve pseudolesions, overlying tissue and asymmetry
Microfocus magnification image Further assessment of microcalcifications

10.1.4.2  Evaluate the possibility of ultrasound guided

Ultrasound
Ultrasound examinations of the breast have to be
performed using a high frequency transducer with
at least 7.5 MHz. The operating frequency should
preferably be higher with 10–13.5 MHz, because
a high spatial resolution is needed. However, the
transmission depth is decreasing with increasing
frequency. Therefore it may sometimes be more
effective to use a 7.5-MHz transducer to evaluate
the posterior, prepectoral tissue in women with
large breasts. For the examination of the upper
quadrants the woman should lift the arm of the
ipsilateral side in order to reduce the depth of the
breast. The breast should be slightly compressed
by the transducer to minimize shadows induced
by Cooper ligaments. Depth compensation should
be suitable for the individual patient. The focus
should visualize the entire tissue from skin to
the prepectoral parts of the breast and should be
adapted to possible focal lesions. The examination
is performed clockwise at each side and should
include the axillary portion and the submamillary
region of the breast. Significant lesions should be
recorded with images clearly annotated to show
side, depth and position of the lesion. The size of
the lesion should be documented with at least two
views.
In mammography screening conditions ultra-
sound examination is required to:
 Correlate mammographic lesions
 Differentiate cysts from solid lesions
biopsy as it is the most available and most suit-
able sampling technique
Especially in women with mamographically
dense breast tissue ultrasound represents an effi-
cient tool for the further assessment of otherwise
unclear lesions (Gordon 2002). Ultrasound features
of breast lesions are summarized in Table 10.7.
It is imperative that all lesions remaining unclear
or suspect after mammography, clinical examina-
tion and image assessment including ultrasound
and – if indicated in particular cases – MRI undergo
histological assessment.
Lesions sonographically proven to be a cyst need
no further examination. Lesions with typical sono-
graphical features of fibroadenoma must not be
sampled, but should undergo one short term follow-
up after six months.
10.1.4.3
MRI
MRI is of proven value in the work-up of women
with breast cancer to evaluate the tumour size and
to exclude multifocality, multicentricity or bilat-
eral disease. Other indications are the follow-up
of a tumour during chemotherapy and the assess-
ment after incomplete surgical resection of a breast
tumour.
In population-based breast screening MRI should
be restricted to the imaging work-up of few individ-
 Oncological Disease: Breast Cancer 189

Table 10.7. Ultrasound features of breast lesions

Features indicating malignancy Features indicating benign character

Ill-defi ned or hyperechogenic margin Smooth margins

Hypoechogenic appearance Homogeneously hyperechogenic appearance
Vertical extent Horizontal extent
Lesion induces acoustical shadow Acoustical amplification
Spread into duct Oval shape
Microlobulation Macrolobulation

Table 10.8. Assessment strategies for the evaluation of mammographic lesions

Mammographic lesion Assessment Findings Recommendation

Lesion seen in two views Ultrasounda Cyst Normal follow-up interval

Typical fibroadenoma Ultrasound follow-up in
6 months
All other lesions Needle core biopsy
Microcalcification
Typical benign features – – Normal follow-up interval
Unclear or suspicious Magnification view Benign appearance Normal follow-up interval
Unclear or suspicious Vacuum assisted needle core
biopsy, open biopsy in special
cases
Architectural distortionb Compression spot Complete disappearance Normal follow-up
view
Distorsion unchanged Open biopsy after preoperative
hook-wire localization
Asymmetry Palpation and ultra- No mass palpable, no Normal follow-up interval, MRI
sound, additional lesion seen by ultrasound in few individual cases
views if necessary
Palpable mass or lesion Needle core biopsy
seen by ultrasound
a Exceptions are lesions with fatty content (small intramammary lymph node, typical oil-cyst) or a fibroadenoma represent-
ing with typical calcifications). These lesions do not need further assessment
b If not due to scar after previous surgery

ual cases. MRI may be helpful for the localization of

a suspicious mammographic lesion, which cannot be
visualized in the second view even after performing
additional views and ultrasound. In cases of focal
asymmetric densities MRI could be indicated in few
cases, if palpation, additional views and ultrasound
do not allow a definitive recommendation. The value
of MRI in women with high-risk for breast cancer is
discussed in Chapter. 15.1.
A summary of diagnostic assessment strategies is
given in Table 10.8.
10.1.5
Image Guided Sampling Techniques
Histological assessment should not be performed,
until the radiological and clinical assessment is
totally completed. The most frequent indication for
histological assessment is a BI-RADS 4 recommen-
dation following screening mammography or fur-
ther diagnostic assessment. Since the positive pre-
dictive value for malignant results in this group is
190 K. Hellerhoff, C. Perlet, and T. Schlossbauer
20%–30%, open biopsy can be avoided in 70%–80%
of patients (Liberman et al. 1998; Laquement et al.
1999). Lesions classified as BI-RADS 3 should not be
routinely sampled, since the malignancy rate among
these lesions is much less than 2%. In BI-RADS 5
lesions the preoperative biopsy should be performed
to allow therapy planning including therapeutical
surgery and sentinel lymph node biopsy proce-
dures after malignancy is proven by percutaneous
biopsy.
Sampling techniques should be carried out with
respect to the imaging modality carrying the most
suspicious features. In general it is most suitable
to perform sampling under ultrasound control.
Microcalcifications should be sampled by vacuum
assisted needle core biopsy. It is regarded consent,
that significant architectural distorsions should not
be sampled by percutaneous biopsy, because associ-
ated malignancy may not be demonstrated. In these
cases women should primarily undergo open biopsy
after preoperative wire localization.
10.1.5.1
Fine Needle Aspiration Cytology
The accuracy of Fine Needle Aspiration Cytology
(FNAC) is highly dependent on the experience of
the operator and requires a well-trained pathologist
(Wells 1995). Although FNAC is less expensive and
less time consuming than needle core biopsy, some
substantial drawbacks limit the value of the method.
The reported sensitivity is much lower compared to
needle core biopsy (Pisano et al. 1998). Poor cel-
lularity may cause an inadequate sample rate of
10%–15%, especially in case of sclerosing adenosis,
sclerosed fibroadenoma and invasive lobular car-
cinoma.
10.1.5.2
Needle Core Biopsy
Needle core biopsy (NCB) is the technique of choice
for sampling of non-palpable masses providing
high sensitivity (92%–98%) and specificity (100%)
(Britton et al. 1997; Nguyen et al. 1996). The
biopsy should be performed with a needle of at least
14 G diameter. Since the sensitivity of the method
increases with the number of samples, at least five
tissue specimens should be obtained to ensure a
definitive diagnosis. Moreover the samples can be
used for the assessment of steroid receptor status
and Her2/Neu status.
10.1.5.3
Vacuum Assisted Needle Core Biopsy
Vacuum assisted needle core biopsy (VANCB) pro-
vides the highest accuracy rates obtained by non-
invasive procedures. Negative pressure is used to
suck sample tissue into the biopsy port, being cut
by a rotating cylinder passing down within the
probe. VANCB should be performed using 11 G or
8 G needles to obtain 24 samples within 2 rounds
of 12 clockwise steps. In case of microcalcifica-
tions within the sampled area, the obtained tissue
should be examined by radiography immediately
after the procedure. The obtained samples provide
higher tissue volumes compared to NCB and allow
defi nitive diagnosis even in case of moderate or
low suspicion microcalcification. Moreover asso-
ciated ductal in situ cancer (DCIS) and associated
atypical ductal hyperplasia (ADH) is more often
demonstrated compared to NCB (Burbank 1997).
In a few instances, however, VACB is not appli-
cable. These include microcalcifications located
adjacent to the mamilla or the pectoral muscle. In
small breasts, the compression thickness may be
less than two cm, not allowing complete insertion
of the needle.
The results of any biopsy procedures performed
by the radiologist and evaluated by the pathologist
should be presented in an multidisciplinary panel.
All benign results have to be correlated with the
imaging work-up and the degree of radiological sus-
picion to determine, whether the sample obtained
was representative or not. When imaging findings
suspicious of malignancy are inconsistent with his-
topathological findings, it should be consent, that
the biopsy in case of NCB must be either repeated or
complemented by VANCB or open biopsy. Women
with benign findings correlating with imaging
work-up should undergo one short term follow-up 6
months after the biopsy procedure.
Performance indicators for biopsy techniques
and initial treatment are listed in Table 10.9.
 Oncological Disease: Breast Cancer 191

Table 10.9. Performance indicators for biopsy techniques and initial treatment (European Guidelines, 4th edn)

Performance indicator Acceptable level Desirable level

Sensitivity of core biopsy > 80% > 90%

Specificity of core biopsy > 75% > 85%
Proportion of localised impalpable lesions successfully excised at the fi rst > 90% > 95%
operation
Proportion of preoperative diagnosis of cancer with an FNAC or core 90% > 90%
biopsy
Proportion of image guided core / vacuum biopsy with insufficient result < 20% < 10%
Benign to malignant open surgical biopsy ratio in women with initial and < 1:2 < 1:4
subsequent examinations
Proportion of wires placed within 1 cm of an impalpable lesion prior to 90% > 90%
excision
Proportion of patients with repeat operation after incomplete excision 10% < 10%
Time delay between result of mammography and offered assessment
Time delay between assessment and issuing of results 5 wd
Time delay between decision to operate and date offered for surgery 15 wd 10 wd

10.1.6
Perspectives
In recent years full-field digital mammography has
been increasingly used and it may be expected that
in the near future this techniques will displace fi lm
mammography. There are substantial advantages of
digital mammography in particular for screening
conditions such as image manipulation, electronic
transmission, retrieval and data display. Worksta-
tions with automatic hanging protocols, central-
ized server and Dicom shuttles for the exchange of
images are available to simplify both double reading
at two different sites and possible review by an arbi-
trator (Fröhlich et al. 2007). On-screen magnifica-
tion is sufficient, obviating the need for additional
microfocus magnification views. Future technologi-
cal developments may provide further improvement
like computer-aided detection and tomosynthesis.
The largest comparative study has shown a possible
benefit in the evaluation of mammograms with very
dense breast tissue, because monitor reading pro-
vides the possibility to adjust the image contrast
(Pisano et al. 2005).
Further research considering the different bio-
logical appearances of breast cancer may allow more
individual imaging recommendations with regard to
genetic predispositions and patterns of biomarker.
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Britton PD, Flower CD, Freeman AH et al. (1997) Changing to
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Burbank F (1997) Stereotactic breast biopsy of atypical ductal
hyperplasia and ductal carcinoma in situ: improved accu-
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Oncological Diseases
10.2 Renal Cancer – Ultrasound
Dragana Filipas, Sascha Pahernik and Joachim W. Thüroff
CONTENTS
10.2.1 Introduction 193
10.2.2 The Mainz/Wuppertal Screening Study 193
10.2.3 Discussion 196
References 198
10.2.1
Introduction
Renal cell carcinoma (RCC) is diagnosed in the
United States in more than 36,000 new cases and
is the cause of more than 12,000 deaths each year
(Jemal et al. 2005). RCC accounts for 3% of all adult
malignancies. Unlike in prostate cancer, which has
a decreasing incidence since the early/mid-1990s
(Jemal et al. 2005), the incidence of kidney cancer
is steadily increasing at a rate of about 2.5% per year
across population groups (Chow et al. 1999), partly
because of an increased use of imaging techniques
such as ultrasonography, CT and MRI (Chow et al.
1999; Pantuck et al. 2001). Advances in renal imag-
ing have led to an earlier diagnosis of renal tumors
resulting in an improved survival of a patients with
localized RCC over the last two decades (Patard et
al. 2004b). These changes have induced an evolution
D. Filipas, MD
S. Pahernik, MD
Department of Urology, Johannes-Gutenberg-University of
Mainz, Medical School, Langenbeckstraße 1, 55101 Mainz,
Germany
J. W. Thüroff, MD
Professor and Chairman, Department of Urology, Johannes-
Gutenberg-University of Mainz, Medical School, Langen-
beckstraße 1, 55101 Mainz, Germany
Oncological Disease: Renal Cancer – Ultrasound 193
10
of the surgical management of RCC with increasing
roles of organ sparing tumor excision and minimal-
invasive surgery.
The gold standard for the treatment of RCC
remains surgery. RCC is insensitive to both, chemo-
therapy and radiation therapy. Surgery of localized
RCC either by radical nephrectomy or by nephron
sparing surgery results in excellent survival rates in
early stages (Patard et al. 2004a; Lau et al. 2000).
However, in case of metastatic RCC, prognosis is
extremely poor since effective systemic therapy
modalities do not exist (Lam et al. 2004). Therefore,
early diagnosis of renal tumors when they are still
asymptomatic is of paramount importance for the
improvement of prognosis of RCC.
These facts make RCC a theoretical candidate
for a screening program, provided that an easy to
perform diagnostic tool of sufficient sensitivity and
specificity is available. Several studies have elabo-
rated on detection of renal masses by abdominal
ultrasonography (Kremer et al. 1984; Spouge et al.
1996; Fuji et al. 1995). In all studies the prevalence
of RCC was higher than that of other solid benign
tumors. The sensitivity of ultrasonography for RCC
strongly depends on tumor size. Sensitivity is 96%
for tumors of > 3 cm in diameter and 79% for those
< 3 cm (Kauczor et al. 1992). Thus, ultrasonogra-
phy is capable of early detection of RCC. However,
practicability and efficacy of a systematic screen-
ing protocol by abdominal ultrasonography has not
been validated before.
10.2.2
The Mainz/Wuppertal Screening Study
We have conducted a feasibility study on screening
for RCC by ultrasonography in two cities over a two-
194 D. Filipas, S. Pahernik, and J. W. Thüroff
year period (Filipas et al. 1999, 2002, 2003). This
screening program was established in 1996 in Mainz
(180,000 inhabitants) and Wuppertal (370,000 inhab-
itants). Participants were screened by 55 general
physicians, 79 internists and 19 urologists in private
practice. Overall, 68% of all eligible physicians par-
ticipated in the program. Eligibility of participating
physicians was validated for qualification in renal
ultrasonography and state-of-the-art sonographic
equipment. Additionally, an active medical practice
in the already established German screening pro-
grams was required. In cooperation with different
health insurers, the infrastructure was developed
firstly to recruit physicians and secondly the eli-
gible study population. The screening program was
offered to the citizens of both cities free of charge.
Inclusion criteria were: age > 40 years (according
to the inclusion criteria of the already established
German screening programs), no urinary symptoms
with a possible renal origin (e.g. hematuria, flank
pain) and no history of renal disease. Informed con-
sent was obtained in writing from all subjects. There
were three types of recruitment of subjects for the
RCC screening program, firstly exclusive recruit-
ment for the RCC screening program, secondly as
participant in one of the other established German
screening programs (for skin, colon, breast, cervix
and prostate cancer) and thirdly at the occasion of
an office visit for other than renal symptoms. Based
on data available from German tumor registries on
the reported incidence of RCC and on a previous
retrospective abdominal ultrasound study (Kremer
et al. 1984), it was calculated that 10,000 screening
participants would be necessary to allow statistical
analysis of detected cases.
The screening was conducted over two consecu-
tive periods of 13 months each. The initial screen-
ing started in December 1996 and the second
phase in January 1998. The second screening phase
offered follow-up ultrasonography to the popula-
tion screened in the first phase. A solid renal mass
detected on screening was described either as equiv-
ocal or positive for renal tumor. When an equivo-
cal mass was detected, reference ultrasonography at
each of the two university urology departments was
offered but was not mandatory. The criterion for an
equivocal finding was a solid renal mass suspicious
of RCC, and that for a positive finding a solid mass
typical of RCC. The criterion for a negative result
was no evidence of tumor. Positive findings and
equivocal findings which could not be excluded by
reference ultrasonography were subjected to CT or
MRI imaging and – when positive – to surgery. Other
solid tumors which are mostly indistinguishable
from RCC by imaging such as solid transitional cell
carcinoma, oncocytoma, angiomyoma, leiomyoma
and lymphangioma were accepted to be included
in the group of positive findings. Masses consis-
tent with angiomyolipomas on ultrasound and/or
CT were excluded. To compare cases of RCC in the
screened population to those from an unscreened
population, the clinical data on all patients present-
ing with a renal mass at the departments of Urology
in Mainz and Wuppertal over the study periods were
registered and analyzed. The TNM system of tumor
stage classification according to the UICC of 1997
was used. The results were assessed using descrip-
tive statistical analyses. The analyzed data were sen-
sitivity, specificity and positive predictive value of
ultrasonographic screening for RCC.
In total, 9959 volunteers (49% men and 51%
women) with a mean age of 61 years (range 40–
94 years) participated in the first screening phase.
The participation rate in the second phase was 79%
(7851) of all participants from the first phase. Of all
screened individuals, 49% (4763) participated in the
screening exclusively because of the offered new
program. The remainder was informed about the
program when they visited the physicians office for
other reasons: 15% (1441) came for other screening
programs offered by the German Ministry of Health
and 38% (3755) presented with other than renal
symptoms.
Thirteen (0.1%) findings were classified positive
in the initial screening ultrasonography. Of these
13, 12 subjects were eligible for further diagnostic
evaluation and 6 were histologically confirmed to
have RCC. Thus, the positive predictive value of a
positive screening finding was 50%. In all, 175 (1.8%)
findings were classified as equivocal in the initial
screening ultrasonography; 171 of 175 subjects were
eligible for further diagnostic evaluation and a renal
tumor was confirmed in seven patients. Diagno-
sis was confirmed by histology in five cases (three
RCCs, two benign tumors) and by imaging alone in
two patients, who were not subjected to furgery. In
these latter cases, CT was highly suspicious for RCC
of 2.0 and 2.5 cm diameter. The positive predictive
value of an equivocal screening finding was thus
4.1% for a solid renal tumor, excluding angiomyo-
lipomas, and 1.8% for RCC. The positive predictive
value for both, equivocal and positive screening
findings was 7.1% for a solid renal tumor and 4.9%
for RCC. In the second screening phase, there were
 Oncological Disease: Renal Cancer – Ultrasound 195

no additional positive findings. Equivocal findings
were obtained in 64 of 7851 patients (0.8%), none of
whom was confirmed to have a renal tumor by refer-
ence ultrasound, CT or MRI.
Positive and equivocal findings in the first phase
of screening ultrasonography were false positive in
93% of cases as judged by subsequent imaging stud-
ies. Of all false positive cases, 48% were reclassified
negative after reference ultrasonography alone. Of
all positive and equivocal cases referred to reference
ultrasound before further CT or MRI imaging was
obtained, 62% were reclassified as negative. CT was
obtained in 68 of 9959 subjects who underwent renal
ultrasonography in the first screening phase, 40 of
68 obtained reference ultrasonography and 28 were
directly referred to CT or MRI by the screening phy-
sicians. Of the latter 28, 4 had been classified posi-
tive on ultrasound and 24 equivocal. The false-posi-
tive rate in the second screening phase was 100%. CT
was obtained in 32 of 7851 subjects who underwent
renal ultrasonography, 23 of 32 without previous ref-
erence ultrasound, even when all of them were clas-
sified equivocal on only screening ultrasonography.
Two additional cases of RCC (interval cases) were
detected in patients with no evidence of tumor in
the first screening phase. One participant moved
into another city and had an abdominal ultrasound
for other reasons 13 months after initial screening
at which occasion a small (2.5 cm) centrally located
renal tumor (T1N0M0) was incidentally detected.
In the second case, both screening studies were
negative, when a third abdominal ultrasonography
6 months after the latest study for other than uro-
logical symptoms revealed a renal mass of 3.8 cm in
diameter (pT1N0M0). From these data, the sensitiv-
ity of ultrasound screening for detecting RCC was
82% as assessed at the 1-year of follow-up of 79% of
the original cohort. The specificity was 98% in the
first screening phase and 99% in the second phase.
Table 10.2.1 lists the data of the first screening
phase, including ultrasound and CT findings, sur-
gical procedures, histology, tumor stage and size of
detected tumors. RCC was confirmed on histology
in nine cases, six men and three women (mean age
61.6 years, range 40–85 years). Their age distribution
is given in Table 10.2. 2. Two benign tumors (patients
10 and 11 in Table 10.2.1) were an oncocytoma and a
leiomyoma. Pre-existing medical comorbidities pro-
hibited surgical exploration in two further patients
(patients 12 and 13 in Table 10.2.1). Of the nine cases
with RCC, six had been declared positive and three
equivocal for renal tumor in the on initial screening
ultrasonography (Table 10.2.1). All but two positive
cases (patients 2 and 6) underwent CT imaging with-
out prior reference ultrasonography.
A total of 482 patients (38% women and 62% men)
were admitted to both hospitals with renal tumors
during the same periods. The screened patients

Table 10.2.1. Renal tumors detected by screening ultrasonography (n = 9959)

Patients Screen US Reference US CT Surgery Histology TMN Size [cm]

1 e e + RN RCC pT2, N0, M0 6.0

2 + + + RN RCC pT2, N0, M0 7.7
3 + + RN RCC pT1, N0, M0 2.5
4 + + RN RCC pT3b, N1, M1 7.0
5 + + RN RCC pT3b, N2, M1 13.0
6 + + + RN RCC pT2, N0, M0 9.0
7 e e + NSS RCC pT2, Nx, Mx 2.6
8 + + RN RCC pT3b, N0, M0 7.5
9 e + RN RCC pT2, N0, M0 6.5
10 e + + RN Benign
11 e + + NSS Benign
12 e + + None - 2.0
13 e + + None - 2.5

Abbreviations: US – ultrasound, e – equivocal, RN – radical nephrectomy, NSS – nephron sparing surgery

196 D. Filipas, S. Pahernik, and J. W. Thüroff

Table 10.2.2. Detected renal cell cancers and age groups Table 10.2.4. Other pathological fi ndings of renal sonogra-
(n = 9959) phy screening

Age groups [years] RCC [n] Screened population [n] Finding [n]

40–49 3 1809 (18.2%) Angiomyolipoma 9

50–59 1 2851 (28.6%) Hydronephrosis 13

60–69 2 3017 (30.3%) Kidney stones 214

70–79 2 1835 (18.4%) Renal anomaly (small kidney, aplasia, dysplasia) 40

80–89 1 429 (4.3%)

90–99 0 429 (4.3%)
(Table 10.2.4). None required further therapy. All
Abbreviation: RCC – Renal cell cancer detected angiomyolipomas were small enough to
be followed conservatively. Minor findings such as
renal cysts, duplex systems and renal parenchymal
Table 10.2.3. Tumor stages of RCC (n = 415) from the popu-
lation undergoing surgery for renal tumors in both centers
scars were documented in 1264 (13%) cases in the
during screening period (n = 482) first screening phase and in 1016 (13%) in the second
phase. None of these required treatment.
Stage Screen Incidental Symptomatic Total
detected
[n] [n] [n] [n]

pT1 1 110 (41%) 27 (20%) 137 (33%)

pT2 5 117 (43%) 64 (47%) 181 (44%)
10.2.3
Discussion
pT3 1 28 (10%) 36 (27%) 64 (15%)
pT4 - - - - With advances in diagnostic capabilities of renal
N+ - 3 (1%) 2 (1%) 5 (1%) ultrasound and CT and increased utilization of
these diagnostic modalities, the number of inciden-
M+ 2 10 (4%) 6 (4%) 16 (4%)
tally detected small RCCs has increased markedly
Total 9 271 (65%) 135 (35%) 415 (Konnak and Grossman 1985; Smith et al. 1989;
Abbreviation: RCC – Renal cell cancer Ueda and Mihara 1987). Abdominal ultrasound
contributes about 3/4 of cases because of its wide-
spread use being a non-invasive, low cost and easy
comprised 2% of these, while 34% of tumors were to apply study. Many RCCs have been found during
detected because of symptoms and 64% inciden- ultrasonography of organs such as liver, gall blad-
tally; 78% of the incidental findings were by ultra- der and pancreas or when annual health checks
sonography. Radical nephrectomy was performed with abdominal/renal ultrasound were performed.
in 358 patients (74%) and nephron sparing surgery Several abdominal ultrasound screening studies
(NSS) in 124 patients (26%). RCC was found on (Kremer et al. 1984; Spouge et al. 1996; Fuji et
histology in 415 (86%) patients. Table 10.2.3 lists al. 1995) have shown that the prevalence of RCC
the tumor stages of all 415 RCCs operated over the is substantially greater than that of other benign
screening periods in both participating centers and solid tumors. However, these studies, which com-
distinguishes between incidental and symptomatic prised complete abdominal ultrasonography, were
tumors as compared to the screened population. all done retrospectively on hospital populations or
The mean tumor size of RCC in the screened group healthy adults. Early detection of organ-confined
was 6.9 cm (range: 2.5–13 cm) and did not differ sig- RCC improves prognosis and long-term survival
nificantly from either of the two other groups. (Guinan et al. 1995) and – in case of small periph-
Other pathological findings of less clinical sig- erally located tumors – offers the option of nephron
nificance of renal ultrasound screening were angio- sparing surgery (Fergany et al. 2000; Filipas et al.
myolipomas in nine participants, hydronephrosis 2000; Lerner et al. 1996). A key question addressed
in 13, kidney stones in 214 and renal anomalies in the current study was the willingness of physicians
(small kidney, dysplasia, aplasia) in 40 patients and patients to participate in this type of screening.

The participation rate was 68% for all eligible physi-
cians and 90% for urologists. Almost half (48%) of
all screened patients participated exclusively in the
RCC screening program, indicating a high accep-
tance rate. Currently, 14% of the eligible male and
34% of the female population comply with the exist-
ing screening programs offered in Germany. Com-
pared with a digital rectal examination for detecting
prostate and rectal cancer, and the cervical smear
for detecting cervical cancer, renal ultrasound is less
invasive and disturbing to the patient. This assump-
tion is confirmed by a 79% return rate for the second
screening phase of renal ultrasonography. A total of
13 renal tumors were detected, nine of which were
RCCs on histology which is a prevalence of 9/10,000
from the first phase of this screening study. Based on
older German cancer registry data and abdominal
ultrasound screening studies (Kremer et al. 1984),
we expected to find only 3/10000 cases of RCC in
the studied age groups. It cannot be concluded with
any certainty, whether the difference between the
observed and expected prevalences can be explained
by the limitations of the databases from which the
primary estimates were derived, or by a too small
cohort of our study, or by selection of the study
population, or by actual early detection through sys-
tematic screening as opposed to incidental or symp-
tom-guided detection. The second screening of the
cohort for detection of new cases provides insight
into the true incidence of RCC in the screened popu-
lation over the time period of follow-up when the
data of the first screening represent prevalence of
RCC in an unscreened population. The prevalence
of RCC was similar in abdominal screening studies
(Spouge et al. 1996; Mihara et al. 1998). In contra-
diction to our expectations, we found larger tumors
of higher stages in the screened population as com-
pared to the incidentally detected group. As a result,
fewer tumors were amenable to NSS. Early detec-
tion of RCC by screening did not result in a stage
shift towards lower tumor stages, which was one of
the hypotheses of our study. One explanation may
again be a too small study cohort. Another expla-
nation may be that detection at an early stage by
screening requires screening at regular, tumor-spe-
cific intervals to depict the true incidence of newly
developing tumors. Tumors would be detected at
early stages when the prevalence of RCC including
higher stages had been taken care of with the initial
screening and if the intervals of follow-up screening
are matched to the incidence of RCC and the speed
of tumor growth, provided that most tumors do not
Oncological Disease: Renal Cancer – Ultrasound 197
metastasize early at small tumor volumes. For RCC,
there is a positive correlation between tumor size
and the rate of lymph node and distant metastases
(Hermanek and Schrott 1990). However, in our
first screening of a previously unscreened popula-
tion, tumor prevalence was determined as compared
to 1-year tumor incidence, which was determined in
our second screening of the same population. Even
if detection of a tumor by systematic screening (our
patients had no symptoms at the time of screening)
is by definition ‘earlier’ than detection by symptoms
in the same patients, it does not necessarily mean
that ‘earlier’ detection is also at an ‘earlier’ tumor
stage. PSA screening of prostate cancer resulted ini-
tially in more frequent detection of prostate cancer
of all stages, which led to considerable debate about
the value of such a screening program (Roberts et
al. 1999; Labrie et al. 1999). For a screening pro-
gram to be useful, it must lead to a net benefit in
patient survival. Six cases with low stage (T1 and T2)
tumors in the current cohort are likely to have ben-
efited from screening by detecting and treating an
organ-confined tumor. Conversely, the two patients
with metastases presumably have not benefited from
the program, as there is no effective treatment for
metastatic disease. Furthermore, the two patients
with RCC on CT who were no surgical candidates
because of poor overall health have suffered psy-
chological distress secondary to the screening. They
know of their potentially fatal disease but cannot
be treated.
The sensitivity in the current study was 82%,
as judged from the results of the 1-year follow-up
during which period two interval cases of RCC were
detected after previous negative ultrasonography.
This is based on the assumption, that these tumors
were present but overlooked at the time of screen-
ing (false-negatives). Another possibility is that they
were present but too small to be detected at the time
of screening. A third possibility is that these tumors
truly developed after the last negative screening
(true incidence). In the first case, a 2.5-cm centrally
located tumor almost isoechogenic to normal renal
parenchyma was detected 13 months after ultra-
sound screening. Although considered a false nega-
tive of screening ultrasonography, the time elapsed
since the first ultrasound, the tumor size and the
estimated speed of growth of this stage of the tumor
could justify its classification as a newly developed
tumor. In contrast, the second case was most likely
missed on ultrasonography during the second phase
of screening, if not also in the first. This peripheral
198 D. Filipas, S. Pahernik, and J. W. Thüroff
tumor was 3.8 cm in diameter and detected 6 months
after the second screening ultrasonography.
Other pathological findings were detected at a low
rate of 13% in both screening phases. This is much
less than reported in other studies (Kremer et al.
1984; Fuji et al. 1995), which may be related to the
fact that a complete abdominal ultrasound was per-
formed in these studies as opposed to renal ultra-
sound only in our study. A further concern of our
screening study was the initiation of a sequence of
costly imaging studies for clarification of equivocal
findings. With reference to the 17810 renal ultra-
sound studies at both phases of our screening, 100
CT scans were initiated. Although it was not manda-
tory in the study protocol, reference ultrasonogra-
phy was efficient for further evaluation of equivocal
findings. Half of the equivocal lesions were reclas-
sified as negative by reference ultrasound, which
reduced the incidence of further imaging studies
by 48%. From this experience, reference ultrasound
should be used in equivocal cases before more costly
imaging studies are initiated. Cost-effectiveness
is a critical issue when evaluating any screening
program. Assessing the cost-effectiveness of renal
ultrasonography as a screening tool for RCC in the
current study is difficult, because there is no infor-
mation about both the costs of treating metastatic
RCC and the total prevalence of incurable disease.
As for the costs of the screening process alone, the
relatively low prevalence and incidence of RCC com-
pared to other cancers with established screening
programs raises doubts about the economic benefit
of screening for RCC in a population above 40 years
of age. The widespread availability of ultrasound
and low cost of renal ultrasonography favor its use
as a potential screening tool for RCC. However,
whether the screening benefit will justify the costs
of screening the population aged above 40 years of
age can only be answered in a prospective long term
screening study comparing the mortality from RCC
between screened and unscreened populations.
References
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Rising incidence of renal cell cancer in the United States.
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Fergany AF, Hafez KS, Novick AC (2000) Long-term results
of nephron sparing surgery for localized renal cell carci-
noma: 10-year followup. J Urol 163:442–445
Filipas D, Spix C, Schultz-Lampel D et al. (1999) Pilotstudie
zur sonographischen Fruherkennung des Nierenzellkar-
zinoms. Radiologe 39:350–353
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515
 Oncological Diseases: Colorectal Cancer 201

Oncological Diseases 10
10.3 Colorectal Cancer
Anno Graser

CONTENTS Part I
CT Colonography in Colorectal Cancer
Screening
Part I CT Colonography in Colorectal Cancer
Screening 201

10.3.1 Practical Aspects and Results of 10.3.1

Screening for Colorectal Cancer Using Practical Aspects and Results of
CT Colonography 201 Screening for Colorectal Cancer Using
10.3.1.1 Introduction 201 CT Colonography
10.3.1.2 Screening for Colorectal Cancer 202

10.3.2 Current Role of CT Colonography in 10.3.1.1

Colorectal Cancer Screening 203 Introduction

10.3.3 Examination Protocols for Computed tomographic colonography (CTC),

CT Colonography 204
10.3.3.1 Patient Preparation and Fecal also referred to as virtual colonoscopy (VC), was
Tagging 204 first described by Vining et al. (1994). Over the
10.3.3.2 Colonic Distention and Data last decade it has been used for colorectal cancer
Acquisition 2066 screening with promising results. The introduction
10.3.3.3 Radiation Dose Considerations 206
of multi-detector CT (MDCT) combined with tech-
10.3.3.4 Strategies for Data Interpretation in
CT Colonography 207 nical advances in 3D visualization and large data
10.3.3.5 Future Trends in CT Colonography 208 volume handling have led to an increasing use of this
technique. Over this decade, CT colonography has
evolved from an innovative research tool to a prom-
Part II MR Colonography 209
ising imaging method in colorectal cancer screen-
10.3.4 Introduction 209 ing. Thin collimation multidetector row protocols,
fecal tagging and primary three-dimensional (3D)
10.3.5 Patient Preparation and Examination endoluminal read represent rapidly advancing areas
Technique 210 in CTC research.
10.3.6 Diagnostic Performance of Its current role in clinical practice, however,
MR Colonography 212 remains yet to be determined. As in other new
developments in radiology, widespread clinical
References Part I 212 implementation depends on general acceptance by
References Part II 214
the clinical community. Key problems requiring
further research are its sensitivity in the detection
of small colonic lesions, and the lack of specificity
in the presence of residual fecal matter and poorly
distended colonic segments.
A. Graser, MD
Department of Clinical Radiology, University Hospitals –
Currently, CRC screening suffers from patients’
Grosshadern, Ludwig-Maximilians-University of Munich, reluctance to undergo screening by fiberoptic colo-
Marchioninistrasse 15, 81377 Munich, Germany noscopy, and the lack of reliable and acceptable alter-
202 A. Graser
native screening tests. Although annual fecal occult
blood testing (FOBT) has demonstrated a reduction
in mortality due to colorectal cancer, FOBT does not
evaluate the colonic mucosa itself (Kronborg et al.
1996). Its sensitivity for colonic polyps is extremely
low as most polyps, even large adenomas, do not
bleed, and occasionally cancers will not bleed either.
In addition, there are many false positive results in
FOBT leading to additional diagnostic tests and costs
(Rockey et al. 1998). Any new alternative screening
test will have to be compared to fiberoptic colonos-
copy, the current reference standard. High accuracy
in detection of polyps and cancers will be required,
and at the same time the test has to be accepted by
the screening population.
10.3.1.2
Screening for Colorectal Cancer
The incidence of colorectal cancer, the second lead-
ing cause of cancer death in western countries,
is estimated to be around 150,000 new cases and
about 50,000 deaths per year in the United States
(Podolsky 2004; Winawer et al. 2003). This high
incidence as well as the fact that most cancers of the
colon and rectum develop from benign precursor
lesions makes screening effective. The benefits of
CRC screening outweigh the costs associated with
it, and with CT colonography gaining importance,
screening may become more acceptable to patients.
In general, there is consensus that screening for CRC
is justified, and reimbursable options include fecal
occult blood testing, sigmoidoscopy, double con-
trast barium enema (DCBE) examination, colonos-
copy, and combinations of these tests (Ransohoff
and Sandler 2002).
In the colon and rectum the vast majority of
cancers develop slowly, over a time period of 10–
15 years, from benign precursor lesions, called
polyps (Winawer et al. 1993). Due to this slow
growth rate, removal of these lesions will lead to
a reduction of CRC incidence (Jemal et al. 2005;
Mandel et al. 1993; Muller and Sonnenberg
1995; Ransohoff and Sandler 2002; Winawer
et al. 1993; Winawer and Zauber 2001; Winawer
2005). In accordance with the adenoma-carcinoma
sequence, any adenomatous polyp can harbour low
grade dysplasia which will subsequently progress
to high grade dyplasia as the adenoma keeps grow-
ing. Finally, there is the possibility of progression
to invasive cancer (Aldridge and Simson 2001;
Muto et al. 1975; Winawer 1999). About 80%–
90% of all cancers of the colon and rectum prob-
ably develop like this (Morson 1984; Winawer et
al. 2003). Therefore, resection of polyps can reduce
colorectal cancer mortality by over 90%. Besides
these adenomatous polyps which can be divided
into three histological subtypes (tubular, tubu-
lovillous and villous), there is a benign subtype
(hyperplastic). Hyperplastic polyps do not have
premalignant potential (Winawer et al. 1993).
The prevalence of adenomatous polyps in an
asymptomatic screening population has been
reported to be about 20% (Ahmed 2003; Kahi and
Rex 2004; Weissfeld et al. 2005) and at autopsy
up to 60% of men and 40% of women are reported
to have colonic adenomas (Winawer et al. 2003).
This implies that in 4 out of 5 persons undergo-
ing noninvasive CRC screening by CT colonogra-
phy no subsequent colonoscopy and polypectomy
is required. These 80% of persons may benefit
from a non-invasive evaluation of the colon using
CT colonography. Studies have shown that many
small (< 5 mm) polypoid lesions in the colon are
not adenomas and will never progress to become
cancer (Macari et al. 2004; Pickhardt et al. 2003;
Winawer et al. 2003). Nevertheless, there is still
controversy about what size of polyps should be
considered clinically significant. In CT colonogra-
phy, this is of key importance as several research-
ers emphasized that small polyps are not reliably
identified (Cotton et al. 2004; Johnson CD et al.
2004; Macari et al. 2004; Rockey et al. 2005). One
recent multicenter trial, however, reported high
sensitivities for polyps smaller than 6 mm in size
(Pickhardt et al. 2003). The discrepancy in these
results may be due to differences in CT technique
and image interpretation strategies. The presence
of polyps will determine whether a patient has to
undergo colonoscopy for resection of polyps or
not.
Results from recent multicenter trials comparing
CT colonography and conventional colonoscopy in
the detection of colonic polyps have made the ongo-
ing discussion about how to perform screening for
colorectal cancer more and more animated. In Ger-
many as well as in the United States it is now recom-
mended that asymptomatic persons at average risk
for CRC should undergo screening starting at age 50
(Ransohoff and Sandler 2002; Schmiegel et al.
2004). Complete colonoscopy is considered the gold
standard, and it has been shown to lead to decreases
in morbidity and mortality associated with colon

cancer because it allows detection and removal of its
precursor lesions (Jemal et al. 2005; Mandel et al.
1993; Muller and Sonnenberg 1995; Ransohoff
and Sandler 2002; Weissfeld et al. 2005). At pres-
ent, the only reimbursable means of screening in the
U.S. as well as in Germany are FOBT, DCBE, flexible
sigmoidoscopy and colonoscopy. A fundamental
problem is that FOBT and DCBE lack sensitivity
and colonoscopy lacks acceptance among patients,
requires sedation, and is associated with the risk
of bleeding and colonic perforation which may
have to be treated by laparoscopic or open repair.
Although the risk of these complications is a minor
one if colonoscopy is performed by an experienced
gastroenterologist, many individuals refrain from
undergoing the exam. In Germany, overall partici-
pation in the national colorectal cancer screening
programme was as low as 2.2 % or 300,000 persons
in 2004. Bearing in mind that in this country alone
there are 20 million people in the age group at risk,
it is necessary to think about CTC as a reliable alter-
native screening test.
10.3.2
Current Role of CT Colonography in
Colorectal Cancer Screening
At the present time, CT colonography could be con-
sidered the most important alternative screening
test, although the three largest recent multicenter
trials have shown inconsistent results with sensi-
tivities for the detection of polyps larger than 6 mm
ranging from as low as 51% (Rockey et al. 2004) to
as high as 89% (Pickhardt et al. 2003). The larg-
est study to date evaluating CT colonography and
optical colonoscopy in an asymptomatic population
performed by Pickhardt et al. (2003) suggests that
CT colonography is almost equal to optical colonos-
copy in the detection of clinically significant polyps
larger than 5 mm in size when state of the art MDCT
scanners and 3D visualization methods are used.
Remarkably, in this study the sensitivity of CTC for
the detection of polyps 10 mm or larger in size was
over 90% and was, in fact, greater than that of con-
ventional colonoscopy. Most of the smaller polyps
that were missed turned out to be hyperplastic in
nature (Pickhardt et al. 2004). This suggests that
benign hyperplastic polyps may be more deformable
then adenomas.
Oncological Diseases: Colorectal Cancer 203
Another recent study on 703 higher-than-average
risk patients without symptoms, however, showed
low sensitivities of 34%, 32% and 73% for detection
of polyps > 10 mm for three different experienced
readers (Johnson CD et al. 2003). Other recent
single-institutional studies, on the other hand, have
shown high sensitivities of over 80% for polyps in
this size group (Iannaccone et al. 2003; Yee et al.
2001). In addition, it has been concordantly reported
and accepted by most researchers that CTC reliably
and reproducibly identifies almost all lesions larger
than 2 cm in size with sensitivities ranging from
85% to 100% (Iannaccone et al. 2003; Pickhardt
et al. 2003) and 95% specificity (Macari et al. 2002),
and that carcinomas are well depicted (Chung et al.
2005).
In CTC, reader experience and training is essential
and leads to marked increases in sensitivity (Spinzi
et al. 2001). Several studies suggest that there is a
learning curve associated with CT colonography:
In 1997, a study showed 75% sensitivity for polyps
10 mm or larger (Hara et al. 1997). In 2001, a follow-
up trial showed improved sensitivity, which ranged
from 80% to 89% for polyps 10 mm or larger (Hara
et al. 2001). This was also demonstrated in a recent
multiinstitutional study comparing multi-detector
row CT colonography and conventional colonoscopy
(Cotton et al. 2004). In that study, the overall detec-
tion rate for CT colonography for colorectal polyps
10 mm or larger was only 55%. However, analysis of
results from those centers that had the most prior
experience with CT colonography showed excellent
sensitivity (approaching 90%) for 10-mm or larger
polyps.
CTC particularly benefits from the high resolu-
tion of modern multidetector-row CT scanners
and sophisticated 3D volume rendering techniques
(Dachman et al. 1998; Hara et al. 2001; Macari et
al. 2003; Royster et al. 1997). It is widely accepted
that CTC should best be performed on 16- or 64-
detector row scanners to achieve highest resolution
in order to reliably depict colonic fi lling defects.
Furthermore, patient preparation (see Sect. 10.3.3.1)
consisting of either full or reduced colonic cleans-
ing is key for high diagnostic accuracy (Lefere et al.
2004; Macari et al. 2001). To date, most researchers
believe that full bowel preparation is essential for
good results (Fletcher et al. 2000; Johnson CD
and Dachmann 2000; Macari et al. 2001; Yee et al.
1999), although most patients consider bowel prepa-
ration the most cumbersome part of the examina-
tion (Gluecker et al. 2003).
204 A. Graser
10.3.3
Examination Protocols for
CT Colonography
10.3.3.1
Patient Preparation and Fecal Tagging
For colonic preparation, several techniques may be
used, and the optimum strategy remains to be deter-
mined. Most patients consider bowel preparation the
most tedious part of the examination (Gluecker et
al. 2003; Ristvedt et al. 2003).
The goal is a well-prepared and distended colon
(Fig. 10.3.1) enabling accurate detection of polyps
and masses. Most studies to date have been per-
formed using full colonic cleansing, and the major-
ity of researchers believe that a clean colon is key for
high sensitivity in polyp detection (Chen et al. 1999;
Macari et al. 2001, 2002; Yee et al. 2001; Yee 2002).
In addition, thorough cleansing leads to a decrease
in the number of false positive findings. Currently,
cleansing is mostly achieved by oral ingestion of
3–4 L of polyethylene glycol (PEG, “wet prep”),
cathartics like magnesium citrate and phosphosoda
(“dry prep”), or combinations of both. The use of
PEG alone often leads to residual fluid in the colon,
but facilitates subsequent colonoscopy, if polyps or
masses are identified (see Fig. 10.3.2). At our insti-
a b
Fig. 10.3.1a,b. Endoluminal 3D VRT view (a) and axial soft tissue window CT image (b) of a clean and well-distended
colon. Note extrinsic impression of the colonic wall due to contact of this part of the descending colon to the spleen (arrow).
Diverticula are seen on the endoluminal view (curved arrow)
tution, bowel prep is performed by oral ingestion
of four tablets of bisacodyl and 4 L of PEG the day
before CTC. If instructions for application of these
agents are closely followed, this prep will result in
a very clean colon in more than 90% of patients.
However, one has to bear in mind that in cases
with residual fluid polyps may be concealed on the
supine or prone scan, and that the presence of large
amounts of fluid prevents evaluation of the entire
colonic mucosa (Macari et al. 2001). The advantage
of a polyethylene glycol preparation is that it is not
hyperosmolar and does not cause fluid shifts or elec-
trolyte imbalances. Therefore, it should be used in
all patients with substantial cardiac or renal insuf-
ficiencies.
Considering the limitations of bowel preparation
and sometimes poor patient compliance, several
possibilities of fecal and fluid tagging for CT colo-
nography have been investigated (Callstrom et
al. 2001; Lefere et al. 2002, 2004). Oral ingestion of
small amounts of iodine or barium leads to incorpo-
ration of high-density contrast material within resid-
ual fecal material, facilitating differentiation from
polyps. Theoretically, this leads to improved polyp
detection and reduction of false positive calls. At our
institution, patients add 25 mL of iodinated contrast
agent with an iodine concentration of 300 mg/mL to
the last 2 L of PEG solution, and this protocol results
in excellent and homogeneous tagging of residual
 Oncological Diseases: Colorectal Cancer 205

a b

c d

Fig. 10.3.2a–d. Axial soft tissue window CT images (a,b) and 3D endoluminal views (c,d) demonstrating a fluid level in the
transverse and descending colon (curved arrow) on the supine scan. When the patient is turned over to the prone position,
fluid shifts from the descending colon towards the anterior wall of the transverse colon (straight arrows)

fluid. Occasionally, however, tagged fecal material
may obscure polypoid lesions, and the presence of
large amounts of tagged fecal residues may prevent
3D endoluminal evaluation of the colonic surface if
no electronic subtraction algorithms are used. In
the largest multicenter trial to date, Pickhardt et
al. (2003) reported very high accuracy rates in polyp
detection using optimal cathartic preparation, fecal
and fluid tagging in combination with 3D evaluation
of the colon. Furthermore, very good preliminary
results were demonstrated in one study using fecal
tagging without bowel cleansing (Callstrom et al.
2001), and in the near future preparation protocols
for CT colonography will probably be more patient-
friendly and less cumbersome, if larger studies are
able to show consistent results for polyp detection.
This would possibly make CTC the test of choice in
colorectal cancer screening (Rex 2002). Preliminary
data suggests that even “prepless” CT colonogra-
phy with administration of tagging agents 48–72 h
before the scan may become feasible in the near
future (Zalis et al. 2003).
206 A. Graser
10.3.3.2
Colonic Distention and Data Acquisition
If the colon is well prepared and any residual fluid
has been evacuated from the rectum by the patient,
the examination can be performed. Colonic disten-
tion can be achieved by manual or automated insuf-
flation of room air or carbon dioxide (CO2). Gener-
ally, the presence of a radiologist is not required for
this step of the examination, although in some cases
assessment of distention on the scout radiograph
may be difficult. At our institution, a radiology resi-
dent performs digital rectal examination prior to
rectal catheter placement and supervises distention
in order to minimize the number of collapsed or
poorly distended segments. If distention is insuf-
ficient, collapse of colonic segments will prevent
complete evaluation. This most frequently happens
in the descending and sigmoid colon.
If room air is being used to distend the colon, it
can be administered manually. The volume of air
depends on patient discomfort, with approximately
2 L leading to sufficient distention in most normal
size patients. Although excellent results in achiev-
ing bowel distention without a relaxant have been
reported, intravenous administration of hyoscine
butylbromide may improve colonic distention
(Taylor et al. 2003c). The major advantage of using
CO2 rather than room air is that pain and cramp-
ing occur much less frequently as the gas is quickly
absorbed by the colonic wall. Therefore, it should be
administered using an automated insufflator guar-
anteeing optimal distention for the entire duration
of the examination (Burling et al. 2006). The inci-
dence of delayed discomfort is much less of a prob-
lem with CO2. When using CO2, the amount of gas
will be 3–4 L due to continuous absorption during
examination, and a maximum pressure of 25 mm
of mercury will not be exceeded by commercially
available systems (Burling et al. 2006). The rectal
catheter will be left in place using an automated
insufflator, and with manual insufflation it allows
for administration of additional gas if there is col-
lapse of segments.
After sufficient distention is achieved, CT colo-
nography is performed with the patient in the supine
position using narrow collimation and low dose
techniques (see Sect. 10.3.3.3). Phantom studies
have demonstrated improved detection of diminu-
tive polyps (< 5 mm) using thin (1–2 mm) colli-
mation (Johnson KT et al. 2003; Wessling et al.
2003), although detection of these lesions may not
be important as their clinical significance remains
uncertain (Ferrucci 2001). Thin collimation proto-
cols may improve depiction of flat adenomas (Laghi
et al. 2003) which are difficult to detect with CT colo-
nography (Iannaccone et al. 2003), and in some
cases, at colonoscopy, too. Furthermore, recent work
suggests that thinner collimation increases specific-
ity compared with thicker sections, enhancing the
ability to distinguish retained stool from polyps
because of improved morphological resolution (Lui
et al. 2003).
After acquisition of the supine scan, the patient
is turned over to the prone position, and the second
data set is acquired. It has been shown that frequently
single colonic segments will be submerged in fluid
if only one patient position is acquired (Chen et al.
1999), and scanning in both positions enables dem-
onstration of mobility of residual stool.
Modern multidetector row CT scanners obtain 16
or 64 sections at rotation speeds of less than 0.5 s
resulting in very short scan times. Using a 64-MDCT
scanner, patient breathhold time per acquisition is
going to be 6–7 s, and breathing artifacts were not
observed in a study on 100 patients performed at the
University of Munich (Graser et al., 7th International
Symposium on Virtual Colonoscopy, Abstract). Spa-
tial resolution of 0.4 mm isotropic voxels allows for
optimal three-dimensional reformation of data.
Additionally, data can be reformatted in any desired
imaging plane, and coronal as well as sagittal refor-
mats should be obtained from the transverse source
data. Multiplanar reformats facilitate detection and
classification of fi lling defects (Macari et al. 2003;
Taylor et al. 2003b; Wessling et al. 2003).
10.3.3.3
Radiation Dose Considerations
Radiation exposure of persons undergoing CT colo-
nography for colorectal cancer screening is of seri-
ous concern. In CTC, ionizing radiation is being
applied to healthy individuals, and thus has to
be kept to a minimum. In addition to CTC, other
screening examinations use ionizing radiation, like
mammography and DCBE. Potential risks of radia-
tion exposure have to be considered when using
imaging studies for early detection (Obuchowski
et al. 2001). Initial studies using single-detector
scanners at tube current-time products of up to
300 mAs at 140 kVp reported radiation doses of 15–
18 mSv (Fletcher et al. 2000; van Gelder et al.

2004). Theoretically, in modern multidetector row
CT scanners even higher doses would be necessary
to compensate for the much thinner collimation.
However, the very high intrinsic tissue contrast of
more than 1000 Hounsfi eld units between bowel
wall and gas-fi lled lumen enables low dose scan-
ning. As absorbed dose and milliampere-seconds
level are directly proportional, lowering mAs set-
tings is the easiest way of decreasing radiation dose
to the patient (Kalra et al. 2004a). Furthermore,
lowering the tube voltage to 120 or 100 kVp is fea-
sible in normal size patients. The increase in image
noise induced by these changes does not seem to
affect polyp detection (Macari et al. 2002). Recent
advances in automatic tube current adaptation to
patient anatomy and dose modulation lead to even
further reduction in patient exposure (Kalra et al.
2004b). A study by Graser et al. (2006) showed that
use of an automated dose modulation technique that
adjusts tube current in the patient’s x, y, and z-axes
leads to a 35% dose reduction in CT colonography.
The algorithm measures patient attenuation during
the topogram scan and consecutively automatically
adjusts the mAs level to patient anatomy. Using ref-
erence values of 120 mAs and 40 mAs for supine and
prone scans, mean overall radiation dose is going
to be 4.8 mSv on a 16-detector row scanner. Pre-
liminary data from the University of Munich suggest
similar values for a 64-detector row scanner.
When performing CT colonography, extraco-
lonic organs should also be evaluated. One study on
250 patients showed extracolonic findings in more
than 30% of patients, of which 12.5% were highly
important and 40% were moderately important
(Rajapaksa et al. 2004). Too much image noise pre-
vents assessment of parenchymatous organs; there-
fore, image noise should be kept to a minimum.
10.3.3.4
Strategies for Data Interpretation in
CT Colonography
Two primary techniques for data interpretation have
been described in CT colonography, a primary 2D
and a primary 3D approach. In each of these tech-
niques, the alternative visualization has to be at
hands for problem solving and characterisation of
polyps, residual stool and fluid, and folds.
Traditionally, most researchers have relied on a
primary 2D technique for CTC reading (Dachman
et al. 1998; Fenlon and Ferrucci 1997; Johnson
Oncological Diseases: Colorectal Cancer 207
CD and Dachman 2000; Macari et al. 2000, 2004;
Royster et al. 1997). In this approach, the colon
is tracked from the rectum to cecum using axial
intermediate window source images. On most com-
mercially available workstations, supine and prone
images can be linked and scrolled simultaneously in
order to discriminate between polyps and residual
fecal matter, and to assess the distribution of fluid.
Coronal, sagittal and endoluminal reformatted
images can be obtained if an abnormality is detected.
In order to discriminate stool from polyps, the inter-
nal attenuation of a lesion can be used. Internal gas
or areas of high attenuation suggest that a lesion is
residual stool, while homogeneous attenuation sug-
gests polypoid nature (Fletcher et al. 1999; Macari
and Megibow 2001). Furthermore, morphology of
a lesion helps to determine its nature: geometric or
irregular borders are almost always found in resid-
ual stool. Morphology of a lesion is best assessed on
3D endoluminal VRT images. Mobility of a lesion is
another important criterion that facilitates differen-
tiation between residual fecal material and polyps.
Stool tends to move towards the dependent surface
of the colonic mucosa (Macari and Megibow 2001;
Taylor et al. 2003a; Yee et al. 2003), while polyps
maintain their position. One has to bear in mind
that pedunculated polyps can alter their position in
relation to colonic folds thereby simulating mobility
(see Fig. 10.3.3). Furthermore, polyps in segments of
the colon with a long mesentery may appear to be
mobile because the entire colonic segment changes
its location between supine and prone scans (Laks
et al. 2004).
One reason for using a primary 2D approach
in reading CT colonography is that in theory the
entire colonic mucosa can be visualized with one
pass. Polyps cannot be hidden behind or in between
folds, and CT density of fi lling defects can be read-
ily assessed. A second reason in favor of 2D inter-
pretation is reading time. Several studies showed
that it should not exceed 15 min if a primary 2D
read is used, as opposed to 20–30 min for primary
3D read (Gluecker et al. 2002; Macari et al. 2002;
Yasumoto et al. 2006).
The primary 3D approach relies on visualization
of the colonic mucosa in a fashion that is very simi-
lar to the familiar view at endoscopy. Most worksta-
tions create a centerline path for the endoluminal
“fly through” from rectum to cecum and vice versa,
which allows for viewing both sides of colonic folds.
Using this approach, contact time between the radi-
ologist’s eye and a lesion will be longer than with
208 A. Graser

a b

c d

Fig. 10.3.3a–d. Endoluminal (a,b) and axial (c,d) views from supine (a,c) and prone (b,d) CT colonography datasets dem-
onstrate a 15-mm pedunculated polyp (arrow) in the sigmoid colon. Positional change of the polyp due to the presence of a
stalk simulates mobility. Note homogeneous soft tissue attenuation of the lesion on axial soft tissue window images (c,d)

2D techniques, and smaller polyps may be more 10.3.3.5

easily detected (Pickhardt et al. 2003). When a 3D
approach is employed, all suspicious findings have
to be correlated with two-dimensional images in
order to assess their density and internal structure.
Even when both supine and prone patient positions
are used for interpretation, there may be blind spots
in the colon, and the 3D approach may be more time-
consuming (Beaulieu et al. 1999). One limitation of
3D visualization is that in poorly distended or col-
lapsed segments the centerline cannot be generated
preventing interrogation.
Future Trends in CT Colonography
Bowel preparation is one of the fields in CTC where
ongoing research has shown promising results. Digi-
tal subtraction of tagged fecal material will become
widely available on most workstations in the near
future, thus enabling minimal preparation proto-
cols to be routinely employed. Patients will benefit
from easy, well tolerable preparation regimens,
and acceptance of CTC will be increased. Another
important issue that is being addressed more fre-

quently is the need for reader training. Anecdotally,
a minimum of 50 colonoscopically correlated datas-
ets has been suggested as number of examinations to
be read before starting to read CTC in a clinical set-
ting. Recent work suggests that response to training
is highly variable amongst individual radiologists,
and competence certainly cannot be assumed after
this number of cases (Taylor et al. 2004). Further-
more, reporting strategies and standards have to be
developed in order to guarantee reproducible results
in CTC.
The reported interreader variability even among
expert readers and the need to evaluate large data
volumes in reasonable time have stimulated the cur-
rent interest in computer-aided diagnosis. Continu-
ing advances in computer technology make the use of
CAD algorithms more and more feasible. Normally,
these algorithms will be used as “second reader”
to the reporting radiologist. With CAD having
been used successfully in mammography and lung
nodule detection, CAD tools are becoming more and
more sensitive in polyp detection in CTC. Basically,
all CAD algorithms rely on three steps: extraction of
the colon from the data volume; detection of polyp
candidates; and reduction of false positive detection.
Analysis of shape and internal CT density of lesions
are basic principles of polyp detection and classifi-
cation. Most false positive detections occur because
fecal residues, the ileocecal valve, or prominent folds
are inadvertently detected. Preliminary results show
promising sensitivities of over 90% in the detection
of clinically significant polyps over 6 mm in size
(Bogoni et al. 2005; Yoshida and Dachman 2005).
Nevertheless, validation of these systems in larger
clinical trials is still necessary before they will be
accepted as reliable software tools.
Latest software developments include tools that
visualize “unseen areas” hidden behind colonic
folds on endoluminal evaluation to the radiologist.
These algorithms guarantee complete evaluation of
the colonic mucosa. Our preliminary clinical expe-
rience shows that visualization of over 99% of the
colonic mucosa can be achieved.
In order to evaluate the colonic mucosa with-
out having to perform endoluminal fly through in
two directions, novel visualization algorithms are
being developed including methods of unfolding
and dissecting the colon or visualizing antegrade
and retrograde views at the same time. Although
the approach seems promising, initial results did
not show a decrease in image interpretation time
(Hoppe et al. 2004). Further research is needed, and
Oncological Diseases: Colorectal Cancer 209
one of the major drawbacks is the distortion of geo-
metric shapes (Johnson KT et al. 2006).
In the future, CT colonography will probably play
a unique role in colorectal cancer screening, pro-
viding noninvasive evaluation of the entire colon
without need for sedation and risk of perforation.
Advances in CT protocols, tagging regimens, reader
strategies and computer-aided detection software
will help ensure that the technique becomes estab-
lished as a credible method of colonic investiga-
tion.
Part II
MR Colonography
10.3.4
Introduction
While in colorectal cancer screening excellent sen-
sitivities and specificities have been reported for
CT colonography, MR colonography (MRC), first
described in 1997 (Luboldt et al. 1997), to date is
still considered to perform less well. In a screening
population, MRI would be a perfect imaging tool as
it lacks ionizing radiation. Even if radiation expo-
sure is kept to a minimum in CTC, there is still a
stochastic risk of causing radiation-induced malig-
nancy. Lifetime attributable risk has been estimated
to be as high as one in 50 patients (Brenner and
Elliston 2004).
In order to perform MRC it is recommended to
use a high end multichannel MRI scanner employ-
ing parallel imaging techniques for fast scanning
and high spatial resolution. Dedicated sequences are
mandatory in order to obtain sufficient signal-to-
noise ratio, and to minimize motion artifacts. While
in CT colonography motion artifacts could literally
be eliminated with the introduction of 64-slice scan-
ners, image quality can be seriously hampered by
bowel wall motion at MR colonography. Therefore,
intravenous application of spasmolytic drugs like
Buscopan is advisable.
Generally, MRC can be performed using a dark-
lumen technique that relies on an aqeuous enema
with intravenous administration of a paramagnetic
contrast agent, or in bright-lumen technique that
employs T2-weighted sequences without intrave-
nous contrast agent.
210 A. Graser
As in CTC, bowel preparation is an important
factor that greatly influences MRC image quality and
detection accuracy for colonic polyps. To date, MR
colonography is predominantly being performed
at specialized centers, and most patients have been
examined as part of clinical trials. At the same time,
dissemination of MRC into clinical practice is under
way, resulting in increasing demand for radiologist
and technician training. Further research is needed
to prove that MRC is a reliable tool that can be inte-
grated into screening programmes for CRC.
10.3.5
Patient Preparation and Examination
Technique
Most studies published to date rely on a full bowel
preparation for MR colonography since residual
stool impedes proper evaluation of the colonic
lumen. This can be achieved by oral ingestion of
3–4 L of a polyethylene glycol solution, or a prepara-
tion regimen based on magnesium citrate and other
laxatives. For bright lumen technique, gadolinium
chelate contrast agents can be added to the rectal
enema for T1 weighted imaging. Recently, so-called
prepless protocols without bowel cleansing have
been described in MR colonography in a large single
center study analyzing the performance of MRC in
asymptomatic screening patients (Kuehle et al.
2007). No bowel cleansing was applied, and a tag-
ging agent based on gadolinium, barium sulfate, and
locust bean gum was administered with each meal
within two days prior to MR colonography. In 96%
of all colonic segments, fecal tagging was sufficient
to assess the presence of significant polyps.
For adequate image quality, MR colonography
should be performed on a system with a high-per-
formance gradient system and a minimum of 1.5 T
static magnetic field strength allowing for data
acquisition confined to one single breath hold. Prior
to MRI scanning, possible contraindications like
presence of cardiac pacemakers, metallic implants
in the central nervous system, or claustrophobia
have to be excluded.
MRC should be performed with the patient in
the prone position in order to minimize breath-
ing artefacts. A combination of a multi-channel
surface coils, ideally 32-channel coils covering the
entire abdomen, and the spine array coil should
be used for optimum spatial resolution and use
of parallel imaging technique. After intravenous
administration of 40 mg of scopolamine, the colon
can be fi lled with warm tap water using a rectal
enema tip. At our institution, the enema bag is
positioned 1–1.5 m above the patient resulting in
sufficient hydrostatic pressure for distention of the
entire colon. Proper distention is required because
collapsed segments may mimic bowel wall thicken-
ing. During application of the rectal enema, single
shot online monitoring sequences like HASTE
sequences can be acquired. On average, a volume of
2000–3000 mL will be needed to distend the entire
colon. If bowel distention is sufficient, the colon
can be imaged using different sequence techniques
that will result in high contrast between the bowel
wall and the colonic lumen. Contrast mechanisms
will then depend on the MR sequences employed
and the intravenous and/or rectal administration
of contrast agents. Different types of sequences
should be acquired. First, a fast T2-weighted single
shot sequence like HASTE with or without fat sup-
pression or fast imaging with steady state free pre-
cession (TrueFISP) should be acquired in the axial
and coronal plane. This type of sequence is com-
parably insensitive to motion, and shows the water
in the colonic lumen at high signal intensity, while
the colonic wall and fi lling defects will be displayed
at low signal intensity (Figs. 10.3.4 and 10.3.5). The
colonic mucosa can be optimally visualized on a high
resolution T1-weighted gradient echo sequence (3D
VIBE, volume interpolated breath hold examina-
tion). This sequence should be acquired before and
75 s after intravenous injection of contrast agent.
Depending on the field strength of the scanner and
the number of coil elements, up to 128 slices can be
acquired in one single breath hold. Typically, these
slices will have a thickness of 1.0–1.6 mm, depend-
ing on patient diameter and the properties of the
scanner. The normal colonic mucosa will strongly
enhance, and so will adenomatous polyps. Most
larger studies published to date agree that MRC is
unable to detect hyperplastic polyps as these do
not take up contrast agent (Hartmann et al. 2006).
Furthermore, a T1-weighted axial FLASH sequence
should be acquired for assessment of extracolonic
fi ndings with high image quality. After acquisition
of these sequences, the enema bag can be placed on
the floor to allow for drainage of the water from the
patient’s bowel.
Image analysis should be performed on a dedi-
cated workstation integrating 2D and 3D display
 Oncological Diseases: Colorectal Cancer 211

a b
Fig. 10.3.4a,b. Axial (a) and coronal (b) bright lumen image of the sigmoid colon showing a 1.5-cm pedunculated polyp in
a 50-year-old male patient. TrueFISP sequence acquired on a 3 T magnet (Magnetom Trio TIM, Siemens Medical Solutions,
Erlangen, Germany) using a 32-element abdominal coil

a b
Fig. 10.3.5a,b. Axial (a) and sagittal (b) dark lumen image of the same pedunculated polyp as in Fig. 10.3.4. A 3D VIBE
sequence acquired 75 s after intravenous administration of gadolinium chelate (Multihance, Bracco) shows strong enhance-
ment of the normal colonic mucosa as well as the adenoma

capabilities. Various software systems allow for
three-dimensional endoluminal rendering of the
colon (3D “fly through”, as described in CT colo-
nography). This technique will help to detect small
(< 6 mm) polyps at high sensitivity, as well as visual-
ize larger lesions. Primary 2D reading is even more
popular in MRC than in CTC, because adenomas
strongly enhance. Enhancement is only detectable
on reformatted 2D images. High resolution 3D VIBE
datasets should be used to localize clinically sig-
nificant polyps, as they enable visualization of the
colon in all three orthogonal planes. Comparison
between pre- and post contrast images is manda-
tory for discrimination of stool from residual fecal
212 A. Graser
material. Residual stool does not enhance, while
true colorectal lesions, predominantly the ones that
have precancerous potential, always show contrast
agent uptake.
10.3.6
Diagnostic Performance of
MR Colonography
In the last 2 years, there has been strong evidence
that MR colonography performs fairly well in the
detection of clinically significant colorectal masses,
while small polyps and polyps of hyperplastic nature
will remain undetected. The first trial that showed
good results reported a sensitivity of 100% for ade-
nomatous polyps and cancers larger than 10 mm,
and an 84.2 sensitivity for polyps 6–9 mm in size in
a high risk population of 92 patients (Hartmann et
al. 2006). Recently, one study performed by Kuehle
et al. including 315 average risk screening individu-
als based on a minimal prep protocol reported a
83.0% sensitivity for MRC as compared to optical
colonoscopy (Kuehle et al. 2007). A similar tagging
and minimal prep regimen was used in another trial
on 200 high risk individuals (Florie et al. 2007). In
this study, results were also disappointing with MRC
per-patient sensitivities for polyps > 10 mm ranging
from 58% to 67% for two independent observers
(combined: 75%), and from 50% to 55% for medium
size polyps (combined: 77%). The reduced prep used
in the latter trials resulted in an increased patient
acceptance of MRC over OC. As MRC does not cause
complications or require sedation, all over in-room
time for MRC is shorter than for optical colonos-
copy. It can also be used in patients with incomplete
colonoscopy for visualization of the entire colon. It
has been shown that MRC shows high accuracy in
the detection of extracolonic pathologies, including
liver masses, enlarged lymph nodes, renal masses,
vascular pathologies, and concomitant inflamma-
tory conditions of the bowel (Ajaj et al. 2007).
In conclusion, MRC can be considered as a prom-
ising alternative to optical colonoscopy in screening
for colorectal cancer. Its ability to detect alternative,
extracolonic pathologies is superior to that of CTC,
mainly based on the use of intravenous paramagnetic
contrast agent. To date, patient preparation schemes
relying on fecal tagging rather than complete bowel
cleansing still suffer from somewhat reduced accu-
racy, requiring further research for validation. Inte-
gration of MRC in clinical routine will also depend
on reimbursement strategies and patient acceptance.
As a radiation-free screening tool, it would be per-
fectly suitable for triageing between persons without
significant polyps and patients needing to undergo
optical colonoscopy for polyp resection.
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 Congenital Pediatric Diseases: Pre- and Postnatal Kidney Screening 215

Congenital Pediatric Diseases 11

11.1 Pre- and Postnatal Kidney Screening
Gabriela Stolz

CONTENTS Table 11.1.1. Prevalence of major malformations, 1996–

2003

11.1.1 Practical Aspects and Results of Postnatal Organ category Mainz 1996–2003
Kidney Screening 215
Musculoskeletal system 181
11.1.2 Value of Prenatal Screening for Internal urogenital system 169
the Detection of Malformations with
High Morbidity and Mortality 217 Cardiovascular system 141
Digestive system 71
11.1.3 Outcome Improvement by Early Postnatal
Diagnosis of Renal Malformations 2184 Central nervous system 60
Chromosome aberrations 65
References 2195
External urogenital system 39
Facial clefts 39
Eye 4
11.1.1
Ear 7
Practical Aspects and Results of Postnatal
Kidney Screening Population based cohort 1996–2003: 22,070 infants and
fetuses; 1460 (6.2%) major malformations
Major congenital malformations are diagnosed
in 4%–6% of all infants and fetuses (Lynberg
and Edmonds 1992). About one third of them are To estimate the value of pre- and postnatal ultra-
the leading cause for infant mortality or morbid- sound screening of the internal urogenital tract we
ity (Grandjean et al. 1999). Malformations of the analyzed the population-based birth cohort of the
internal urogenital system are diagnosed in about Mainz Model. Prevalence rates and percentage of
1% of all infants and account for approximately 20% prenatally or postnatally detected malformations
of all congenital malformations, thus being one of are given. Sensitivity rates are calculated and mal-
the three most frequent birth defects (Table 11.1.1). formations with high morbidity and/or mortality
Therefore a pre- and/or postnatally performed ultra- are defined. In addition, the improvement of the
sound screening for malformations of the internal outcome by early postnatal diagnosis of renal mal-
urogenital system should be part of the routine to formations is evaluated.
reduce perinatal mortality and morbidity. The reli- The major aim of a screening program is to detect
ability and value of ultrasonographic screening for treatable diseases in a population as early as possi-
congenital malformations is the subject of ongoing ble. For valuable screening programs the existence
discussions. of preventive or curative interventions is required;
poor prognosis and limited treatment options may
mean lack of adequate possibilities to improve the
G. Stolz, MD
Birth Registry Mainz Modell, Universitätskinderklinik der
infants life (Queisser et al. 2001). It is demonstrated
Johannes-Gutenberg-University of Mainz, Langenbeck- that these criteria are fulfilled by the routinely per-
strasse 1, 55101 Mainz, Germany formed ultrasound scan of the kidneys.
216 G. Stolz

In the population-based birth cohort of the Mainz Table 11.1.2. Number of urinary malformations and prena-
Model (January 1996 – December 2003) 22,070 new- tal detection rate, 1996–2003
borns 0.55% (121) stillbirths, 1.1% (235) abortions
Diagnosis 1996– Prenatally %
and 0.6% (128) induced abortions were registered. 2003 detected
The surveillance covers the region of Rheinhessen
and monitors 89% of all infants born and living in Supernumerary kidney 91 15 16
this area. Nearly all newborns (99%) underwent a Megaureter 65 28 43
postnatal ultrasound screening of the kidney. A mal- a 55 26 47
Hydronephrosis
formation of the urogenital tract was diagnosed in
1.7% (n = 373) of all neonates, findings to be reinves- Reflux 47 12 25
tigated in more detail in 2.1% (Fig. 11.1.1). The most Pyelo ureteral junction 44 15 34
common diagnoses (Table 11.1.2) were supernumer- obstruction
ary kidney (21%) (Fig. 11.1.2), megaureter (15%) Multicystic kidney disease 23 10 43
(Fig. 11.1.3) and hydronephrosis (13%). Infants with
Unilateral renal agenesis 22 6 27
multiple malformations have birth defects in differ-
ent organ systems, infants with complex malforma- Horseshoe kidney 25 7 28
tions have two or more malformations within the Potter-sequence 11 7 64
same organ system (e.g. supernumerary kidneys, Polycystic kidney disease 10 4 10
vesico-renal reflux, megaureter). A single malforma-
Solitary kidney cyst 8 1 12
tion of the urogenital tract was diagnosed in 41.2%
of the infants with malformations of the urinary Vesico ureteral junction 3 0 0
tract, multiple malformations in 11% and complex obstruction
malformations in 49% of these newborn. Urethral valve 6 4 66
Ureterocele 7 1 14
Malformation of urethra 5 2 40
Malformation of ureter 8 5 45
Exstrophy of bladder 3 2 66
Aplasie of bladder 9 4 44
Total 442 149 34

Population based cohort 1996–2003: 22,070 infants and

fetuses; 1460 (6.2%) major malformations, infants with renal
malformations 373 (1.7%)
a Five cases with single hydronephrosis and 50 diagnoses in

combination with other renal malformations

Fig. 11.1.1. Findings in need of further evaluation Fig. 11.1.2. Supernumerary kidney and vesico-renal reflux
(dilated renal pelvis: 9 mm) (postnatal scan)
 Congenital Pediatric Diseases: Pre- and Postnatal Kidney Screening
Fig. 11.1.3. Megaureter (postnatal scan)
11.1.2
Value of Prenatal Screening for
the Detection of Malformations with
High Morbidity and Mortality
The impact of the fetal renal pelvic diameter on
the postnatal outcome is discussed controversially.
Its prognostic value depends on the gestational
week of detection and on the grade of dilatation.
Some authors suggest a pathological cut off- level of
≥ 4 mm until the 33rd week of gestation and ≥ 7 mm
after the 33rd week of gestation (John et al. 2004).
Other investigators are not so strict and rely on a
diameter of 10 mm after the 28th week of gesta-
tion. As a consequence some children with vesico-
urethral reflux are not detected in time (Cohen-
Overbeek et al. 2005). Analyses of the Mainz birth
registry reveal that 41% of all malformations of the
internal urinary tract are diagnosed before birth. In
about 5% the findings are false positive. The sensi-
tivity is 36% respectively (Stolz et al. 2002). The
prenatal detection rate shown in the Mainz birth
registry lies within the range of 20%–89% described
in the literature (Levi et al. 1991; Rosendahl 1990;
Beseghi et al. 1996; Grandjean et al. 1999; Wiesel
et al. 2005). For example, only half of the children
with multicystic kidneys are diagnosed prenatally,
which is a well defined and detectable diagnosis in
prenatal ultrasound.
The data on malformations with high morbidity
and mortality are the more precise indicators for the
clinical value of these screening examinations. Mal-
formations with high morbidity and mortality lead
217
to death or need immediate therapy and/or surgery
shortly after birth (e.g. Potter sequence, exstrophy
of bladder etc.). The most common severe malfor-
mations of the urinary tract diagnosed prenatally
are exstrophy of the bladder in 66%, urethral valves
in 66% and Potter sequence in 64% of the cases.
These diagnoses mainly lead to an induced abor-
tion or stillbirth. In Potter sequence this is the case
in 73%, absent bladder in 44%, exstrophy of blad-
der in 33% and polycystic kidney disease in 30%
(Fig. 11.1.4).
Only 19% of all urinary tract malformations are
detected before the 20th week of gestation, 29%
between the 20th and 30th week, and 52% after the
30th week. These data are corroborated in the litera-
ture (Rosendahl 1990). Most life-threatening diag-
noses like Potter sequence or exstrophy of the blad-
der are diagnosed early in pregnancy. Cystic kidney
diseases are detected mainly between the 21st–29th
week of gestation. All other malformations which
lead to dilatation of the renal pelvis or the ureter (e.g.
megaureter (Fig. 11.1.5), hydronephrosis, urethral
valves, supernumerary kidney (Fig. 11.1.6)) are diag-
nosed after the 30th week of gestation (Economou
et al. 1994). Of the infants with renal malformations,
5% (20) had chromosomal aberrations, 7% (25) non-
chromosomal syndromes, 43% (159) complex mal-
formations, and in 9% (35) multiple malformations.
The prenatal detection rate was 63% in infants with
multiple malformations and only 15% in infants
with just a single renal malformation. The probabil-
ity to detect infants with more than one malforma-
tion of the urinary tract is four times higher than to
detect an infant with only one single malformation
of the urogenital tract.
Fig. 11.1.4. Supernumerary kidney (prenatal scan, 27th
week of gestation)
218 G. Stolz
Fig. 11.1.5. Megaureter (prenatal scan, 33rd week of gesta-
tion)
Fig. 11.1.6. Polycystic kidney (prenatal scan)
The advantage of the prenatal ultrasound scan
lies in detecting malformations with high mortality
(e.g. Potter sequence) and morbidity (e.g. polycystic
kidney, exstrophy of the bladder). These malforma-
tions are mainly detected early in pregnancy. Infants
with additional malformations or syndromes are
diagnosed prenatally with a higher frequency than
single renal malformations. For non lethal renal
malformations – especially the children with just
one renal malformation – the postnatal ultrasound
screening is the method to diagnose and plan the
further follow-up.
11.1.3
Outcome Improvement by Early Postnatal
Diagnosis of Renal Malformations
In the birth cohort of the region Rheinhessen (1996–
2001) 170 newborn had one or more renal malforma-
tion. Prenatal diagnoses were given in 36% (69) of
the infants and 64% (101) newborns were diagnosed
postnatally by ultrasound.
In our nephrological/urological department 120
out of these 170 infants were followed over years
and underwent further evaluation and/or treat-
ment. Finally only 13% (22) were in need of surgery.
In 1994 Riccipetitoni et al. (1992) demonstrated a
prevalence of renal malformations of 1.04% (36 out
of 3454 neonates) which is approximately the same
rate as in the region of Rheinhessen. Only 16% of the
36 infants were diagnosed prenatally and 39% of the
children needed surgery. Out of the cohort 159 infants
(5%) showed findings which had to be rechecked later
on. In a population based study Beseghi et al. (1996)
found similar results: a prevalence rate of 1.1%, pre-
natal detection rate of 25%, and a postnatal detection
rate of 75%. Thirteen (36%) of the postnatally detected
infants were operated, and findings to be reevaluated
were seen in 5% of all cases.
In the study of Bhide et al. (2005), 104 children
with urological problems underwent surgery of
which 60% showed prenatal findings; 26% were
diagnosed because of urinary tract infections later
on. Bhide showed that prenatally diagnosed children
underwent surgery significantly more often than
children with postnatal findings. However, 40% of
the children were not detected prenatally. Especially
the children with vesico-renal reflux were only diag-
nosed in about 27% (Chen et al. 2003).
In conclusion, it appears to us that the routinely
performed prenatal ultrasound scan to detect renal
malformations is not an optimal screening method
for all renal malformations. The prenatally per-
formed scan is the gold standard in fi nding malfor-
mations with high morbidity and mortality. For all
other renal malformations the prenatal scan has to
go hand in hand with a postnatally performed renal
scan to prevent the children from urinary tract
infections and to escort the infants and their fami-
lies through the follow up period when decisions
have to be reached whether surgery is necessary or a
conservative therapy might be sufficient.
 Congenital Pediatric Diseases: Pre- and Postnatal Kidney Screening
Acknowlegments. We would like to express our grat-
itude to Kathrin Trautmann, Department of Gyne-
cology of the Johannes-Gutenberg-University Mainz
for the prenatal sonographic printouts and the Envi-
ronmental Department of the DKFZ Heidelberg for
the statistical support by Klaus Schaefer.
Appendix
Diagnosis Defi nition
Hydronephrosis Dilatation of renal pelvis and
calices with degeneration of
the renal parenchyma
Stenosis Narrow passage of the ure-
teropelvic or ureterocystic
junction
Obstruction Disturbance of the urinary
transport, if persistent harm-
ing the renal function
Megaureter Dilated ureter (minimum
6 mm)
Primary megaureter The cause of obstruction lays
within the terminal prevesi-
cal part of the ureter and with
dilation of the ureter above
this part
Secondary megaureter Dilation of the ureter in asso-
ciation with an anatomic or
functional obstruction
Megaureter with Vesico-ureteral reflux diag-
vesicoureteral reflux nosed with MCU, persistent
dilation of the ureter demon-
strated in ultrasound scan or
IV urogram
Megaureter without No vesico-ureteral reflux dem-
vesicoureteral reflux onstrated in MCU
Obstructive megaureter Demonstrated obstruction
Magaureter without Obstruction could not be
obstruction demonstrated
Leitlinien der AG für Pädiatrische Nephrologie, der
Deutschen Gesellschaft für Kinderchirurgie und
der Deutschen Gesellschaft für Urologie (2002)
219
References
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chini E, Mori M, Ghinelli C (1996) Ultrasound screening
of urinary malformations in normal newborns. Pediatr
Urol 30:108–111
Bhide A, Sairam W, Farrugia M-K, Boddy S-A, Thilganga-
than B (2005) The sitivity of antenatal ultrasound for
predicting renal tract surgery in early childhood. Ultra-
sound Obstet Gynecol 25:489–492
Chen JJ, Pugach J, West D, Naseer S, Steinhardt GF (2003)
Infant vesicoureteral diagnosis and those presenting with
a urinary tract infection. Urology 61:442–446
Cohen-Overbeck TE, Wijngaard-Boom P, Ursem NTC, Hop
WC, Wladimiroff J W, Wolffenbuttel KP (2005) Mild renal
pyelectasis in the second trimester: determination of cut-
off levels for postnatal referral. Ultrasound Obstet Gyne-
col 25:378–383
Economou G, Eggington JA, Brookfi led DS (1994) The impor-
tance of late pregnancy scans for renal tract abnormali-
ties. Prenat Diagn 14:177–180
Grandjean H, Larroque D, Levi S (1999) The performance
of routine ultrasonographic screening of pregnancies in
the Eurofetus study. The Eurofetus Group. Am J Obstet
Gynecol 21:446–454
John U, Kähler C, Schulz S, Mentzel HJ, Vogt S, Misselwitz J
(2004) The impact of fetal renal pelvic diameter on post-
natal outcome. Prenat Diagn 24:591–595
Leitlinien der AG für Pädiatrische Nephrologie, der Deut-
schen Gesellschaft für Kinderchirurgie und der Deut-
schen Gesellschaft für Urologie (2003) Diagnostik bei
konnatalen Dilatationen der Harnwege AWMF online
Levi S, Hyjazi Y, Schaaps J-P, Defoort P, Coulon R, Buekens
P (1991) Sensitivity and specificity of routine antenatal
screening for congenital anomalies by ultrasound: The
Belgian Multicentric Study. Ultrasound Obstet Gynecol
1:102–110
Lynberg MC, Edmonds LD (1992) Surveillance of birth
defects. In: Harpin W, Baker EL (eds) Public health sur-
veillance, Chap 12. Van Nostrand Reinhold, New York,
pp 157–177
Queisser-Luft A, Wiesel A, Stolz G, Borck G, Schlaefer K,
Zabel B, Spranger J (2001) Klinisches Neugeborenen-
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Riccipetitoni G, Chierici R, Tamisari L, De Castro R, Man-
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Postnatal ultrasound screening of urinary malforma-
tions. J Urol 148:604–605
Rosendahl H (1990) Ultrasound screening for fetal urinary
tract malformations: a prospective study in general pop-
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A (2002) Prä- und postnatales Nierenscreening im Ver-
gleich: eine Analyse von 34,450 Neugeborenen des Gebur-
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(2005) Prenatal detection of congenital renal malfor-
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 Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip
Congenital Pediatric Diseases
11.2 Sonographic Screening of the Infant Hip
Dieter Weitzel
CONTENTS
11.2.1 Summary 221
11.2.2 The Clinical Picture of Hip Dysplasia and
Hip Dislocation 221
11.2.3 Incidence of the Disorder 222
11.2.4 Diagnostic Workup Based on
Risk Selection 223
11.2.5 Sonographic Examination of the Hip by
Graf’s Technique 223
11.2.6 Neonatal Hip Screening 225
11.2.7 Follow-Up after Screening Examinations in
the Neonatal Period 227
11.2.8 Conclusions 230
References 230
11.2.1
Summary
Sonographic hip screening has led to a significant
decrease in inpatient treatments of congenital
(= developmental) dislocation /dysplasia of the hip
(DDH). In recent years, prognosis for this disor-
der has notably improved owing to early diagnosis
and accordingly earlier initiation of treatment – by
simple therapeutic measures quite often. By inter-
national comparison, this undisputed success was
D. Weitzel, MD
Professor, Department of Pediatrics and Adolescent Medicine,
German Diagnostic Clinic, Aukamm-Allee 33, 65191 Wiesbaden,
Germany
221
11
paid for by a very high rate of treatment (6.7%). The
expectation to reduce follow-up costs by establish-
ing the screening period between the 4th and 6th
week of life has not been met.
On January 01, 1996, sonographic hip screening
was introduced in the Federal Republic of Germany at
the time of the scheduled U3 examination (i.e. within
the framework of routine developmental checks for
infants at weeks 4 to 6 of life). Greater experience as
to sonographic screening had to date only been avail-
able with neonates. Setting the time for screening
between weeks 4 and 6 of life was based on the expec-
tation of fewer follow-up checks on account of more
advanced development of the hips. The objective was
to avoid inpatient treatments, surgical interventions
(extension procedures, surgical reducing, acetabular
grafting, displacement osteotomies) by conservative
growth-manipulating therapies of hip dislocation
and dysplasia as early as possible.
This study was designed to assess the practical
value of this hip screening and to see inasmuch the
expectations placed in it had been met.
11.2.2
The Clinical Picture of Hip Dysplasia and
Hip Dislocation
The terms congenital dysplasia and dislocation of
the hip encompass a spectrum of abnormal ana-
tomical changes of the hip unfolding in various peri-
ods of growth. In both the American and European
literature, these terms have therefore been replaced
by “developmental dysplasia of the hip” (DDH).
We distinguish the following degrees of anatomi-
cal severity:
• Displaced hip: the head of femur is located out-
side the acetabulum.
222 D. Weitzel
• Displaceable hip: the head of femur can be shifted
from the acetabulum by flexion with synchro-
nous adduction, and can also be returned to the
acetabulum by flexion and adduction.
• Semiluxated hip: the head of femur is only partly
in contact with the acetabulum, i.e. it is decen-
tered.
• Semiluxable hip: there is normal contact between
head of femur and acetabulum in the resting posi-
tion, the head of femur, however, can be decen-
tered by external maneuvers.
• Dysplasia: abnormal anatomy and/or defective
growth of the acetabulum.
Prognosis for dislocation /dysplasia of the hip
depends on:
• The time of onset of defective development:
• Embryonic: teratologic displacement of the
hip
• Fetal: breech position, genetic disposition
• Infantile: imbalance between osteochondro-
genesis and motor development
• The time when the diagnosis is made, since the
growth rate is exponentially declining during the
first year of life. This sets a time limit to growth-
guiding treatment.
Teratologic hip displacement is the most severe
form of the disorder, and it is subdivided into a form
generating approximately during the 12th week of
gestation, and into a form materializing approxi-
mately in the 18th week of gestation. In the 12th
week, the fetal leg will also rotate in medial direction.
Defective development during this period involves
any part of the hip joint. The muscular system of the
hip starts to develop in week 18. Malformations at
that time will likewise result in complete displace-
ment and are frequently associated with neuromus-
cular abnormalities, e.g. myelomeningocele, arthro-
gryposis.
During the last 4 weeks of pregnancy (fetal phase),
acetabular development is impaired by a particular
form of breech presentation in which the legs are
folded upward.
The increased incidence in girls and the familial
disposition are suggestive of genetic factors involved
in developmental dislocation/dysplasia of the hip
(DDH).
Postnatal hip displacement occurs when osteo-
chondrogenesis of the acetabulum and neuromus-
cular development do not coincide, i.e. when, in the
course of growth, ossification and gradual develop-
ment of the acetabulum are asynchronous as strain
is increasing strain due to progressing motor devel-
opment.
We may thus conclude that normal hip devel-
opment does not only depend on regular skeletal
development per se, but also on the concordance of
skeletal and neuromuscular development. Faulty
development of the skeletal system and disturbed
neuromuscular development are likely to result in
malformation of the hip. Sonography as an imaging
procedure can merely demonstrate the anatomy of
the hip joint, meaning the shape of the acetabulum
and its relation to the femoral head, besides showing
the proportion of the osseous acetabular segment to
the chondral segment. It cannot visualize the forces
acting on the hip joint that may have a detrimental
impact on hip maturation.
11.2.3
Incidence of the Disorder
Data on the incidence of this disorder vary greatly.
This might for once be due to the different defini-
tions used – as we pointed out earlier – since the
terms displacement/dislocation and/or dysplasia
of the hip (DDH) include a spectrum of disorders
with differing therapeutic and prognostic conse-
quences.
On the other hand, the origin of the studies is play-
ing a part as well, since the genetic disposition for the
development of disease is not universal but may be
varying from country to country, which is making
for the differences in the epidemiologic incidence.
The methods and the quality of diagnostic workup
are another reason for the greatly diverging data on
the incidence. In Austria for instance, the rate of
treatment used to be 11.92% in the presonographic
era, and could be reduced to 6.57% within 7 years
after the introduction of sonographic hip screen-
ing Müller (1995). This reduction in treatments
cannot be explained by fewer cases of disease; it
has to be attributed to improved diagnostics alone.
The rate nevertheless continues to be significantly
higher than the average figures of 0.15–2% quoted
by Bialik et al. (1999) in their survey.
All studies maintain that the teratologic form of
hip dislocation is a rare disorder.
Whether at all, and if so to what extent develop-
mental displacement/dysplasia of the hip (DDH)
 Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip
can be related to arthrosis of the hip joint in adult
years, has been controversially discussed. A caus-
ative relation is hard to establish owing to the large
span of years between hip dysplasia in infancy and
arthrosis of the hip joint in adulthood. A connec-
tion with early arthrosis was corroborated only for
hip displacements operated after the third month of
life. Longterm studies are lacking with regard to the
development of dysplasias left untreated or conser-
vatively managed in infancy.
11.2.4
Diagnostic Workup Based on Risk Selection
The place-value of risk factors in the diagnostic
workup of DDH had been high, especially in the
presonographic era. Breech position and familial dis-
position used to be an indication for pelvic survey at
the age of 3–6 months. Approximately 3%–5% of the
babies are delivered from a breech position. About
20%–30% of those will develop dislocation /dyspla-
sia of the hip (DDH). The highest risk is encountered
with the legs placed to the trunk, i.e. bent in the hips
and stretched in the knees. The lowest risk is found
in children who have been in the squatting position,
as commonly seen in twin pregnancies.
Data on heredofamilial features are difficult to
assess, for the grade of relatedness and the inci-
dence of hip disorders are variables to be consid-
ered. 15%–20% of the newborns do have a relative
who had been affl icted with hip disease in infancy.
Heredity of this disorder is still not fully elucidated;
there seem to be several forms of hereditary trans-
mission. In our group of 247 children who had a
fi rst-grade relative with DDH, 67 (27%) required
treatment in infancy.
Although DDH has meanwhile been generally
accepted to be a developmental disorder, there
are but a few studies relating clinical findings to
age (Mau and Michaelis 1983; Pfeil et al. 1988;
Schuler and Rossak 1984). Inhibited abduction,
for instance, is shaping up as a risk factor for hip
defects as motor development advances. Risk selec-
tion by clinical examinations is possible at increas-
ing infant age. This is supported by the results of
preventive clinical checkups. According to Patel’s
survey, the rate of surgical treatments went down
by more than 50% to a level of 0.2–0.7/1000 (Patel
2001) owing to preventive clinical checks alone.
223
Of all children with congenital displacement/dys-
plasia of the hip (DDH), 60% do not present with risk
factors (Patel 2001). Within the context of our pilot
study and based on 7198 neonate screening exami-
nations, we were able to prove that risk-selective
screening will at most catch 40%–50% of the infants
in need of therapy. At least 20% of the newborns
ought to be tested because of their risk factors.
The problem is that prospects for a favorable out-
come of treatment are greater when the infant is still
very young, whereas clinical diagnostics are more
reliable the older the infant is getting. The neces-
sity of earliest possible sonographic screening has
thus been postulated. Such screening has a double
function: it detects disorders manifest already and
it identifies the risks of faulty development. Since it
cannot provide for diagnosis by exclusion, it has to
be supplemented by follow-up on the clinical course,
the expressiveness of which will be more weighty the
older the infants are.
11.2.5
Sonographic Examination of the Hip by
Graf’s Technique
By the description of imaging elements, Graf suc-
ceeded in defining a reproducible cut surface in the
craniodaudal as well as in the lateromedial plane
(Graf 1980, 1985; Graf et al. 1987). This cut surface
goes precisely through the center of the hemispher-
ical joint. Recognition of acetabular development
was facilitated by the accurate presentation of the
fibrochondral acetabular labrum, the hyalinochon-
drally preformed roof of acetabulum as well as of the
bony part of the acetabulum reaching to the y-joint
(Fig. 11.2.1a). Steepness of the osseous acetabulum
will increase with normal hip development, while
the width of the chondrally preformed part of the
roof of acetabulum decreases as ossification goes
on; the shape of acetabulum is turning more concave
(Fig. 11.2.1b).
Standardization of the cut surface moreover per-
mits quantitative processing of the developmental
process by angle measurements. A base line can be
defined due to the horizontal presentation of the
iliac bone. The acetabular line runs from the lower
margin of the acetabular part of the iliac bone to the
bony rim. The so-called acetabular angle D is thus
made up by the base line and the acetabular line. The
224 D. Weitzel

a b

Fig. 11.2.1a,b. Presentation of normal hip anatomy of a neonate and of a 3 month-old infant (Graf´s standard plane)

base line and a labrum line extending from the tip of

labrum to the bony rim form the so-called angle E.
When the bony rim is rounded, acetabular line and
labrum line have to be defined differently. This is
no problem with regard to the acetabular line, as it
may thus be viewed as the tangent to the osseous
roof of acetabulum. Regarding the labrum line, this
is more difficult as the pedal is missing and suitable
auxiliary constructions cannot be precisely defined
(transition from convexity to concavity). The great
range of dispersion of angle E reflects this problem.
Graf had initially defi ned four types: the mature
hip (Fig. 11.2.1b), the immature hip (Fig. 11.2.2),
the decentered hip (Fig. 11.2.3) and the dislocated
hip (Fig. 11.2.4). The risk of faulty development Fig. 11.2.2. „Immature“ hip with prominently enlarged car-
increases with decreasing ascent of the acetabulum, tilaginous roof of acetabulum, rounded bony rim and rather
i.e. angle D becoming flatter. Flattening of the bony flat osseous acetabulum: hip type IIg according to Graf
acetabulum marks defective hip development, the
chondrally preformed part of the roof of acetabu-
lum is shifted in cranial direction along with the 4. Differentiation according to angle E (hips at risk
acetabular labrum, and the head of femur is eventu- with incipient decentration), and finally also
ally located in the soft tissue. Increasing decentra- according to the dynamic examination (decen-
tion is demonstrated by shifting of the acetabular terable and/or nondecenterable hip). Typing
labrum. becomes extremely complex and rigid this way.
These four simple hip types originally described
by Graf, have undergone numerous modifying dif- Despite the problematic aspects of typing, the
ferentiations: particular value of hip sonography consists in the
1. Age differentiation, i.e. a differentiating age- visualization of the osteochondrogenesis. It enables
dependent rating of equal morphologic findings us for the first time to recognize congenital disloca-
(delayed physiologic and pathologic ossification) tion /dysplasia of the hip (DDH) not only in its pres-
2. Differentiation depending on the osseous acetab- ymptomatic but also in its premorbid stage.
ular angle D, which reflects the developmental Presymptomatic means that there is decentration
risk (hip at risk, defectively maturing hip) of the hip in absence of clinical evidence. A premor-
3. Differentiation based on the reflex behavior of bid condition is given with the sonogram showing a
the chondrally preformed roof of acetabulum discrepancy between the osseous and cartilaginous
(hip types IIIa and IIIb) part of the roof of acetabulum in the presence of
 Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip
Fig. 11.2.3. Decentered hip: 1 shifting of the acetabular
labrum, 2 enlargement and shifting of the chondral roof of
acetabulum, 3 flattening of acetabulum
Fig. 11.2.4. Displaced hip: labrum not demonstrated, hya-
linochondral roof of acetabulum is rolled, head of femur
outside of the acetabulun
otherwise normal acetabular morphology – which
bears the risk of faulty development. Whether this
developmental risk will indeed result in pathology
depends on the ossification process of the acetabu-
lum – synchronous or asynchronous to muscular
strain.
Normal sonographic findings must thus be
defi ned in an age-specific fashion. Graf’s classi-
fication of mature and immature hips ignores the
basic notion that any neonate hip is immature per
se. One could at most speak of physiologic imma-
turity. It remains unclear when to term a hip as
mature. When it is fit for upright gait or preferably
after completion of growth? The hips Graf termed
mature are merely at a lower risk of defective devel-
opment.
225
11.2.6
Neonatal Hip Screening
It seemed to be quite natural to use sonography of
the hips as a screening method very early in the post-
natal period. Many studies have meanwhile been
published on screenings in the newborn period, sus-
taining that early sonographic hip screening reveals
a high percentage of inherent disorders to which
neither risk factors nor clinical examinations had
given any hint.
Data as to the distribution of types, however, are
extremely incongruent in the literature, especially
as concerns the percentage of type I and follow-up-
requiring type IIa hips. These discrepancies raised
substantial doubt about the pertinence of sonogra-
phy as a screening method (Table 11.2.1).
These differences in large groups of newborns
can only be method-related, i.e. to either different
approaches in typing procedures or to technical
measuring problems. Some authors determined hip
types by morphologic criteria alone. Others resorted
to angle-measurement on demand as well, or they
principally measured the angle.
In our pilot study we dealt with the following
questions (von Kries et al. 2003):
1. Does the sonographic picture of the neonatal
hip definitely correspond with the morphologic
constellation described by Graf to enable typing
beyond controversy? In our group, 85% of the
cases fell in with Graf’s description; in 15%, this
morphologic classification had to be called into
question.
2. Does typing based on morphologic criteria cor-
respond with typing according to angle sizes?
It fits nicely with types IIg and hips worse than
that. However, there are serious discrepancies
in types I (mature hip) and type IIa (physiologic
delay in ossification).
The problem obviously consists in the differen-
tiation of these two types of hips. It is quite doubtful
whether it really covers two categorically different
conditions, or whether the type IIa hip is age-spe-
cifically normal rather. This aspect is the pivotal
point of hip screening for it determines the need for
follow-up.
Drawing the line would become most transparent
when the angle D is incorporated – either in the form
of mean value and standard deviations (Tschauner
et al. 1994) or by percentile charts as we did it
226 D. Weitzel

Table 11.2.1. Classification of hip types in various neonatal screenings

Reference Measurement of Number of Perecentage of hip typesa studied

the angles hips
Ia/b IIa IIg/d IIIa/b IV

Borchert et al. (1987) No 2,030 90.5 8.8 0.7

Langer (1987) No 2,920 75.9 23.3 0.1 0.6 0.07
Sellier et al. (1987) Yes 544 54.7 41 4.3
Szöke et al. (1988) Yes 2,000 47.9 50.2 1.5 0.31 0.15
Pauer et al. (1988) Yes 4,782 77.1 18.0 2.4 0.6 0.02
Stein et al. (1988) ? 1,024 9.3 83.1 7.6
Exner and Mieth (1987) Yes 615 84.7 13.0 2.3 0.33
Dorn (1990) On demand 16,442 72.5 25.6 1.7 0.16 0.01
Tönnis et al. (1990) Yes 5,174 67.3 30.0 2.1 0.5 0.04
Riebel et al. (1990) No 4,290 77 21 1.4 0.2
Mellerowicz et al. (1991) No 10,152 25.3 73.9 0.4 0.34 0.04
Ganger et al. (1991) Yes 2,584 50 47.9 1.74 0.23
b Yes 39,072 43.8 53.2 2.7 0.3
Weitzel et al. (1994)
c Yes 33,239 89.7 7.5 2.5 0.3
Weitzel et al. (1994)

Table 11.2.2. Percentiles of angle D

0–< 2 weeks 2–< 6 weeks 6–< 10 weeks 10–14 weeks > 14 weeks
n = 15.794 n = 250 n = 967 n = 682 n = 770

P1 45 50 52 55 57
P5 50 52 55 57 60
P 10 52 54 56 58 60
P 25 55 56 58 60 61
P 50 58 60 61 62 63
P 95 63 69 69 69 68
P 99 65 74 73 73 74

(Table 11.2.2). We are convinced that a child without
a conspicuous history or clinical abnormality should
only be followed if angle D were below percentile 5.
At any rate, precise measurement of angle D will
be absolutely essential. It depends on the accurate
adjustment of the cut surface as well as on an ade-
quate scale. One should also mind that the size of a
neonate’s hip joint is only about thumbnail. Precise
measurements are impossible on a 1:1 scale. On such
shaky grounds, initial diagnostics are first of all
unreliable, and second the solid measuring base for
diagnostic follow-up is lacking. Delayed ossification
in the course of development can only be quantified
when we have correct baseline values to compare
with. So we frequently found an implausible dete-
rioration of angle D in our study, when the opening
examination was carried out with a device set to a
1:1 scale.
 Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip
11.2.7
Follow-Up after Screening Examinations in
the Neonatal Period
A number of studies have been conducted aimed at
proving the effectiveness of screening. In part of the
studies, follow-up on screened children is compared
with the results obtained in children who did not
participate in the screening. It could be shown that
in screened children the incidence of dislocated hips
was substantially lower, and that decentered hips
were treated at a considerably earlier date. In the
group that did not undergo screening, 50% of the
infants with decentered and dislocated hips were
subjected to treatment only after the third month
of life. Mellerowitz evaluated the data of 17,000 chil-
dren. In the neonatal period 5000 had been screened,
and 12,000 had been referred to an outpatient sonog-
raphy unit. In the screening group, he diagnosed
0.32% decentered and 0.04% dislocated hips. Among
the referred children, he identified 16.6% decen-
tered and 5.8% displaced hips (Mellerowicz et al.
1991).
When the infants of this group were diagnosed to
have IIIa hips, they were up to 1 year, in some cases
even up to 2 years old. The diagnosis of a decentered
hip was made at a mean age of 3 months; dislocated
hips were detected later.
By scientific standards, the comparison of screen-
ing groups with outpatient sonography groups is a
disputable approach. We therefore tried to get fur-
ther information on the course and thus on the effi-
cacy of screening by a poll among the parents whose
children had partaken in the screening. In July 1991,
we wrote to 11,629 parents of the children, who
had been screened in 1988, 1989 and 1990; and we
received 6103 answers. The distribution of hip types
according to the response pattern of parents is sum-
marized in Table 11.2.3.
There is an inverse relation between angle D
and the incidence of treatment – as depicted in
Figure 11.2.5. The lower angle D, the higher the
number of treated hips. The rate of treatment was
Table 11.2.3. Answering behavior of parents in correspondence with hip type distribution in neonatal screening (patient-
related, the worse hip taking the lead)
Type Ia/Ib Type IIa
Response (n = 6103) 38.6% 56.4%
No response (n = 5526) 42.9% 53.6%
227
altogether very high (10.4%). Only 10.89% of IIa-hips
were treated, their share in the overall total of cases
treated, however, amounted to 58.87%. In contrast
to that, the percentage of definitely pathologic hip
types IIIa/b among the cases treated was notably
low, 7.46% (Table 11.2.4). Follow-up parent polls via
phone revealed that the result of screening had been
the determinant cause for treatment in 89%. Pro-
vided that the data obtained from parents are reli-
able regarding the reason for and the beginning of
therapy, we must conclude that treatment was started
too early, and/or performed too often judging from
the prevailing recommendations at that time.
In our own outpatient clinic, we performed follow-
up on 1376 infants Results of neonatal sonography
had been submitted to us. Of these children, 724 did
not present with any risk at the time of follow-up;
abduction was found to be inhibited in 357; 48 had
been delivered from a breech position and 247 had
a family history of hip disease at infant age. More
than half of those children were diagnosed to have a
IIa hip in infancy; 12% of them were treated. Out of
the hips presenting with an angle > 50q in neonatal
screening, 0.3% were treated without risk, 33% with
inhibited abduction in the course, 19% with breech
position, and 15% with familial disposition. This
group includes nevertheless 52% of all children,
who had been followed because of the finding of a
IIa hip. This permits the conclusion that a risk selec-
1st
DKD
Fig. 11.2.5. Percentile of angle D in the neonatal period and
incidence of subsequent treatments
Type IIg Type IIIa/IIIb Type IV
4.6% 0.39% 0.05%
3.6% 0.24% 0.04%
228 D. Weitzel
Table 11.2.4. Percentage of treatments per neonatal hip types and percentage of neonatal hip types in treatments
Parent answers n = 6103
Treatments n = 637
Percentage treatments per neonatal hip type
Percentage of neonatal hip type in treatments
tion based on parameters from history and clinical
picture is possible in due course.
In addition we polled office-based pediatricians
to learn that merely three children had inpatient
treatment. One infant did not participate in the
screening. The other two children, who had been
enrolled in the screening, were taken to follow-up
too late. This reveals an inpatient treatment rate of
3/11,629 corresponding with 0.26/1000. This figure is
lower by factor 8 than the one obtained by Melzer
(1994) in his Hessian study (2/1000).
Rosendahl et al. (1994) conducted the only
study comparing a general sonographic screen-
ing (n = 3613), a risk-selective screening (n = 4388)
and a purely clinical screening (n = 3924) with each
other, and following all children screened over a
mean period of 42.4 months (24 months minimum).
These researchers investigated the effect of a gen-
eral screening on the primary diagnosis, on the
management and incidence of later forms of con-
genital/developmental dislocation /dysplasia of the
hip (DDH). It turned out that 3.4% of the infants
in the general screening group received treatment,
which held true for only 2.0% in the risk-selective
group and 1.8% in the group left unscreened. Later
forms of DDH were found in the general screen-
ing group at a ratio of 0.3/100, in the risk-selective
group at 0.7/1000, and in the unscreened group at
1.3/1000. Of the untreated children, 13% were fol-
lowed in the screening group, and 3% in the risk-
selective group. Treatment on account of ultrasonic
criteria was applied to just 3% of all the children
followed. The authors thus infer that the incidence
of later forms of developmental dislocation /dys-
plasia of the hip (DDH) will at most be marginally
reduced by general sonographic screening while
the diagnostic expenditure is at the same time sig-
nificantly increased. One side effect of this study is
obvious: Based on the data available from the period
before the study was started, late forms of DDH were
Neonatal hip type
Ia/b IIa IIg IIIa/b IV
2350 3445 281 24 3
31 375 204 24 3
1.32% 10.89% 72.60% 100.00% 100.00%
4.87% 58.87% 32.03% 3.77% 0.47%
expected to amount to 2.6/1000. Just by implement-
ing the study and by data processing, this figure was
decreased to 1.3/1000.
Niethardt et al. (2000) gave a first account of
the results of nationwide hip screening performed
between the 4th and 6th week of life. This screen-
ing had been introduced in Germany on January 01,
1996. The expectation to lower the follow-up rate
by choosing a later time for screening was not met.
The follow-up rate was indeed 23.7%, albeit having
defined the need for follow-up only from angle D
56q – contrary to Graf’s model. Taking Tauscher’s
maturation curve (mean value minus simple stan-
dard deviation) or our percentiles (percentile 25),
and the limit set like this, this follow-up rate should
not come as a surprise. There are no data as to the
number of repeated follow-ups.
In a separate poll it was assessed whether the
maternity clinics had been following the guidelines
as to risk-selective screening within the framework
of U1/2. This revealed that some centers did not per-
form any hip screening at all, others attended to risk
selection merely in part or just focused on general hip
screening. According to the resulting computer pro-
jection, approximately 50% of the neonates under-
went hip sonography already when still in the mater-
nity ward (Stoll 2001). These infants were likely to
be screened again then within the scope of U3. The
effective costs, in fact, would thus not differ much
from the costs incurred by a general screening of
neonates plus a general follow-up screening at a later
date. A cost-benefit analysis would have to include
the aspect that in number of the children requiring
treatment as a result of U3 screening, therapy had
been delayed, which is making for higher costs in
the end. Stoll points out that 25% of the extension
treatments were carried on in the first trimester
(Stoll 2001). This indicates that those infants had
had been diagnosed and treated too late, since soft
tissue atrophy had already been setting in.
 Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip 229

Niethart found out that 23.5% of the pediatri-
cians, 38.9 % of the orthopedists and 21.6% of
other medical specialists did not comply to the
screening guidelines. Pediatricians went beyond
the recommendations for follow-up and treat-
ment in every 5th case, whereas orthopedists did
so in every 3rd case. Only in every 20th case less
was actually done than provided for by the guide-
lines. Investigation is called for as to why these
guidelines are not being adhered to. The rate of
treatment was 6.7%, which is very high by inter-
national comparison.
The effect of ultrasound screening on the rate
of first operative procedure for developmental hip
dysplasia in Germany was published by von Kries
et al. (2003). Cases who had had operations were
identified through active surveillance from May
1997 to April 2002, by use of the German paediatric
surveillance unit (ESPED, Table 11.2.5). From 1887
returned questionnaires only 535 meet the criteria
for inclusion. 608 children were excluded, because
they were younger than 10 weeks and 27 because
they were older than 5 years, when the first opera-
tive procedure was performed.
The fact that 55% of the infants receiving inpa-
tient treatment had been screened in due time and
45% had either a negative ultrasound screening or
delayed or no ultrasound screening leaves us with
the following questions:
1. What about the appropriateness of the technical
equipment used and/or the quality of examina-
tion?
2. Had there been malpractice?
3. Would this treatment have been avoidable if
screening had taken place during the neonatal
period?
4. What about parent compliance?
5. Is congenital dislocation /dysplasia of the hip
(DDH) so complex a disorder that a certain per-
centage of inpatient treatments is going to be
inevitable despite early diagnosis and adequate
medical procedures?

Table 11.2.5. Children with first operative procedures by the time of sceening and screening result (von Kries et al. 2003)

Correct timing of ultrasound screening Delayed ultrasound No ultrasound

screening screening
Positive screen Negative screen

Closed reduction 176 (53.17%) 44 (13.29%) 53 (16.01%) 58 (17.52%)

Open reduction 36 (61.02%) 7 (11,86%) 6 (10.17%) 10 (16.95%)
Osteotomy 60 (57.14%) 13 (11.86%) 11 (10.48%) 21 (20.00%)

Table 11.2.6. Prevalence of inpatient and surgical treatments of developmental dysplasia/displacement of the hip (DDH)
by international comparison (from Stoll 2001). FDR = Federal Republic of Germany (West Germany) and GDR = German
Democratic Republic (East Germany) before the 1990 unification

Prevalence per thousand FDR GDR U.K South Australia Germany

1983 1989 1993/1994 a 1988–1993b 1997/1998

First measure
Inpatients total 1.32 5.78 0.385 0.4 0.202
Surgery only - 0.78 0.092 0.15 0.152
Most serious measure
Inpatients total 1.97 7.7 0.264
Surgery only 0.129
a Godward and Desateux (1998)
b Chan et al. (1999)
230 D. Weitzel
This basic aspect apart, it is helpful to compare
the results of 2 years of nationwide hip screening
with earlier data back of those days when a general
screening had been established in neither East nor
West Germany, and to take a look at data from the
UK and Australia (Table 11.2.6).
This historical comparison of data from Ger-
many shows that the number of inpatient treatments
and operations for developmental displacement/
dysplasia of the hip (DDH) has been substantially
decreasing after or owing to hip screening. The
Western/Eastern comparison. however. illustrates
that factors have been involved bearing probably
no relation to the screening.
Another notable finding is the low rate of hospital-
izations in both Australia and the UK. Hip screening
is not performed in these countries. Whether this
might be due to different genetic dispositions. to the
quality of clinical examinations or other structures
of the Health Care systems. remains in the open.
11.2.8
Conclusions
Screening does make sense when clinical disorders
cannot be diagnosed otherwise or in due time. and
when an early diagnosis contributes to preventing
substantial expenses for treatment later on. These
savings must be balanced against the additional
expenditure incurred by a screening.
Owing to fewer cases. the costs for inpatient
treatment have defi nitely been decreasing since
1996. although this cannot be attributed in a mono-
causative fashion to hip screening alone. Fact is
that screening costs money, too. These costs are
likely to be reduced when the focus of evaluation
goes beyond inpatient treatments by extending it to
the performance of screening. the documentation
of clinical diagnoses. and the diagnostic and thera-
peutic procedures ensuing as a result of the screen-
ing. Such an evaluation could be exemplified in a
selected area. provided the case numbers would
ensure statistically valid data. Such insights would
help to optimize the guidelines for screening and
to improve the quality of outcome. From the view-
point of cost containment. the previous abstention
from a comprehensive evaluation accompanying
the introduction of screening has proved to be a
costly mistake.
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362(9399):1883–1887
Weitzel D, Schneider R, Oberman B (1994) Sonographische
Befunde in einem flächendeckenden neonatalen Hüft-
screening: Ist die Grafsche Typeneinteilung der Hüftso-
nogramme korrekturbedürftig? Monatsschr Kinder-
heilkd 142:425–431
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 233

Magnetic Resonance Imaging in 12

Prevention of Alzheimer´s Disease
Marco Essig and Johannes Schröder

CONTENTS 12.1
Introduction

12.1 Introduction 233 In 1907 Alois Alzheimer (1864–1915) described the

case report of a woman who had presented with a
12.2 Mild Cognitive Impairment 234
12.2.1 Prevalence and Course of Mild Cognitive history of progressive cognitive decline with dis-
Impairment 235 orientation, incomprehension, perseveration, dys-
phasia, dysgraphia and dyspraxia, accompanied
12.3 Neurobiological Markers in Preclinical by psychopathological symptoms such as delusions
Diagnosis 235
and hallucinations at age 51 (Alzheimer 1907). She
12.3.1 Imaging in Dementia 236
12.3.2 Neuroanatomical Findings in Structural died 4.5 years after her admission to the Frank-
Imaging 236 furt Asylum for Lunatics and Epileptics. The post-
12.3.3 Differentiation of Other Forms of mortem examination revealed cerebral extracellular
Dementia 240 plaques and intracellular neurofibrillary bundles
12.4 Vascular Imaging in Cognitive – Alzheimersche Fibrillen – i.e. those changes which
Decline 241 are generally recognized to represent the hallmarks
of the disease. As proposed by E. Kraepelin in the
12.5 Functional Neuroimaging in Cognitive 8th edition of his textbook, the condition was sub-
Decline 242
sequently named after Alzheimer.
12.5.1 Perfusion MRI in Psychiatric Diseases 242
12.5.2 Diffusion MRI 243 Alzheimer´s disease (AD) is the most common
of all neurodegenerative illnesses of later life,
12.6 Neurofunctional MRI in Mental approximately two-thirds of all cases referring to
Decline 243 this condition. Prevalence of dementia rises from
12.7 Discussion and Conclusion 244
less than 5% among the under 75 to approximately
10% of those between 80 and 84 years of age. After
References 245 age 85 approximately 20%, after age 90 approxi-
mately 40% are affected. Typically, AD takes an
insidious onset and progression in a timeframe of
years with decline in a broad range of neuropsycho-
logical domains such as memory, executive func-
tions and attention, language and praxia, leaving
the patient in a helpless, severely demented state
unable to perform even simple activities of daily
M. Essig, MD living. Apart from these cognitive deficits, non-
Professor of Radiology, Head of MRI and Neuroimaging, cognitive or behavioural symptoms complicate the
German Cancer Research Center (DKFZ), Im Neuenheimer condition even in its early phase. The latter include
Feld 280, 69120 Heidelberg, Germany depressive mood and apathy, formal thought dis-
J. Schröder, MD
Professor, Section for Geriatric Psychiatry, Centre for
order, delusions and misidentifications, hallucina-
Psychosocial Medicine, University of Heidelberg, Voß- tions, and psychomotor changes (Schröder et al.
strasse 4, 69115 Heidelberg, Germany 2004).
234 M. Essig and J. Schröder
The preclinical phase of AD is characterised by
mild cognitive deficits that exceed age-related cog-
nitive decline but which are not severe enough to be
a dementia. Clinical and epidemiological evidence
indicate that this syndrome – generally labelled
mild cognitive impairment (MCI) – remains subtle
over a longstanding phase before the threshold
of dementia is reached. This conclusion corre-
sponds to the high prevalence of MCI even in the
“young” old. It is assumed that the mild cogni-
tive impairment syndrome is associated with a
strongly increased risk of dementia, especially of
AD (Pantel and Schröder 2006). Accordingly, a
progression to AD has been reported in 10%–15%
of subjects with MCI (Petersen et al. 1997; Jack
et al. 1999; Ritchie et al. 2001; Busse et al. 2003;
Toro et al. 2006).
However, a defi nite clinical delineation between
cognitive changes due to aging and neurodegen-
erative brain changes is difficult to be established.
The “discontinuity concept” considers physiologi-
cal aging and dementia as opposite states, while
the “continuity concept” assumes a continuous
transition from healthy aging to cognitive deficits
associated with aging and dementia. Following
the “discontinuity concept”, MCI could be differ-
entiated from normal aging also by clinical and
neurobiological means, whereas the “continuity
hypothesis” would predict a continuum of fi nd-
ings from one extreme to the other (Pantel and
Schröder 2006). The respective questions cannot
be solved on the basis of the epidemiological stud-
ies cited above. The high prevalence of MCI admits
the assumption that not all subjects affl icted are
in a preclinical state of AD and will subsequently
develop dementia. However, the longitudinal stud-
ies mentioned above clearly demonstrate that at
least a high proportion of subjects with MCI are at
high risk to develop AD.
In the following, we will summarize the most
important concepts of MCI. To elucidate further the
character to the condition: extreme variant of physi-
ological aging vs preclinical state of AD findings
from recent neurobiological studies will be drawn
upon. The impact of imaging, mainly magnetic res-
onance imaging (MRI), in the diagnostic work up of
patients with mental decline will be presented and
the role of imaging in a possible prevention scenario
will be discussed.
12.2
Mild Cognitive Impairment
Kral (1992) introduced the concept of benign senes-
cent forgetfulness to describe mild memory problems
in the elderly and to distinguish them from a dementia.
Since then a variety of concepts, scales and diagnos-
tic classification systems have been developed for the
operational diagnosis of these conditions (Schröder
et al. 1998). In the following the most important con-
cepts, “aging-associated cognitive decline”, “mild cog-
nitive impairment” according to Peterson, and “mild
cognitive disorder” will be described.
The research criteria of “aging-associated cogni-
tive decline” were developed by a working group of
the International Psychogeriatric Association (Levy
1994). Apart from a self-reported or a collateral his-
tory of cognitive decline, criteria include reduced
neuropsychological test performance of at least one
standard deviation below the mean in at least one of
the following cognitive domains: attention and con-
centration, abstract thinking, speech and visual-spa-
tial conception. Potential effects of age and education
are met by referring to adjusted norms; exclusion
criteria are physical disorders sufficient to explain
the respective cognitive deficits. Accordingly, MCI is
considered as a rather heterogeneous group condi-
tion which involves different cognitive domains.
In contrast, the concept of “mild cognitive impair-
ment” from Petersen et al. (2001) in its´ originally form
solely referred to declarative memory deficits. Accord-
ing to epidemiological studies however, this “purely”
amnestic subtype appears to be rather rare and tends
to be unstable (Ritchie et al. 2001; Schönknecht et
al. 2005). Therefore, the revision of the Peterson con-
cept (“International Working Group on Mild Cogni-
tive Impairment” in Winblad et al. 2004) also consid-
ers deficits in other cognitive domains. The parallels
with AACD are unmistakable. Continuing on, four
subgroups are differentiated: “amnestic MCI”, “Mul-
tidomain MCI amnestic”, “Multidomain MCI non-
amnestic”, and “single non-memory MCI”.
The ICD-10 “mild cognitive disorder” is to be distin-
guished from MCI (World Health Organization
1992). The former characterises deficits closely related
to a definite physical disorder, such as a tumor or
severe cardiorespiratory disorder, i.e. conditions
which actually exclude the diagnosis of MCI.
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease
12.2.1
Prevalence and Course of Mild Cognitive
Impairment
Beginning in 1993/94 the prevalence and course of
MCI (AACD criteria) in the 500 participants of Inter-
disciplinary Longitudinal Study on Aging (ILSE)
was examined. At the time of the first examination
the average age was 62.4 ± 2.4 years, at second exam-
ination time point the participants were on average
66.7 ± 1.1 years. With a prevalence of 13.4% mild
cognitive impairment was a common condition even
in the “young-elderly”. In follow-up after 4 years
(examination wave 1998/99) the frequency of MCI
increased to 23.6% and further to approximately
30% in the third examination wave conducted in
2005/2006. In contrast the prevalence of mild cog-
nitive disorder (ICD-10) remained almost constant,
a finding which obviously refers to the prognosis of
the underlying somatic disorders (Toro et al. 2006;
Schönknecht et al. 2005).
The established prevalence rates are generally
consistent with the results from previous popu-
lation-based studies that applied the criteria for
aging-associated cognitive decline (Schönknecht
et al. 2005). While previous studies mainly focused
on subjects in their 70s and 80s, our study demon-
strates that MCI is also common in the population
of “young-old”. Moreover, prevalence rates of MCI
in the presented study may not be attributed to the
early effects of severe systemic or neurological dis-
orders, because all subjects underwent a thorough
physical examination.
Furthermore, the diagnosis of MCI according to
aging-associated cognitive decline criteria was char-
acterized by a relatively high temporal stability. This
finding emphasizes the existence of a distinct diag-
nostic entity, such as MCI, that has been challenged
(Larrieu et al. 2002; Milwain 2000). Similar data
were reported by Ritchie et al. (2001), who found
that 50%–60% of the subjects classified as having
aging-associated cognitive decline retained this
diagnosis when they were reexamined after 1 year.
Taken together, these findings indicate that in con-
trast to other concepts of MCI, aging-associated
cognitive decline defines a distinct syndrome that is
reproducible over time in a considerable proportion
of elderly subjects.
Whereas aging-associated cognitive decline did
not predict conversion to dementia in the young-
old, literally all of the 5% who developed dementia
at age 75 had previously been ascribed to the MCI
235
group. Ritchie et al. (2001) and Busse et al. (2003)
determined conversion rates of 28% and 47% within
a comparable time interval. Previous studies on cog-
nitive deficits in preclinical AD have revealed some
empirical evidence that deficits across multiple
cognitive domains are apparent not only years but
even decades before the diagnosis of dementia can
be made (Tierney et al. 1996) and that the magni-
tude of those preclinical cognitive deficits appears
to be relatively stable until a few years before the
clinical diagnosis is made (Small et al. 2003). Con-
sequently, the likelihood of observing accelerated
changes in cognitive performance among incident
AD increases as time before the eventual diagnosis
decreases. When we take into account that the inci-
dence and prevalence of dementia are relatively low
during the seventh decade of life but increase expo-
nentially from the age of 70, the divergent results
with respect to conversion rates might mainly be
explained by age differences between the studied
populations. Accordingly, our results suggest that
age and length of follow-up interval are of crucial
relevance when the predictive validity of different
concepts of MCI is assessed.
12.3
Neurobiological Markers in Preclinical
Diagnosis
According to the amyloid cascade hypothesis
(Bayreuther 1997) proteolytic cleavage of the
amyloid precursor protein leads to the production
of AE-protein which is the central component of
neuritic plaques and has cytotoxic properties. The
significance of the amyloid cascade hypothesis
for our understanding of AD can hardly be over-
emphasised. From a clinical standpoint, the amyloid
cascade hypothesis facilitates the development of
new therapeutic strategies and corresponds to the
long course of the disease. The amyloid burden as
determined on post-mortem examination infers an
overall course of the illness of 20–30 years, of which
7–10 may correspond to the time after manifestation
of dementia symptoms. Accordingly, increased Aß
levels were reported in patients with mild cogni-
tive impairment and beginning dementia (Jensen
et al. 1999; Mayeux et al. 1999). With progression
of dementia, Aß concentrations consistently decline,
a finding which is less due to dilution because of
236 M. Essig and J. Schröder
enlarged cerebrospinal fluid spaces than f increas-
ing accumulation of this protein in cerebral tissue
(Näslund et al. 2000; Schröder et al. 1997).
Neurofibrillary bundles are composed of a smaller
precursor protein, W-protein. Due to pathological
hyperphosphorylation, tau protein can no longer
fulfi l its function of stabilising microtubules. In
turn, hyperphosphorylation of tau protein contrib-
ute indirectly to neuronal destruction due to desta-
bilisation of the axonal cytoskeletal structure with
subsequent disturbance of axonal transport and
increasing metabolic impairment (Blennow and
Hampel 2003). Thus W-protein is released. While
increased W-protein concentrations are character-
istic although not specific for AD, values obtained
in MCI typically show a wide range between those
determined in AD and those measured in otherwise
healthy controls. Longitudinal studies indicate that
this heterogeneity of W-values correspond to the risk
of developing AD in the near future (Schröder, per-
sonal communication).
12.3.1
Imaging in Dementia
In the past years there has been an increasing use of
neuroimaging in the diagnostic work-up of individ-
uals suffering from mental decline. Both computed
tomography (CT) and Magnetic Resonance Imag-
ing (MRI) are used to rule out secondary demen-
tias (which refer to somatic disorders other than
neurodegenerative diseases) or concomitant condi-
tions that may be associated with the dementing
disorder. This includes in particular the diagnosis
of treatable conditions like chronic subdural hema-
toma, tumors, infections, or normal pressure hydro-
cephalus as well as the exclusion of concomitant
neurovascular changes (Schröder et al. 1997).
Beside the exclusion of these secondary causes
the detection of subtle changes in the early stages of
dementia, including the investigation of the under-
lying pathophysiology, has gained more and more
interest. Accurate diagnosis and prognosis is not
only of great importance for the patient himself but
also for the developing new therapeutic concepts
including preventive strategies. Since the different
pathological processes that produce cerebral dys-
function at a cellular level also produce macroscopic
effects which may be detected with imaging, struc-
tural neuroimaging plays an important role, and is
regarded as a major part of the investigation of a
patient mental decline. Beside structural analyses,
however, functional neuroimaging methods allow
an even more detailed view into the pathophysi-
ologic changes associated with the development of
dementia.
12.3.2
Neuroanatomical Findings in Structural Imaging
Structural imaging is an integral part of the rou-
tine diagnostic procedure to exclude secondary,
in particular treatable causes of dementia. Pre-
vious studies revealed about 1%–10 % of clinical
relevant imaging findings in patients with mental
decline. Hejl et al. 2002 reported on 1000 consecu-
tive memory clinic patients of whom 89% had cross
sectional imaging, mainly CT. Of 891 patients that
had a scan, 42 (almost 5%) had an identifiable lesion
(tumour or hydrocephalus) that altered the diagno-
sis and required acute or subacute treatment. About
the same percentage was reported for the work-up
of demented patients (n = 432) with 4% having a
lesion. In their series they found significant findings
in about 3% of submitted cases (Fig. 12.1).
The amount of cerebrovascular findings is even
higher. Massoud et al. (2000) found clinically
unsuspected cerebrovascular disease in 26% of their
sample by routine imaging. Beyond those findings
cross sectional imaging is able to detect classical
morphologic changes in patients with dementia.
According to Braak and Braaks’ staging scheme
of AD (Braak et al. 1993), it would be expected that
the earliest morphological changes affect the tran-
sentorhinal cortex, including parts of the parahip-
pocampal gyrus (Fig. 12.2). With clinical manifesta-
tion of the disease, the hippocampus and amygdala
are also affected; other neocortical areas such as the
frontal and temporal cortices are involved later in
the course. These changes can be identified most
sensitively and precisely with MRI (Fig. 12.2).
Using volumetric MRI (Pantel et al. 2003) the
early diagnostic values of parahippocampal gyrus
and hippocampus volume reduction as predilec-
tive sites of entorhinal and limbic atrophic change,
respectively, have been investigated (Fig. 12.3) in
21 healthy subjects, 22 MCI patients as well as 12
patients with mild AD as an additional control
group. All subjects except the AD patients were
recruited within the “Longitudinal Study of Adult-
hood” (ILSE) from the general population of the Pal-
atine. Patients with MCI showed a significant right
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 237

parahippocampal gyrus volume reduction com-

Fig. 12.1. Secondary cause of dementia. A 75 year old pati-
ent with a short history of mental decline. MR was perfor-
med to exclude secundary causes of dementia. FLAIR and
T2-weighted imaging confi rmed the presence of a normal
pressure hydrocephalus with enlarged lateral ventricles and
third ventricle, CSF diapedesis over the epedyma into the
white matter surrounding the lateral ventricles. These fi n-
dings are normally most pronounced at the frontal lateral
ventricle caps. There are only minor vascular changes peri-
ventricular
pared to healthy controls. These changes were more
pronounced in patients with manifest AD, whilst
individuals with MCI took an intermediate position.
Hippocampal changes were only demonstrable in
patients with manifest AD. Similar differences were
obtained for the volumes of the frontal and temporal
lobes. Within the MCI group, the volume reduction
of the right parahippocampal gyrus was signifi-
cantly associated with global cognitive impairment.
These findings confirm the hypothesis that initial
cerebral changes in MCI primarily strike the ento-
rhinal area and the parahippocampal gyrus. The
integrity of the hippocampus is consistent with this
hypothesis since hippocampal changes would only
be expected at a later point of time, namely in the
limbic stage (Fig. 12.2).
In contrast to the parahippocampal gyrus the
hippocampus has been more often studied in MCI.
Similar to our study, Soininen et al. (1994), Laakso
et al. (1995, 1998), and Visser et al. (1999) found no
significant volume reduction of the hippocampus in
MCI. However, due to sampling differences of index
subjects as discussed above, a direct comparison of
these studies is not possible offhand. Having said
that, hippocampal atrophy in MCI was only dem-
onstrated in severely affected, almost manifestly
demented subjects and corresponds to the pro-
nounced atrophy of the amygdala and hippocampus

a b c

Fig. 12.2a–c. Progressive temporal atrophy according to Braak and Braak. Temporal lobe morphology in three subjects
at the age of 70. (a) Normal morphology of the medial temporal lobe. With increasing atrophy a shrinking of the medial
aspects and an enlagement of the basal cisterns can be observed (b). With increasing atropy (c) the changes also affect the
cap of the temporal lobe with pronounced enlargement of the basal cystern, the insula and the temporal horn of the lateral
ventricles
238 M. Essig and J. Schröder

4000,0
right parahippocampal gyrus right
righthippocampus
hippocampus
3500,0

3000,0

2500,0
2000,0

1500,0 1000,0
a Volunteers MCI AD Volunteers MCI AD b

Fig. 12.3a,b. Volumetric fi ndings in the right hippocampus and right parrahipocampal gyrus in age matched healty volun-
teers, minor cognitive impairment and Alzheimer´s disease (according to Pantel et al. Am J Psych. 2003). Subjects with
MCI showed significant right parahippocampal gyrus volume reduction compared to healthy controls. These changes were
more pronounced in patients with manifest AD, whilst individuals with MCI took an intermediate position. Hippocampal
changes were only demonstrable in patients with manifest AD

Fig. 12.4a–c. Corpus callosum changes in MCI and mild AD. Five anatomic areas have been evaluated (a). While manual
tracing demonstrated atrophy for the more rostral parts (b), voxel based morphometry only confi rmed the more pronounced
alterations in manifest AD (c)

with volume reduction of up to 20% typically found
in the early stages of AD (Jack et al. 1999; Convit et
al. 1997; Kaye et al. 1997).
Although these atrophic changes primarily
involve cortical structures, interhemispheric fiber
connections are also compromised by Wallerian
degeneration. Through this process the respec-
tive segments of the corpus callosum become atro-
phic, a finding which can be typically visualized on
mid-sagittal slices (Fig. 12.5). As demonstrated by
manual segmentation, these changes particularly
involve the more rostral parts of the corpus callo-
sum in both, MCI and AD. In contrast, by using a
voxel-based approach, significant changes could
only be demonstrated in AD but not in its preclini-
cal state suggesting a greater sensitivity of manual
tracing.
Neuropathological changes – i.e. neurofibrillary
tangles – primarily develop in the entorhinal cortex,
but extend to the entire limbic circuit including
the hippocampus in the second stage of the disor-
der. While initial pathology can be compensated
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 239

Fig. 12.5. Microangiopathic changes in a patient with mental decline. Three consecutive slices of a 65-year-old patient with
mental decline. Anamnestic a hypertension and diabetes have been documented. FLAIR imaging shows multiple conflu-
encing white matter lesions periventricular. Involved are primary the white matter tracks with involvement of the cortical
structures at a later stage of the disease

for by large and thus involving only mild cognitive
deficits, limbic and hippocampal changes typically
lead to more pronounced neuropsychological defi-
cits in particular involving the declarative memory
domain. The term hippocampal dementia has been
coined by Ball et al. (1985) to address this associa-
tion and the clinical importance of mnestic deficits.
Subsequently, neuropathological changes extend to
the entire neocortex except the sensorimotor and
visual cortices resulting into severe dementia.
In the later stages of AD the degenerative process
leads to progressive loss of brain volume that is sig-
nificantly greater in AD patients as compared to age-
matched controls or subjects with MCI (Schröder
et al. 2004) and strongly correlates with the rate of
cognitive deterioration (Pantel et al. 2002). The
assessment of the medial temporal lobe structures
are limited on CT; however there are some newer
techniques which may overcome this problems by
the use of indirect measurements of the medial tem-
poral lobe volume.
Giesel et al. (2006) proposed an indirect mea-
surement of the temporal lobe atrophy by volumet-
ric analysis of the temporal horn of the ventricular
system. The new methodology is based on an “Inter-
active Watershed Transform” (IWT) which allows
a fully automated segmentation of the temporal
horn volume (THV) and a temporal horn index
(THI) which is defined as the ratio of temporal horn
volume to lateral ventricular volume. The respec-
tive indices were assessed in 52 patients with MCI
or AD and healthy controls on the basis of the static
T1-weighted 3D-data sets. The method proved to be
fast and rater independent. Qualitative ventricular
inspections using surface rendering shading could
uncover atrophic processes with enlargement of the
whole and especially temporal horn volume. The
authors found a significant difference between both
the temporal horn volume and index of AD patients
compared to MCI subjects and controls (p < 0.005).
THV and THI of both MCI subjects and controls did
not differ significantly (p > 0.05). In their study they
found also a significant negative correlation between
the neuropsychological performance and both THI
and THV (p < 0.01). Although the study used MRI
data, the used method should also work with CT
data in which the intensity of water and brain tissue
can be clearly differentiated.
In MRI the technical requirements for a volumet-
ric analysis are at least 3-mm or thinner slices ori-
ented parallel to the medial temporal lobe and skil-
ful handling of the caliper.
In our series using volumetric analyses (Pantel
et al. 2003) we achieved sensitivity values up to 95%
in differentiating AD patients from controls with a
specificity up to 90%.
The prognostic significance of hippocampal atro-
phy in MCI is still under investigation. Accumulat-
ing the evidence from quantitative MRI studies we
can suspect that hippocampal or parahippocampal
240 M. Essig and J. Schröder
atrophy is already present before dementia onset
(Johnson et al. 2000; Saykin et al. 1999; Prvulovic
et al. 2002; Kato et al. 2001; Rombouts et al. 2000)
and dramatically increases with conversion to clini-
cally apparent disease (Small et al. 1999).
However, in most studies no significant correla-
tion between the clinical status and the volumetric
changes was found. In a large prospective study of
MCI patients, Jack et al. (1998) found a fourfold
increase in the percentage of individuals convert-
ing to dementia within 5 years when hippocampal
size was two standard deviations below age- and
sex-defined norms. Similar findings were noted in
a second study, although memory scores were also
significant predictors (Jack et al. 2000).
These findings may support the utility of ana-
tomical brain imaging in MCI to predict a conver-
sion to AD within the near future (Whitwell and
Jack 2005). Importantly, future work from popula-
tion-based studies (e.g. the Heidelberg ILSE study)
will be helpful in clarifying the utility of anatomical
imaging in the early diagnosis of AD for populations
in which clinical definitions of MCI are less predic-
tive (Pantel et al. 2003).
12.3.3
Differentiation of Other Forms of Dementia
In order to be able to diagnose a mental decline
as AD or to predict the disease, the process needs
to be differentiated from other forms of dementia,
especially from the fronto-temporal lobar degen-
eration. The clinical criteria of frontal dementia
have been described by Neary et al. (2005) who
also differentiated frontal and temporal atrophy as
supportive diagnostic features for fronto-temporal
dementia, while. However, the absence of one or the
other does not rule out the diagnosis. Asymmetric,
predominantly left-sided perisylvian atrophy char-
acterises progressive nonfluent aphasia and asym-
metric anterior temporal lobe atrophy is diagnostic
of AD. With progression of the disease and over
time, atrophy becomes more widespread in both
diseases but usually remains asymmetric in AD.
A study by Galton et al. (2001) focused on MRI
of fronto-temporal dementia, including patients
with semantic dementia and the frontal variant
of fronto-temporal dementia (fvFTD). In a study
consisting of 30 patients with AD, 17 with seman-
tic dementia, 13 with fvFTD and 18 controls, the
authors used a new visual scale based on atrophy of
the temporal pole, the parahippocampal gyrus and
the lateral temporal gyri that could be helpful in
distinguishing AD from semantic dementia as the
semantic dementia group has significantly more
atrophy in all these regions in both hemispheres.
Boccardi et al. (2003) performed a discriminant
function on a set of AD and FTD patients, showing
that including the asymmetry values of frontal and
temporal regions one could separate fronto-tempo-
ral dementia from AD with a 90% sensitivity and
a 93% specificity.
They concluded that a pattern of atrophy is more
useful than atrophy of single regions in the differ-
ential diagnosis. Chan et al. (2001) showed that, in
addition to asymmetry, a marked anterior to pos-
terior gradient of atrophy within the temporal lobe
also suggests a diagnosis of fronto-temporal demen-
tia rather than AD.
Vascular dementia is the second most common
cause of dementia, following Alzheimer disease
(Erkinjuntti 2002; Roman et al. 2002). The
diagnosis of vascular dementia requires a decline
in memory and intellectual ability that causes
impaired functioning in daily living, associated
with evidence of cerebrovascular disease demon-
strated by either history, or clinical examination,
and brain imaging. Therefore modern neuroimag-
ing is required for confi rmation of cerebrovascular
disease in vascular dementia and provides infor-
mation about the topography and severity of the
vascular lesions. Both CT and MRI are suitable in
the diagnostic workup of vascular lesions with a
clear advantage for MRI (Guermazi et al. 2007).
Absence of vascular lesions on brain CT or MRI
rules out probable vascular dementia and repre-
sents the most important element to distinguish
Alzheimer disease (Roman 2002). Since there are
no pathognomonic CT or MR fi ndings of vascular
dementia, the correlation with the clinical evidence
is mandatory. The sensitivity of MRI to vascular
pathology (Fig. 12.5) has allowed a substantially
better differentiation between Alzheimer disease
and other forms of dementia, especially the vas-
cular forms. However, there are possible overlap
syndromes between the two disorders, and opera-
tional defi nitions for “mixed” dementia, indicating
the presence of both Alzheimer disease and VaD,
are still lacking (Scheltens et al. 2002).
With the use of modern MRI or CT angiographic
techniques it is also possible to assess non-inva-
sively the vascular situation of both the supraaortic
and intracranial vessels in a single exam.
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 241

12.4
Vascular Imaging in Cognitive Decline

Magnetic Resonance Angiography (MRA) is the

method of choice for diagnosing changes in cervical
vessels (Kaufmann and Kallmes 2005; U-Kim-Im
et al. 2004; Jewells and Castillo 2003). MR angi-
ography has many different advantages over con-
ventional angiography using the DSA technique and
over computed tomography (CT) angiography:
First, the method does not require ionizing radia-
tion and is much less invasive, especially compared
to conventional angiography. As a result, the level of
patient safety is higher. MRA can be performed on
an outpatient basis and requires little preparation.
It offers a more favorable cost-benefit ratio, espe-
cially with regard to the much lower complication
rates. The latter particularly applies to brain sup-
Fig. 12.6. Contrast enhanced MRA of the aortic arch and
plying vessel territories, the carotid artery, and the the supraaortic vessels including the circle of Willis and the
vertebral arteries because complications with those intracerebral vasculature. The noninvasive MRA allows the
vessels can frequently lead to cerebral symptoms, assessment of arteriosclerotic changes with high anatomic
often with subsequent extensive neurological defi- coverage in a single exam
cits (Beltramello et al. 1994). The diagnostic per-
formance of MRA of the cervical vessels is compa-
rable with that of CTA and conventional techniques, it possible to arrive at a more precise diagnosis of the
which is why MR angiography should be selected various vascular lesions.
as the primary diagnostic modality for diagnostic
workup prior to treatment (Barth et al. 2006) or for
staging atherosclerosis (Fig. 12.6). The aim of MR
angiography in this context is to classify the degree
of a stenosis, and with regard to hemodynamic rel- 12.5
evance, to exclude other stenoses in the vascular Functional Neuroimaging in Cognitive
course as far as possible, and characterize the steno- Decline
ses to establish whether they require treatment.
Imaging of intracerebral vessels has long been The assessment of cerebral functions has long been
a domain of MR angiography (Fiebach and the domain of nuclear medicine using positron emis-
Schellinger 2003; Ozarlak et al. 2004; Fasulakis sion tomography (PET) and single photon emission
and Andronikus 2003). Due to noninvasiveness and computed tomography (SPECT) imaging (Tatsch
excellent practicability the competing procedures and Ell 2006; Coimbra et al. 2006). With the use
like conventional digital subtraction angiography of fast imaging sequences and the availability of
(DSA) and CTA are only indicated for certain medi- contrast agents the assessment and monitoring of
cal questions and acute diagnosis. Another advan- physiologic and pathophysiologic cerebral processes
tage of MRI over both procedures is the low inva- using magnetic resonance imaging has become pos-
siveness and the limited need for the use of contrast sible. Today, T1-weighted, as well as T2*-weighted
agents (Summers et al. 2001). Another key advan- contrast enhanced fast imaging sequences can be
tage of MR angiography is the ability to integrate the used for the assessment of tissue perfusion, vas-
technique into a conventional MRI examination of cularity and microcirculation (Essig et al. 2004).
the brain and combine it with other, so-called func- Diffusion MRI allows the functional assessment of
tional MRI methods like MR perfusion or MR diffu- white matter viability and structure (Stieltjes et
sion. In particular, the combination with perfusion al. 2001). Neurofunctional MRI (fMRI) enables the
measurements and diffusion -weighted MRI makes depiction of cognitive and memory functions.
242 M. Essig and J. Schröder
While perfusion MRI is already an established
method in the assessment of subjects with neuro-
cognitive changes, diffusion MRI and fMRI are
still considered as investigative procedures and are
therefore not described in detail.
12.5.1
Perfusion MRI in Psychiatric Diseases
Perfusion is physiologically defined as the steady
state delivery of blood to an element of tissue. The
term “perfusion” is also used to emphasize contact
with the tissue, or in other words capillary blood
flow. Because perfusion and blood volume is dis-
turbed in many disease processes, monitoring of
this key physiological parameter can often provide
insight into disease. Consequently, the measure-
ment of perfusion for medical purposes has been
performed in almost all organs using many tech-
niques (Barbier et al. 2001).
During the last decade several methods have been
described to measure perfusion non-invasively with
magnetic resonance imaging. Most effort has been
made in the perfusion imaging of the brain with two
major approaches: contrast-enhanced techniques
based on tracer kinetic models (Rempp et al. 1994)
and non-enhanced techniques based on arterial
spin-labeling (Wong et al. 1998).
While the contrast-enhanced techniques are well
established, the non-enhanced techniques are of
increasing interest with the use of high field MR sys-
tems. Especially in the latter the limited anatomic
a b
coverage and common EPI artifacts have been limi-
tations in the past. With the use of parallel imaging
techniques the method might be improved substan-
tially.
At a field strength of 1.5 T the main approaches to
assess brain tissue perfusion are dynamic contrast
enhanced techniques (DCE-MRI): T2* perfusion
MRI and tracer kinetic MRI.
T2* perfusion MRI is based on a rapid contrast
media injection and the evaluation of the signal
intensity time curve with spin-echo or gradient-
echo EPI sequences. The dynamic data is used to
calculate the regional cerebral blood volume (rCBV)
and regional cerebral blood flow (rCBF) (Fig. 12.7).
Perfusion MRI is routinely used in the diagnostic
work-up of cerebral ischemia and cerebral tumors
(Essig et al. 2004). In the diagnostic process of demen-
tia there are only limited data available (Maas et al.
1997; Harris et al. 1998; Bozzao et al. 2001; Alsop
et al. 2000). Previous perfusion studies using PET
have shown alterated rCBV and rCBF values in both
grey and white matter. Perfusion imaging with MRI
has been applied to this problem as well, with early
studies indicating similar results to those of PET and
SPECT. These early studies indicate that rCBV map-
ping may have a sensitivity and specificity similar to
that of nuclear medicine approaches for the diagnosis
of AD.
Vascular causes of dementia have also been stud-
ied with perfusion MRI. Several studies have shown
that these patients present with a generally decreased
cerebral perfusion. The white matter changes are
more pronounced than in patients with AD. As in
Fig. 12.7a,b. Perfusion MR ima-
ging. Color coded maps of regio-
nal cerebral blood volume (a) and
blood flow (b) of a normal subject.
In the early stage of disease there
is no obvious reduction, howe-
ver, with a detailed data analysis
suitable changes can already be
observed
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 243

many other areas of clinical application, these per-

fusion studies are still under investigation.
In a recent study by Du et al. (2006) arterial spin
labeling (ASL) MRI could detect a pattern of hypo-
perfusion in frontotemporal dementia (FTD) vs cog-
nitively normal (CN) control subjects. In a study on
21 patients with FTD, 24 patients with AD, and 25 CN
subjects ASL-MRI detected a pattern of hypoperfu-
sion in right frontal regions in patients with FTD vs
CN subjects, similar to PET and SPECT. FTD had
higher perfusion than AD in the parietal regions and
posterior cingulate. Frontal hypoperfusion in FTD
correlated with deficits in judgment and problem
solving. Adding frontal perfusion to gray matter (GM)
atrophy significantly improved the differentiation of
FTD from normal aging to 74%, and adding parietal
perfusion to GM atrophy significantly improved the
Fig. 12.8. Fractional anisotropy map of diffusion tensor MR
classification of FTD from AD to 75%. Combining
imaging of a young patient with mental decline. Displayed
frontal and parietal lobe perfusion further improved are the neuronal tracks with red representing the tracts from
the classification of FTD from AD to 87%. They con- left to right, green anterior-posterior and blue as craniocau-
cluded that frontotemporal dementia and Alzheimer dal fiber direction
disease display different spatial distributions of
hypoperfusion on arterial spin labelling MRI which
might be a differential diagnostic tool which further patients converted to AD, while symptoms in 8
allows an early specific prediction of AD. patients remained stable. The most pronounced
difference in FA was found in the fi rst third of the
body of the CC (position 2). The FA at this position
12.5.2 was significantly lower in AD vs healthy controls
Diffusion MRI and MCI vs healthy controls. When splitting the
MCI group in conversion vs no conversion, the
The pathologic alterations in AD may influence the converted group showed no significant difference
diffusivity of the cerebral tissue. The amyloid depo- in FA when compared with AD whereas the non-
sition and its following pathophysiologic changes converted group showed significantly higher FA
may influence both the apparent diffusion coeffi- values when compared to AD and no significant
cient as well as the fractional anisotrophy, a measure differences from healthy controls. Moreover, the
of the fiber integrity in Diffusion Tensor MR Imag- FA in the conversion group was significantly lower
ing (Kabani et al. 2002). than in the non-conversion group. The results of
In an early study by Bozzao et al. (2001), no signifi- this fi rst longitudinal study using an automated
cant differences between AD and normal controls could and reader independent method of diffusion MRI
be observed for the apparent diffusion coefficient. Only quantification indicate that DTI of the CC can be
a trend towards a reduction of anisotropy in the pos- used as a fast and reliable method for the evalua-
terior white matter was found. A major drawback of tion of patients with early forms of AD.
this early study was the used ROI analysis and its focus
only on the diffusivity. In a recent study by Stieltjes
et al. (2006) a fast method for automated ROI-analysis
based on probabilistic voxel classification for quantifi-
cation of corpus callosum (CC) fiber integrity (3) was 12.6
used (Fig. 12.8). In a longitudinal study on 33 patients Neurofunctional MRI in Mental Decline
with either MCI (n = 18) or AD (n = 15) and 15 healthy,
age matched controls were assessed. Conventionally, Alzheimer‘s disease (AD) and other
All patients in the MCI group had comparable dementias are diagnosed using clinical assessment,
initial MMSE scores (26–28) In this group, 10 neuropsychology and also structural neuroimag-
244 M. Essig and J. Schröder

ing, However, there is a need for the assessment
of the neuronal functionality beside the morpho-
logic changes. A new promising technique that may
be used for this is to measure local brain activa-
tion using functional magnetic resonance imaging
(fMRI), since functional loss predates structural
loss of brain tissue. Functional MRI was recently
used to examine activation associated with aging
and dementia (Buckner et al. 2000; Johnson et al.
2000; Saykin et al. 1999).
Johnson et al. (2000) correlated the effect of atro-
phy with the MRI signal. In their study they first
described a compensatory recruitment of cortical
units in cases of Alzheimer`s disease.
Newer studies focus on the effects of pathologic
ageing and the findings in minor cognitive impair-
ment subjects.
Studies in MCI and early AD addressed activa-
tion changes under declarative memory tasks, since
the latter refer to the core symptoms of the disease.
However, results appear to be somewhat conflict-
ing. Some studies (Machulda et al. 2003) reported
increased activation values – generally interpreted
as compensatory effects – while decreased activa-
tions described by others (Dickerson et al. 2005)
are assumed to refer to atrophic changes. Interpre-
tation of the respective effect which were primarily
described in mesial temporal structures is further
compromised by methodological issues, in particu-
lar the question whether patients were trained before
the examination or not. This point is further under-
lined by the results of fMRI studies under repetitive
motor tasks or working memory tasks which yielded
a decrease of activation values at an increased per-
formance following practice (Fig. 12.9).
12.7
Discussion and Conclusion
The assessment of atrophic changes is well estab-
lished in the assessment of subjects with mental
decline. The most likely future use of imaging, how-
ever, will be the identification of patients at risk

at baseline after 2 weeks after 4 weeks

Fig. 12.9. Functional MRI during a working memory task in healthy controls. At baseline, execution of the task led to
an activation of fronto-parietal cortices as described in previous studies. While the respective regions showed activation
increases with improved performance after the initial 2 weeks of training. The activation values decreased at the time of
consolidation of performance gains after 4 weeks
 Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease
for Alzheimer’s disease or suffering from preclini-
cal Alzheimer’s disease, most likely mild cognitive
impairment. For imaging this will mean focusing
on those areas that are affected earliest in the dis-
ease, i.e. entorhinal cortex and hippocampus, using
high-resolution structural or functional MR imag-
ing methods. Work from different groups has shown
that moderate medial temporal lobe atrophy, as mea-
sured qualitatively or quantitatively may serve as a
prediction of development of AD. With the ability
to rapidly acquire high contrast, high spatial resolu-
tion, three-dimensional brain images, a number of
laboratories are experimenting with sophisticated
brain-mapping algorithms. This process allows an
individual MRI to be compared to an ‘average’ or
‘ideal’ brain, enabling the detection of anatomical
differences at one point in time as well as change in
anatomical structure over repeated observations.
In an evidence based evaluation, however,
Wahlund et al. (2005) recently summarized that
only at specialized settings does the MRI based
evaluation of atrophy of medial temporal structures
contribute to the diagnostic accuracy. However,
these findings cannot be transferred into clinical
radiological practice because there are no reliable
cutoff values established from large population
based cohorts of healthy elderly subjects.
Therefore, screening for subjects with a high risk
for developing AD or a conversion of MCI into AD
might be possible. The most important prerequisites
are the development of standardized imaging pro-
cedures and automated or semiautomated postpro-
cessing tools. To detect individual changes and to
compare the data with normal values, the establish-
ment of age, sex and education independent normal
values based on a large number of normal volunteer
data is mandatory and should allow the assignment
of a risk profi le. This is only possible with a multi-
disciplinary and multifunctional assessment of the
patients.
Based on the currently available and above pre-
sented data we can propose an MRI based screening
protocol as follows:
1. Native T1 and T2-FLAIR to rule out secondary
causes of mental decline and to rule in typical
imaging changes associated with the develop-
ment of dementia. T2 imaging is also able to
quantify the vascular component of the disease.
2. Volumetric analysis using T1-weighted 3D gra-
dient echo sequences. The use of standardized
imaging parameters is mandatory to gain com-
parable results from different sites.
245
The 3D data postprocessing and the volumetric
analysis should also be standardized and com-
pared with previous data. The postprocessing
should be fast and reliable.
3. Contrast enhanced MRA of the supraaortic ves-
sels including the carotid arteries and the intra-
cerebral vessels. Multiphasic acquisition to eval-
uate both the arterial and venous system. MRA
enables a better analysis of the vascular compo-
nent, e.g. to rule out vessel stenoses or vasculitic
changes.
4. Spin-labelling or contrast enhanced MR perfu-
sion measurements allowing an absolute quanti-
fication of the cerebral blood flow and volume.
Postprocessing using a standardized software
solution.
5. Diffusion Tensor MRI with quantification of the
fractional anisotropy. Postprocessing using a
standardized and reader independent software
solution.
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 Osteoporosis 249

Osteoporosis 13
Andrea Baur-Melnyk and Holger Boehm

CONTENTS tures associated with osteoporosis (fragility frac-

tures) are found in the spine, hip and wrist. Osteo-
porosis can be classified as primary or secondary.
13.1 Epidemiology, Socioeconomic Impact 249 According to the time of manifestation primary
13.2 Diagnosis of Osteoporosis 250 Osteoporosis is termed as juvenile, post-menopausal
or senile. A wide spectrum of causes may lead to sec-
13.3 Imaging Methods for Osteoporosis 251
13.3.1 Conventional Radiography 251 ondary osteoporosis. The most common conditions
13.3.2 Vertebral Fractures 252 include osteoporosis due to drugs (e.g. corticoids,
13.3.3 Differential Diagnosis of phenytoin) renal or hepatic insufficiency, hyper-
Vertebral Fractures 252 parathyreoidism, hyperthyroidism, metastases or
13.3.4 Stress Fractures 254
13.3.5 Osteodensitometry 254
hematologic bone marrow neoplasia.
13.3.6 Screening 256 Osteoporosis affects one in two women and every
13.3.7 Follow-Up BMD Measurements 256 third man older than 60 years. There is a wide varia-
13.3.8 Radiation Exposure 257 tion in fracture rates between and within popula-
13.3.9 Trabecular Imaging 257
tions reflecting genetic and environmental risk
13.3.10 Therapy 257
13.3.11 Initiation of Drug Therapy 258 factors. An estimated 40% of US women and 13%
of men above the age of 50 will experience at least
13.4 Summary 258
one fragility fracture within their lifetime (Melton
References 2591 et al. 1992). With increasing age, the probability of
osteoporosis increases.
Osteoporotic fractures are associated with a sub-
stantial rate in mortality and morbidity. According
to Cooper (1997), during the first year following a
hip fracture, death occurred in 20% and permanent
disability in 30% of the patients. Altogether 40% of
13.1 patients were unable to walk without assistance and
Epidemiology, Socioeconomic Impact 80% were unable to carry out at least one activity of
daily living. Fractures result in pain, functional lim-
Osteoporosis is defined as a progressive systemic itations, decreased quality of life and psycho-social
skeletal disease characterized by diminishing bone isolation. Decreasing activity further increases the
mass and deterioration of the microarchitecture extent of osteoporosis. These factors lead to a vicious
of bone tissue, resulting in a loss of mechanical circle of recurrent fractures.
strength and susceptibility to fracture. Typical frac- In the US, osteoporosis-related fractures amount
to healthcare expenditures of as much as US$20 bil-
lion per year, over a third of the total being caused by
fractures of the hip (Praemer et al. 1992). The larg-
A. Baur-Melnyk, MD, Associate Professor of Radiology est amount is spent on inpatient medical services
H. F. Boehm, MD
Department of Clinical Radiology, University Hospitals –
and nursing home care. Direct costs include an esti-
Grosshadern, Ludwig-Maximilians-University of Munich, mated 547,000 hospitalisations and 4.6 million hos-
Marchioninistrasse 15, 81377 Munich, Germany pital bed days for osteoporotic fracture care in the
250 A. Baur-Melnyk and H. Boehm

USA in 1995 (Ray et al. 1997). Annual expenditures ography and bone mineral density measurements).
for osteoporotic fractures exceeded all health care Secondary reasons for osteoporosis and osteomala-
expenditures for breast and gynaecological cancers cia need to be excluded (Fig. 13.1). Patient‘s history
combined, only being surpassed by costs related to should explore risk factors, genetical disposition
cardiovascular disease (Hoerger et al. 1999). In the (mother) and recent fractures in clinical history. It
industrialized nations, medical expenditures are has to be recorded whether or not the patient has
rising faster than the rate of inflation. The prevalence already suffered a fracture in the past, whether
of osteoporosis is so great that the decision whether significant loss of body height has occurred or the
or not to treat the individual patient will have tre- patient complains about back pain. Since 2/3 of fra-
mendous economic impact. For instance, treating the gility fractures are clinically inapparent, as a mini-
whole population of postmenopausal women in the mum requirement, lateral X-ray fi lms of the tho-
US (35 million) with hormone replacement therapy
at just $430 per year would total nearly $15 billion
annually, reaching the direct medical expenditures
for treatment of the fractures themselves (Melton
2002). How best to balance the benefits of treatment
with these potentially ruinous treatment costs is the
subject of ongoing discussions. Cost effectiveness
of treatment is extremely difficult to ascertain. On
the other hand, using costs and criteria applicable
to the US, pharmacological treatment that aims at
the reduction of hip fracture risk has been shown to
be cost effective in high-risk individuals (Eddy et al.
1998; Jönsson et al. 1999). Widespread use of expen-
sive drugs for prevention of fractures may not be
affordable in many countries where effective drugs Fig. 13.1. A 54-year-old female with severe osteomalacia. In
are not reimbursed by government health insurance contrast to osteoporosis the structure of the trabeculae is
plans even for patients at high risk of fractures. blurred. Note also the bilateral insufficiency fractures of the
pubic bones

Table 13.1. Risk factors that provide indications for the

diagnostic use of bone densitometry (Kanis 2002)
13.2
Diagnosis of Osteoporosis Indications for bone mineral density measurements
1. Radiographic evidence of osteopenia or vertebral
Osteoporosis is a medical condition which is sub- deformity
stantially underdiagnosed. It is often ignored by 2. Previous fragility fracture
3. Loss of height, thoracic kyphosis
many physicians in private practice even though
4. Presence of strong risk factors
patients present obvious signs of osteoporosis, such Anorexia nervosa
as a loss of height and substantial thoracic kypho- Malabsorption syndromes
sis. But even in hospitalized patients the disease is Primary hyperparathyreoidism
often not recognized. In several studies, lateral chest Post-transplantation
radiographs of women aged older than 60 years were Chronic renal failure
reviewed. Only in 15%–55% of cases with vertebral Hyperthyreoidism
Prolonged immobilisation
fractures these were actually reported and only Cushing´s syndrome
in 2%–19% of fracture patients further diagnostic Oestrogen deficiency
work-up and treatment was initiated (Gehlbach et Corticoid therapy
al. 2000; Kim et al. 2004; Mueller et al. 2004). Premature menopause (< 45 years)
The diagnostic process in the context of osteo- Maternal family history of hip fracture
porosis requires a close look at the patient‘s history, Long term secondary amenorrhoea (> 1 year)
Low body mass index (< 19 kg/m2)
a thorough clinical examination as well as assess-
Primary hypogonadism
ment with radiological methods (conventional radi-
 Osteoporosis 251

racic and lumbar spines ought to be obtained at first nia is detectable) have been poor (Lachmann and
presentation. Clinical examination focusses on the Whelan 1936; Doyle et al. 1967; Wagner et al.
identification of spinal deformities (kyphosis) and 2005). Typical radiological signs of osteoporosis are
height measurements. Testing the sense of balance increased radiolucency of bones, accentuation of the
is essential because of its great impact on the inci- vertebral end-plates and accentuated trabeculae of
dence of falls, which is itself a dominant risk factor the principal tensile and compressive group of the
for hip fractures. The radiologist plays a key role hip (Figs. 13.2 and 13.3).
in the diagnostic process by detection of fractures
as well as by assessment of bone mineral density
(BMD) for base-line and follow-up examinations.
BMD measurement represents the only method
to determine osteopenia and osteoporosis prior to
fracture (Table 13.1).

13.3
Imaging Methods for Osteoporosis

13.3.1
Conventional Radiography

Conventional radiography is of limited use in detect- Fig. 13.2. An 80-year-old female with severe osteoporosis
ing osteoporosis prior to fracture but plays a cen- of the pelvis. Increased radiolucency and accentuation of
trabeculae of the femur
tral role in the assessment of the fracture status of
the osteoporotic patient. Furthermore, radiographs
serve to exclude differential diagnoses, such as osteo-
malacia, hyperparathyroidism, renal osteodystro-
phy, malignant bone marrow disorders, as well as
local bone or soft tissue conditions which may lead to
significant errors in bone mineral measurements.
In the appendicular skeleton, radiographs readily
allow to identify osteoporotic fractures. The presence
of a fragility fracture – after exclusion of all other
possible causes of the fracture – justifies the diagno-
sis of osteoporosis. A fragility fracture is a fracture
that occurs inappropriately at minimal mechanical
impact (e.g. fall on the hip from standing position,
coughing, bending over). The primary goal is to
detect osteoporosis before a fracture occurs rather
than identify fracture-associated deformities.
Many semi-quantitative indices have been devel-
oped to assess indirectly BMD from radiographs,
e.g. trabecular quantification or combined cor-
tical thickness quantification (Chen et al. 1994;
Veenland et al. 1994; Buckland-Wright et al.
1994; Millard et al. 1998). Due to inherent vari-
ability concerning image quality in standard radio-
Fig. 13.3. Lateral projection radiograph of the spine in a 76-
graphs, sensitivity and reproducibility of radio- year-old female with severe osteoporosis (T-value: –4,4 SD).
graphic techniques (a reduction of bone mineral Increased radiolucency and accentuation of end-plates. Note
in excess of 20%–40% is required before osteope- also wedge shape deformity of L2
252 A. Baur-Melnyk and H. Boehm
13.3.2
Vertebral Fractures
Vertebral fractures are the most common type of
fracture in osteoporosis. If clinically symptom-
atic, they may manifest in back pain, loss of body
height, impaired range of motion which in turn may
have a serious impact on the patient’s quality of
life possibly leading to social isolation. It has to be
emphasized that a substantial number of vertebral
fractures remains clinically silent, though. Once a
vertebral fracture has occurred, the individual risk
of suffering subsequent vertebral fractures is five-
fold increased. In 20% of women with osteoporotic
fracture these will follow within the first 12 months
following fracture (Melton et al. 1999; Lindsay et
al. 2001).
In the spine, typical radiographic features of
osteoporosis include anterior wedge compression
fractures, bi-concave central compression fractures,
symmetric transverse compression fractures and
an overall increased kyphosis (Figs. 13.3 and 13.4).
Genant et al. (1993) have proposed a semi-quantita-
tive classification scheme using the so-called “spinal
Fig. 13.4. A 66-year old female with severe
osteoporosis of the spine and multiple “codfish
vertebrae”
fracture index” to describe the degree of vertebral
deformity from visual inspection The classification
comprises four grades based on the reduction in
vertebral height (Fig. 13.5). Other grading systems
based on, for example, the “spine deformity index”,
or the “radiological vertebral index” are less com-
monly used (Minne et al. 1988; Leidig-Bruckner
et al. 1994).
13.3.3
Differential Diagnosis of Vertebral Fractures
Vertebral fractures may be traumatic, due to osteo-
porosis with or without minor trauma or due to bone
tumors and metastases, respectively. Traumatic
fractures do not represent a diagnostic dilemma.
However, spontaneous vertebral fractures occa-
sionally may be difficult to be recognized as such
since they may present features similar to traumatic
fractures on radiographs as well as in cross sec-
tional studies. Each fracture diagnosed by plain
fi lm radiography, that occurs above the seventh
thoracic level, any fracture with end-plate angula-
tion (unilateral infraction of the vertebral body)
and structural irregularities or osteolytic lesions
should be worked up further by tomographic imag-
ing modalities. In CT, osteolytic or osteoblastic
lesions or paravertebral soft-tissue masses are a
defi nite sign of a neoplastic process. The presence
of an intravertebral vacuum phenomenon is highly
predictive of an osteoporotic fracture. MRI is the
method of choice for differentiation of osteoporotic
and neoplastic fractures (Cuenod et al. 1996; Yuh
et al. 1989). In consolidated osteoporotic fractures,
normal bone marrow signal (hyperintense on T1-
w SE and hypointense signal on fat suppressed
sequences) is present. In acute or subacute osteo-
porotic vertebral fractures, bone marrow edema is
apparent yielding low signal on T1-w SE and high
signal on fat suppressed sequences. Edema usually
diminishes after 3–6 months. Typically, the edema
is band like along the fractured end-plate (Fig. 13.6).
However, in more advanced fractures it may involve
larger areas of the vertebral body but in fact in most
osteoporotic fractures small islands of normal fat
containing red marrow still persist. In some cases,
the whole vertebral body is altered in signal inten-
sity just like in neoplastic fractures making the dif-
ferentiation difficult. Under those circumstances
diffusion-weighted imaging has proved to be more
specific (Baur et al. 1998, 2003).
 Osteoporosis 253

Normal
(Grade 0)

Wedge deformity Biconcave deformity Crush deformity

Mild deformity
(Grade 1)

Moderate deformity
(Grade 2)

Severe deformity
(Grade 3)

Fig. 13.5. Semiquantitative scoring system of vertebral fractures according to

Fig. 13.6a–c. A 70-year-

old female with an acute
osteoporotic fracture of
the 11th thoracic vertebral
body. Hypointense band like
signal changes on T1-w SE
images (a) with correspond-
ing increased signal on STIR
images (b) indicating bone
marrow edema. On diffu-
sion-weighted SSFP images
hypointense signal is consist-
ent with the benign nature
of the fracture (c). Neoplas-
tic infi ltration would show
hyperintense signal on diffu-
sion-weighted images a b c
254 A. Baur-Melnyk and H. Boehm
13.3.4
Stress Fractures
Stress fractures can be divided into fatigue and insuf-
ficiency fractures of bone according to the underly-
ing condition of bone. Fatigue fractures occur within
normal bone due to repetitive trauma at one site of
the skeleton, e.g. march fracture of the metatarsal
bone or runner‘s fracture of the tibia. Insufficiency
fractures occurs when normal stress is placed on
a bone with deficient elastic resistance (e.g. osteo-
porosis, osteomalazia, renal hyperparathyreoidism,
Paget‘s disease). Osteoporotic vertebral fractures
are therefore classified as insufficiency fractures.
However, insufficiency fractures may occur also at
other sites, for example in the sacrum (Blake and
Connors (2004). This can lead to serious problems
in differential diagnosis. Especially in patients with
a clinical history of cancer, those lesions may be
confused with metastases. MRI findings are often
misleading. Insufficiency fractures appear as areas
of hypointense signal on T1-w SE sequences and
hyperintense signal on fat suppressed sequences just
like metastases. Both metastases and oedema, due to
an insufficiency fracture, usually exhibit strong con-
trast enhancement. CT shows a typical serpingenous
a pre-menopausal females and non-Caucasian post-
b over-proportional reduction in fracture risk and in
Fig. 13.7a,b. Two CT slices of a 66-year old female with S.p.
ovarial cancer and radiation therapy to the pelvis 2 years
ago. She suffers from pain in the sacrum since several
weeks. In CT typical insufficiency fractures of the sacrum
are present on both sides
fracture line bordered by sclerosis paralleling the
sacoiliacal joint in the massa lateralis (Fig. 13.7).
13.3.5
Osteodensitometry
At present, the assessment of areal bone mineral
density (BMD) or bone mineral content (BMC) is
the clinical gold standard for determination of
individual fracture risk and follow up the course of
patients treated for osteoporosis. The predominant
densitometric techniques in clinical practice are
DXA and QCT. Both procedures are based on the
attenuation of photons passing through bone tissue.
Quantitative ultrasound (QUS) measurements have
recently been proposed as an alternative to current
radiation-based bone densitometry techniques to be
applied to peripheral skeletal sites.
Since BMD is easily accessible, has a high pre-
cision and correlates well with bone strength, the
World Health Organization (WHO) has issued a
definition of osteoporosis based on the so-called
T-score which expresses the standard deviation of
BMD with respect to a young, female, adult, Cauca-
sian reference population (WHO 1994). Osteoporosis
is diagnosed in an individual if the T-score is below
–2.5. With a T-score between –2.5 and –1 the condi-
tion is referred to as osteopenia. Originally, the T-
score was established for hip BMD and anterior-pos-
terior lumbar spine as assessed by dual energy X-ray
absorptiometry (DXA) (Fig. 13.8) but subsequently
has been used to define diagnostic thresholds for
various skeletal sites and diagnostic modalities.
It has to be emphasized, that the WHO-definition
of the T-value is not applicable to males, children,
menopausal females and other densitometric meth-
ods such as QCT.
BMD accounts for 60%–80% of the variation in
bone strength while the remaining 20%–40% can
be attributed to factors other than BMD referred
to as the quality of bone (McBroom et al. 1985;
Mosekilde et al. 1987). The concept of bone quality
helps to explain observations from pharmacological
studies in which small changes in BMD lead to an
which fracture risk decreases long before maximal
changes in BMD are achieved.
The term “bone quality” summarizes a number of
contributors to bone strength namely micro-archi-
tectural aspects, biological turnover, cell viability,
 Osteoporosis 255

Fig. 13.8. Example for densitometric evaluation of the lumbar spine by DXA. The patient’s lumbar bone density is compared
to reference populations. The “T-score” is calculated as the standard deviation (SD) variance of the patient’s BMD compared
to a healthy young-adult reference population. The reference population may vary according to the manufacturer and there-
fore also mean SD of the reference population is variable. Comparison of serial DXA studies should therefore always relate
to absolute BMD values expressed in g/cm 2 , and should not be based on T-scores. The “Z-score” is the standard deviation
(SD) variance of the BMD compared to an age- and sex-matched reference population, and should not serve for diagnosis of
osteoporosis. It is calculated according to the same formula as the T-score, with the exception of the reference population
being age- and sex-matched instead of young-adults. In this case, due to degenerative spondylarthrosis, the BMD value of L4
is significantly higher than the BMD for L1-3. This vertebra should be excluded from T-score evaluation. Thus, the T-score
for this patient (L1-L3) is –2.6 indicating osteoporosis

damage accumulation (e.g. micro-fractures) and
matrix composition and as such is not as trivially
accessible by diagnostic methods as bone density.
BMD obtained from DXA is a good predictor of frac-
ture risk and measurements can be performed at or
close to the site of interest, i.e. at the spine, the proxi-
mal femur and the distal radius. However, there is
considerable overlap in the BMD results between
individuals who have fractured and those who have
not. The anatomic sites that are routinely and most
frequently studied using DXA are the lumbar spine
and the hip. Whole body acquisition and BMD mea-
surement at the distal radius and the calcaneus may
also be obtained.
AP examination of the lumbar spine is typically
conducted for L1-L4 and has an in vivo precision of
1% and a high accuracy of 4%–10% (Pacifici et al.
1988; Glüer et al. 1990; Mazess et al. 1989). The
scans are evaluated using automatic segmentation
and positioning of ROIs (Fig. 13.8). Several limit-
ing factors and conditions are associated with AP
lumbar measurements, though inter-individual
anatomic variability in vertebral size may lead to
a bias in the sense that larger vertebrae with larger
transverse diameters result in higher BMD values.
A major disadvantage in AP examinations is the
relevance of errors caused by calcifications of sur-
rounding soft tissue and degenerative alterations
of the spine. The posterior vertebral elements fre-
quently involve osteoarthritic changes (i.e. facet
sclerosis, degenerative disc disease, osteophytes)
– particularly in the elderly – which may lead to an
over-estimation of bone mineral density. The same
is true for aortic calcifications if superimposed onto
the ROIs, or deformed vertebrae which must not be
included in the evaluation of BMD. Lateral lumbar
DXA which assesses solely the vertebral bodies is
less affected by the above factors but measurements
256 A. Baur-Melnyk and H. Boehm
have lower precision and involve higher doses of
radiation (Larnach et al. 1992; Rupich et al. 1992).
Osteopenia fi rst and most severely affects the
trabecular bone compartment. Therefore, trabecu-
lar bone is considered the most reliable indicator
of overall metabolic integrity. Today, quantitative
computed tomography (QCT) is the only com-
mercially available technique allowing volumetric
measurement of the trabecular interior of bone
(Fig. 13.9). All other densitometric techniques
evaluate a combination of both trabecular and the
overlying cortical bone. QCT is the most accurate
modality to measure bone density being two to three
times more sensitive than DXA in detecting loss of
bone mineral. In vivo precision of up to 1.3% can be
achieved for trabecular BMD in the spine (Lang et
al. 1999). QCT can be performed on standard clini-
cal scanners, which are equipped with a calibration
phantom and specialized software allowing for
Fig. 13.9. Measurement of bone mineral density by quan-
titative computed tomography. CT-scanners are equipped
with a calibration phantom and specialized software for
ROI positioning allowing for high precision measurements.
Absolute mineral content is important for diagnosis of
osteopenia (80–120 mg CaHA/ml) or osteoporosis (< 80 mg
CaHA/ml). T-values according to WHO (1994) are not eli-
gible for CT measurements. CT should be the second line
examination method if DXA yields inconsistent values or if
DXA cannot be performed (e.g. scoliosis, strong atheroscle-
rosis of aorta, strong degenerative changes of vertebrae etc)
since all standardized recommendations are based on DXA
measurements
high precision measurements. However, all stan-
dardized therapy regimens and diagnosis of osteo-
porosis based on BMD measurements rely solely on
DXA T-values, and therefore QCT measurements
should be reserved for special circumstances: sus-
pected BMD loss despite normal DXA values, metal
implants in the spine, severe scoliosis and expected
false negative DXA measurements (massive athero-
sclerosis of the aorta, severe scoliosis, degenerative
alterations of the lumbar spine, metal implants).
13.3.6
Screening
Costs of screening vary corresponding to the tech-
nique and average reimbursement rates in 2000 in
the U.S. were $133 for DXA and $34 for ultraso-
nography (National Physician Fee Schedule
Payment Amount File 2000).
If 10,000 women 65–69 years of age underwent
DXA of the femoral neck, 12% would be identified
as high-risk (T-score d2.5). The number of women
in this age group needed to screen to prevent 1 hip
fracture in 5 years would be 731, and the number of
women with low bone density needed to treat for
benefit would be 88 (Nelson et al. 2002).
Abnormal ultrasonography results may require
a confirmatory DXA before treatment is initiated
because clinical trials are based on DXA as entry
criteria. Patients would require follow-up tests over
several years before receiving a diagnosis of osteo-
porosis and leaving the screening population.
13.3.7
Follow-Up BMD Measurements
For consistency, serial DXA measurements (e.g. for
follow-up or for monitoring therapy) should always
be performed on the same scanner. Due to variabili-
ties in calibration between different manufacturers
the BMD measurements are not directly transfer-
able from one scanner to another. Arai et al. (1990)
examined three different DXA devices revealing that
the BMD results in a specific spine phantom varied
by between 5% and 8%. The appropriate interval
between bone density tests depends on the preci-
sion of the modality, the expected rate of change
in BMD, and the level of statistical confidence. For
monitoring the response to therapy, a repeat test
in 1–2 years is usually sufficient. An increase or no

change in BMD is considered to be a good response,
a significant decrease of BMD is worrisome. In situa-
tions where a rapid change in BMD can be expected,
e.g. initiation of high dose glucocorticoid therapy,
a baseline test is recommended, with a follow-up
study in intervals of 6 months until a stable level
is reached.
13.3.8
Radiation Exposure
Radiation exposure in DXA ranges from 1 to
50 µSv depending on the location of the measure-
ment (axial/peripheral skeleton) and the tech-
nique (pencil beam/fan beam scanner) (Link and
Majumdar 2003) Effective doses associated with
QCT are quoted as 60–500 µSv for the lumbar spine
and about 1 µSv for the distal radius. Quantitative
ultrasound is a test that does not utilize ionizing
radiation and therefore does not contribute to radia-
tion exposure.
13.3.9
Trabecular Imaging
Bone densitometry is based on the absorption of
photons passing through the tissue but (unfortu-
nately) does not consider the underlying architec-
tural features of bone which strongly influence the
biomechanical properties. Various of studies have
shown that micro-structure and BMD are widely
independent contributing factors to bone strength
(Genant et al. 1996; Ulrich et al. 1997).
Recently, imaging techniques have become avail-
able allowing to depict individual trabeculae (Link
et al. 1999). In this context high-resolution magnetic
resonance imaging (HR-MRI) has received consid-
erable attention both as a research and as a clinical
tool. Since the MR signal corresponds to the proton
content of a particular tissue – due to the surround-
ing marrow and fat – bone is represented as a nega-
tive image. Depending on the field strength, coil
design, and the choice of the specific pulse sequence
and imaging parameters HR-MRI can be used for
in vitro as well as in vivo situations. Anatomic sites
which have successfully been studied in human
subjects using HR-MRI are the phalanges, the distal
radius, the proximal femur and the calcaneus.
From the image data, micro-structural features
obtained by quantitative measures are analysed with
Osteoporosis 257
respect to the presence of osteoporotic fractures of
the spine (in vivo) or correlated with biomechani-
cal strength (in vitro). Fairly well established are
linear structural measures in 2D based on standard
histomorphometry (trabecular spacing, trabecular
volume, connectivity).
Micro-CT- or HRMRI-based microstructural
computer models of trabecular bone can be exam-
ined by finite element analysis (FEA), thus pro-
viding additional and relevant information about
anisotropy and mechanical properties in a direct
and non-destructive way (Ulrich et al. 1998; van
Rietbergen et al. 1998). Due to the complexity of
natural bone, the computational effort is extremely
high and – at present – only available at specialized
centers.
Recently, non-linear techniques for structural
analysis of trabecular bone in 3D have been devel-
oped, which proved to be superior to both the stan-
dard measures and BMD in predicting bone strength
and fracture risk. The new parameters are based
on the scaling index method (SIM), the Standard
Hough Transform, and the Minkowski functionals
(Boehm et al. 2003a,b, 2005). Although the results
of structural analysis are very promising further
development in hardware and software are required
to make these new techniques available for clinical
practice.
13.3.10
Therapy
Osteoporosis is a disease which is not only underdi-
agnosed but also undertreated. The aim of treatment
should be to prevent fractures. By preference the
occurrence of the first fracture should be prevented
in patients at high risk for osteoporotic fractures. In
patients with a previous fracture, treatment should
be initiated soon after the fracture has occurred.
Therapy challenges the patient in terms of measures
in life style and the doctor in terms of selecting the
ideal medication.
Live style recommendations include avoiding risk
factors such as smoking, alcohol abuse, adequate
calcium and vitamin D intake by food and physical
activity. In older patients fall prevention exercises
and training of body balance, can reduce the risk
of falling. Hip protectors decrease the incidence for
hip fractures. In patients with solely osteopenia,
life style recommendations in combination with
a daily dose of calcium and vitamin D are recom-
258 A. Baur-Melnyk and H. Boehm
mended. In patients with osteoporosis, with or with-
out a fracture, further medication has to be initiated
(Geusens 2003).
Bisphosphonates are the treatment of choice for
the prevention and treatment of fragility fractures.
At present, three types of bisphosphonates are used
clinically in both postmenopausal and glucocorti-
coid-induced osteoporosis, namely cyclic etidro-
nate, alendronate and risedronate. According to
several studies the incidence of vertebral fractures
and hip fractures can be reduced by 50%–70% after
the use of bisphosphonates. The optimal duration of
bisphosphonate therapy has not been established.
A number of oral and transdermal hormone
replacement preparations are licensed for the pre-
vention of postmenopausal osteoporosis. However,
in spite of the epidemiologic evidence of a protective
effect of hormone replacement on osteoporosis and
the incidence of fractures, no anti- fracture effect
in the spine has been documented in a randomised
controlled trial. Furthermore the role of long term
hormone replacement therapy is discussed contro-
versially since the results of the “women`s health ini-
tiative” study were released. A 26% relative increase
of invasive breast cancer in the combined hormone
replacement group as well as an increased risk of
cardiovascular and cerebrovascular incidents was
observed causing more harm than benefits.
Raloxifene, a selective estrogen receptor modu-
lator (SERM), a non hormonal substance, is used
for the treatment and prevention of osteoporosis in
postmenopausal women. It has a spectrum of effects
when binding to the estrogen receptor, with agonist
effects on bone and antagonist effects on the breast.
It has been shown to reduce the incidence of verte-
bral fractures. No relevant effect was observed for
non-vertebral fractures.
13.3.11
Initiation of Drug Therapy
The T-score cutoff points for defining osteoporo-
sis and osteopenia are not the same as the T-score
thresholds for initiating drug therapy. The WHO
cut-off for defining osteoporosis is –2.5. The Fed-
eral Drug Administration (FDA) approves starting
medications, such as bisphosphonates or calcito-
nin, for the treatment of osteoporosis, in women
if the T-score is below –2.0 with no risk factors,
T-scores below –1.5 with one or more risk factors,
or in patients with a prior vertebral or hip fracture.
Women may benefit from pharmacologic treatment
if T-score is –2.5 or below, if T-score is –1.5 and
below and risk factors are present, or if non-phar-
macologic preventive measures are ineffective (bone
loss continues or low trauma fractures occur). In
Germany, according to the new DVO guidelines,
treatment start point has been changed recently.
Treatment is dependent on T-scores in combination
with age and five risk factors (peripheral fracture,
hip fracture of a relative, nicotine abuse, multiple
falls, immobilisation). This new more complicated
scheme was introduced in order not to overtreat
patients only because of low DXA levels and to limit
costs for treatment.
Several organizations have developed helpful
guidelines for initiation of pharmacologic therapy.
All patients should be advised about non-pharma-
cologic therapy, such as physical exercise, fall pre-
vention, calcium, vitamin D, and lifestyle modifi-
cations such as avoidance of smoking and alcohol
abuse. Some may benefit from additional interven-
tions, such as balance training or hip protectors.
The main aspect is to consider the T-score values in
conjunction with the patient’s clinical profi le and to
have a good working understanding of the risks and
benefits of the therapeutic options.
13.4
Summary
With the development of highly effective drug thera-
pies osteoporosis has become a potentially treatable
disease. If diagnosed at an early stage the worst of
complications – osteoporotic fractures – may be pre-
vented. The central – but limited – role of conven-
tional radiography is the assessment of the patient’s
fracture status which bears a strong correlation with
the individual fracture risk. Once osteoporotic frac-
tures have occurred there is a high risk for future
fractures. The standard clinical parameter for osteo-
porosis today is bone mineral density, upon which
the WHO definition of osteoporosis is based and
which can readily be assessed by standard DXA
techniques. High resolution imaging modalities in
conjunction with advanced image processing tools
allow to evaluate the micro-architecture of trabecu-
lar bone quantitatively which, in the future, will help
to improve the prediction of the patient´s fracture
risk and assessment of therapeutic effects.

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 Exogenous Exposition: Asbestos 263

Exogenous Exposure: 14
Occupation and Environment
14.1 Asbestos
Roger Eibel and Dennis Nowak

CONTENTS Between 90% and 95% of all asbestos used in the

United States has been chrysotile.
The world production and use of asbestos climbed
14.1.1 Introduction 263 steadily since its commercial introduction in the late
nineteenth century and fell rapidly after documen-
14.1.2 The Special Entities 266
14.1.2.1 Pleural Effusions 266 tation of its hazards in the 1970s and 1980s. Its use
14.1.2.2 Pleural Plaques 266 has now been banned in many Western countries.
14.1.2.3 Diffuse Pleural Thickening 267 Asbestos is still mined in Russia and China, mainly
14.1.2.4 Mesothelioma 267 for local use, and in Canada, where most of the
14.1.2.5 Asbestosis 268
products is exported to Asia and Africa (American
14.1.2.6 Lung Cancer 269
14.1.2.7 Screening 270 Thoracic Society 2004).
14.1.2.8 Conclusions and Recommendations 271 Today, asbestos remains a problem in at least the
following settings (American Thoracic Society
References 272 2004):
 In some industrialized countries in Asia und for-
merly belonging to the Eastern bloc
 Older workers
 In certain occupations managing the remaining
14.1.1 hazard, such as building and facility mainte-
Introduction nance
 Asbestos abatement operations, removing insu-
Asbestos is a general term for a heterogeneous lation and other asbestos-containing products
group of hydrated magnesium silicate minerals that  Renovation and demolition of structures con-
have in common a tendency to separate into fibers taining asbestos
(Committee on Nonoccupational Health Risks
1984). Asbestos fibers have great tensile strength, The great problem in using asbestos was the lack
heat resistance, and acid resistance, varieties are of awareness of the long latency period and the
also flexible (American Thoracic Society 2004). interval between initial exposure and subsequent
The traditionally defined six minerals include: biological consequences.
 Chrysotile asbestos Nowadays, there is widespread anxiety among
 The amphiboles: crocidolite, amosite, anthophyl- the public, based on the misunderstanding that
lite, actinolite, and tremolite a casual exposure, such as walking by a demoli-
tion site or entering a schoolhouse that is being
R. Eibel, MD repaired, represents a significant health risk to
Chief, Department of Radiology, HELIOS Clinics Schwerin, the passer-by or to the school child (Cugell and
Teaching Hospitals of the University of Rostock, Wismarsche Kamp 2004).
Strasse 393–397, 19049 Schwerin, Germany In general, asbestos related diseases are gener-
D. Nowak, MD
Professor, Institute and Outpatient Clinic for Occupational,
ally dose dependent. However, the dose-response-
Social and Environmental Medicine, University of Munich, relationship for asbestosis and lung cancer is much
Ziemssenstrasse 1, 80336 Munich, Germany more clear-cut than for pleural plaques (Cleemput
264 R. Eibel and D. Nowak
et al. 2001) and malignant mesothelioma (Goldberg
and Luce 2005).
In the United States, the initial exposure limit was
established in 1971 at 5 fibers per cubic centimetre,
reduced to 2 fibers in 1976, to 0.5 fibers per cubic
centimetre in 1983, and to 0.1 in 1994 (Brownson
1998).
Because of difficulties in quantifying exposure,
the variable persistence of asbestos fibers in tissue,
differences in elapsed time from first exposure to
the manifestations of asbestos-related disease, and
interindividual differences in susceptibility to dis-
ease, the existence of “safe” exposure level remains
highly questionable (Cugell and Kamp 2004). But
low-level exposure, as encountered in public build-
ings, probably does not represent a measurable
additional health hazard beyond what is incurred
breathing outdoor air (Health Effects Institute
1991; Mossman et al. 1990).
Asbestos fibers enter the body either by inhala-
tion, ingestion, or skin contact. But for the public at
large, asbestos is harmless if swallowed. Essentially
all adverse effects on health are due to inhalation
(Fig. 14.1.1). Chrysotile fibers are less harmful than
the amphiboles, in part because they are broken
down and removed from the lung (Roggli and
Sanders 2000). Short asbestos fibers can be success-
fully phagocytized and incorporated into lysosomes.
This phenomenon may explain in part why long thin
fibers, i.e., > 8 µm in length, are more carcinogenic
after inhalation or injection into the pleura or peri-
toneum of rodents (Mossman et al. 1990; Kamp and
Weitzman 1999).The different types of exposure
have been categorized as:
 Primary (occupational)
 Household (family members of the occupation-
ally exposed) (Sider et al. 1987)
Fig. 14.1.1. Ferruginous bodies (coated asbestos fibres) in
the lung
 Bystander (those working near insulation install-
ers, for example)
 Environmental (naturally occurring sources)
(Fig. 14.1.2)
Frequently the diagnosis of asbestos-related dis-
eases must be made in a particular person without
the aid of pathology. That is, asbestosis must often
be diagnosed on clinical grounds by the use of (Ross
2003):
 Appropriate exposure/history
 Latency
 Signs and symptoms
 Chest radiograph and CT scan
 Lung function tests
Every point has its drawbacks. For example, the
chest radiograph is problematic when trying to
diagnose minimal or mild disease. A lot of workers
were unaware that they were exposed 30 and more
years ago.
It is therefore extremely important:
 To take a very detailed and gapless exposure his-
tory covering the time since leaving school
 To refer to trade names of various asbestos prod-
ucts (e.g., Eternit, Marinite, Navelite), since work-
ers are frequently unaware that their working
material contained asbestos
 To show pictures of particular working condi-
tions where asbestos contamination was typical
but frequently unknown
Restriction in lung function testing is too non-
specific to be used as a sole diagnostic tool and is
relatively insensitive for the detection of mild fibro-
sis.
Asbestos-related diseases can be summarized as
follows:
 Pleura
– Pleural effusion
– Pleural plaques, circumscribed, with / without
calcification
– Diffuse pleural thickening and diffuse pleural
fibrosis
– Mesothelioma
 Lung parenchyma
– Fibrosis (asbestosis)
 Lung cancer
 Laryngeal cancer
 Exogenous Exposition: Asbestos 265

a b

c d

e f

Fig. 14.1.2. a Asbestos milling. b Spraying of asbestos cement with extremely high fiber concentrations. c Asbestos exposure
in the construction industry. d Textile asbestos exposure in the textile industry. e Asbestos exposure in the construction
industry. f Asbestos exposure in a car repair shop while cleaning brake pads (courtesy of Ernst Hain, Hamburg-Harburg)
266 R. Eibel and D. Nowak
14.1.2
Special Entities
14.1.2.1
Pleural Effusions
Pleural effusions have a shorter latently period
than the other above-mentioned asbestos related
diseases. They can occur within 1 year to t20 years
after first exposure (Epler et al. 1982; Hillerdal
et al. 1987). They vary from a completely asymptom-
atic event, with either total resolution or a blunted
costophrenic angle as the only residual evidence, to
an active, inflammatory pleurisy, with fever, pleu-
ritic type pain, and a substantial accumulation of
bloody pleural fluid. The fluid usually conforms to
the criteria of Light (Light 1995) for an exudate.
Frequently, considerable restrictive lung function
impairment persists.
Computed tomography (CT) and ultrasound
are much more sensitive for visualizing pleural
fluid than chest radiography. To differentiate pleu-
ral effusions from solid tissue magnetic resonance
imaging (MRI) can be of particular value (Knisely
et al. 2000). Chemical, bacteriologic, and cytologic
analyses are often necessary, to find the reason of
an effusion. And, important to take into account,
effusions are frequently in the early stage of meso-
thelioma, and can be very difficult to distinguish
from a benign effusion. So, unless the findings are
diagnostic, and in the absence of contraindications,
a biopsy of the pleura should be performed (Cugell
and Kamp 2004). Asbestos pleural effusions may be
the pathophysiological starting point for rounded
atelectasis.
14.1.2.2
Pleural Plaques
Pleural plaques are circumscribed areas of fibrous
tissue limited to the parietal pleura and considered
as benign markers of prior asbestos exposure. They
are often incidental chest radiographic findings and
frequently overlooked or not actively addressed in
radiological reports (Fig. 14.1.3). On the other hand,
small plaques are often difficult to detect, particular
if the radiographic technique is suboptimal and in
obese patients. Pleural plaques were defined by CR
or CT as circumscribed, pleural areas of opacity
with well-demarcated edges (Remy-Jardin et al.
Fig. 14.1.3. A 72-year-old male. 30 years of asbestos expo-
sure in the construction industry. Plain fi lm. Pleural plaques
at the lateral (white arrows) and diaphragmatic pleura (black
arrows) seen en face and in profi le
2004). Ultrasound has no role in identifying pleural
plaques, and again, CT and especially high-resolu-
tion CT (HRCT) is the method of choice in evaluation
of the pleura (Fig. 14.1.4). A substantial proportion
of plaques can be identified with CT, not detected on
plain fi lms. And on the other hand, plaques reported
by radiologist using plain fi lms may not be found
on CT or on autopsy (Ren et al. 1991). Differential
diagnoses, especially on plain fi lms are:
 Subpleural fat deposits
 Old rib fractures
 Muscle bundles
MRI can be helpful in identifying rounded atelec-
tasis (Knisely et al. 2000).
The dose-response relationship for plaque for-
mation is highly variable, but they are found with
increasing frequency with advancing age (Sargent
et al. 1984).
Using the classification system for rating chest
radiographs, known as the International Labor
Organization system (ILO), pleural plaques on the
front or rear thoracic surface are designed en face
(face on) plaques. The thickness and extension of
plaques on the lateral chest wall must be measured.
Calcium deposition occurs in pleural plaques of long
standing. It is unusual among workers with a < 30-
year interval from time of first exposure (Epler et
al. 1982).

a b
Fig. 14.1.4. a Same patient as in Fig. 14.1.3. Calcified and non-calcified pleural plaques at the lateral and mediastinal (arrows)
parietal pleura. b Calcified and non-calcified pleural plaques (chest wall and diaphragmatic pleura) (arrows)
Limited or circumscribed pleural plaques have
no clinically significant adverse impact on pulmo-
nary function (Jones et al. 1988). Furthermore,
plaques do not increase the cancer risk, but plaques
are markers of asbestos exposure, and asbestos is a
recognized carcinogen (Cugell and Kamp 2004). In
other words, the risk of lung cancer is not restricted
to workers with pleural plaques (Welch 2003).
14.1.2.3
Diffuse Pleural Thickening
Diffuse pleural thickening is defined as a contiguous
sheet of pleural thickening that was more than 5 cm
in extent along the pleural surface on transverse
CT images, more than 8 cm in extent on craniocau-
dal CT images, and more than 3 mm thick (Remy-
Jardin et al. 2004). Diffuse pleural thickening is no
marker of asbestos exposure and can has multiple
origins.
Unlike pleural plaques, it can cause significant
restrictive ventilatory impairment (Jones et al. 1988;
Schwartz et al. 1990; McGarvin et al. 1984). The
hallmark of diffuse pleural thickening is involve-
ment of the visceral pleura, with blunting of the cos-
tophrenic angle the most frequent radiologic clue.
Plaques do not extend into this region. Copley et
al. (2001) found an inverse relationship of the area
and thickness of abnormal pleura, using CT scans
with the FVC.
With ILO, the extension along the chest wall and
the thickness of the diffuse pleural thickening can
Exogenous Exposition: Asbestos 267
be classified. Nevertheless, with CT the detection of
these pleural abnormalities has a better sensitivity
and specificity and nowadays, a CT classification
system had been introduced for the description of
pleural findings (Hering et al. 2004).
14.1.2.4
Mesothelioma
Mesotheliomas have an average lag time of 25–
40 years. Extremes are seen around 10 and more
than 50 years. They are signal tumours for asbes-
tos exposure. This is true for pleural, peritoneal
and manifestations at the tunica vaginalis testis.
Exposure to amphibole fibers is much more likely
to produce a mesothelioma than chrysotile fibers
(McDonald et al. 1996). As many as 10%–20% of all
mesotheliomas are of peritoneal origin (Berry 1981;
Mossman et al. 2002). Again, a CT scan provides
much greater sensitivity than plain fi lms for iden-
tifying fluid and visualizing pleural-based masses,
lymph nodes, blood vessels, and lung parenchyma.
MRI may be useful for distinguishing between chest
wall, pleural, and peripheral parenchymal lesions
(Müller 1993). Positron emission tomography
(PET) scanning can be helpful for differentiating
benign from malignant effusions, and identifying
nodal or other metastases that are not otherwise
apparent (Eibel et al. 2003).
Three histologic types with the distribution
according to a study from Hillerdal (1983) can be
differentiated:
268 R. Eibel and D. Nowak
 Epitheloid (50%)
 Sarcomatous or mesenchymal (16%)
 Mixed (34%)
Comparably favorable factors are the following:
 No more than 5% body weight loss
 Tumor confined to the parietal pleura
 Epitheloid cell type
 Tumor confined to the ipsilateral pleura, lung,
and pericardium
The diagnosis of pleural mesothelioma is difficult
and often delayed for 6–8 months after the initial
symptoms (Senyigit et al. 2000). The most frequent
presenting symptoms of malignant pleural mesothe-
lioma (MPM) are dyspnea and nonpleuritic chest pain
(Marom et al. 2002). Unfortunately, most patients
present with advanced-stage disease and die within a
year of presentation (De Pangher et al. 1993; Hern-
don et al. 1998; Ong and Vogelzang 1996). However,
the interest in pleural tumors has markedly increased
in recent years because of the growing incidence of
MPM in Europe and in the US (Connelly et al. 1987;
Peto et al. 1999) and because of new therapeutic strat-
egies that have recently been proposed. Among these
are multimodality oncologic treatments combining
surgery, radiotherapy, and chemotherapy, and experi-
mental treatments such as immunotherapy, gene ther-
apy, and photodynamic therapy (Sugarbaker et al.
1999; Sterman et al. 1998; Takita and Dougherthy
1995; Boutin et al. 1994).
14.1.2.5
Asbestosis
CT features of asbestosis include five major abnor-
malities that can be depicted when the subject is
scanned in the prone position:
 Thickened interstitial short lines in the subpleu-
ral region such as septal and intralobular lines.
Septal lines are short and discrete nonbranch-
ing lines, whereas intralobular lines appear
as Y-shaped branching structures. Both lines
can be detected in the subpleural parenchyma
(Fig. 14.1.5).
 Curvilinear subpleural lines were defi ned as
linear areas of opacity within 1 cm of the pleura
and parallel to the inner chest wall.
 Areas of ground-glass opacity were defined as
areas of increased attenuation in which the ves-
sels and the bronchial walls remained visible.
Fig. 14.1.5. A 77-year-old male with 8 years of asbestos
exposure. HRCT in prone position. Subtle changes in the
subpleural posterior areas of the lower lobes with small
pleuropulmonary bands, fi ne reticular and linear patterns
(arrows)
 Areas of ground-glass opacity could be accom-
panied by bronchiectasis – that is, abnormally
depicted airways either 1 cm of the parietal
pleura or abutting the mediastinal pleura.
 Honeycombing is defi ned as an area of lung
containing cystlike spaces with thickened walls
(Remy-Jardin et al. 2004)
Additional CT features that are directly related to
asbestos exposure are:
 Parenchymal bands, which were defi ned as linear,
2–5-cm-long areas of opacity extending through
the lung to contact the pleural surface.
 Rounded atelectasis, which were defined as a mass
near an area of pleural thickening, with a partial
interposition of lung parenchyma between the
pleura and the mass and a visible “comet tail”
of vessels and bronchi sweeping into the lateral
aspect or the medial and lateral aspects of the
mass (Figs. 14.1.6 and 14.1.7).
Further additional findings, not directly related
to asbestos exposure consist of smoking-induced
abnormalities and including emphysema (Copley
et al. 2007), bronchial wall thickening, and noncal-
cified lung nodules.
Although thin-section CT is more sensitive
than radiography in the detection of early asbes-
tos-related pleural and parenchymal changes and
the correlation between thin-section CT findings
and pathologic findings has been established, CR
remains the main radiologic tool for the detection

Fig. 14.1.6. Overview of patterns in HRCT
of interstitial lung diseases. 1 interlobu-
lar/septal thickening; 2 pleuropulmonary
(parenchymal) bands; 3 subpleural curvi-
linear lines; 4 honeycombing; 5 bronchi-
ectasis (signet ring sign); 6 centrilobular
lines/branching; 7 bronchioloectasis; 8 tree
in bud; 9 rounded atelectasis; 10 interlobu- 13
lar/septal nodules; 11 centrilobular nodules
(clusters); 12 thickening of the broncho-
15
vascular bundle in the centre of the lobu-
lus; 13 subpleural pearls/pseudoplaques;
14 peribronchovascular nodules/interface
sign; 15 interstitial micronodules; 16, 17
alveolar, centrilobular nodules (courtesy of
Dr. Hering, Dortmund)
Fig. 14.1.7. Same patient as in Fig. 14.1.3. HRCT. Fine sub-
pleural lung fibrosis not reversible in prone position (not
shown here). Please note the ground-glass appearance adja-
cent to the pleural plaques (arrows)
of these lesions, with CT reserved for problem solv-
ing (Aberle and Balmes 1991). In former years,
both the expense and the time required to perform
CT of the entire thorax have made this examination
impractical for examining large asbestos-exposed
populations (McLoud 1988). In addition, typical
chest CT protocols have been associated with rela-
tively high radiation doses to patients, which have
raised concern about the potential for induced
malignant disease, particular in screening settings
(Remy-Jardin et al. 2004).
The introduction of low-radiation-dose scan-
ning techniques has facilitated renewed interest in
Exogenous Exposition: Asbestos 269
10 1
11 2
12
3
14
4
5
9
16
8
7 6
17
the potential usefulness of CT as a fi rst-line imag-
ing tool (Remy-Jardin et al. 2004). The advent of
multi-detector row spiral CT has generated addi-
tional possibilities for screening in terms of both
low radiation dose requirements and high spatial
resolution. In a recent study Remy-Jardin et al.
(2004) could conclude that low-dose multi-detec-
tor row spiral CT enables the accurate detection of
asbestos-related disease and the concurrent search
for malignant asbestos-related processes of the
lungs and pleura. With use of low-dose protocols,
negative low-dose CT results were found to be suffi-
cient to exclude asbestos-related pleuropulmonary
diseases.
14.1.2.6
Lung Cancer
Overall, the Nicholson study projected that nearly
500,000 workers would die from asbestos related
cancers between 1967 and 2030; deaths from asbes-
tosis are above and beyond this number. The poor
prognosis of lung cancer (5-year survival 12%) is
attributable to the lack of efficient diagnostic meth-
ods for early detection and the inability to cure meta-
static disease. By contrast, when detected at an early
stage (I–II) as radically resectable disease, the 5-year
survival can be as high as 50%–70% (Flehinger
et al. 1992; Nesbitt et al. 1995; Strauss 1998). All
major types of lung cancer are caused by asbestos.
Numerous studies show that there is a dose-response
relationship between exposure to asbestos and the
risk of lung cancer, with increasing exposure leading
270 R. Eibel and D. Nowak
to increasing risk of disease. Asbestosis is a sur-
rogate measure of exposure, but it is important to
know that asbestosis is not a necessary intermedi-
ary for development of asbestos related lung cancer
(Welch 2003).
The Helsinki Criteria establish an exposure level
of 25 fiber-years, or the equivalent exposure using
an occupational history, as a level of exposure that
significantly increases the risk of lung cancer. Sev-
eral European countries have established this or a
similar level of exposure as the criterion to be used
for compensation of lung cancer in asbestos exposed
workers (Welch 2003).
Smoking and asbestos multiply the lung cancer
risk conferred by the other:
 Non-smoking asbestos workers were five times
more likely to die from lung cancer.
 Smokers not exposed to asbestos were approxi-
mately 10 times more likely to die from lung
cancer.
 Asbestos workers who smoked were more than 50
times more likely to die from lung cancer.
 Asbestos workers who stopped smoking demon-
strated a sharp decrease in lung cancer mortal-
ity.
14.1.2.7
Screening
In the USA, from 1940 to 1979, 27.5 million work-
ers were occupationally exposed to asbestos in
shipyards, manufacturing operations, construc-
tion work and a wide range of other industries and
occupations, 18.8 million of these having high levels
of exposure. As a result hundreds of thousands of
workers and their family members have suffered or
died from asbestos-related cancers and lung disease,
and more than a million more cases are expected.
Because of the long lag between exposure and the
development of cancer or other asbestos diseases,
the worldwide asbestos disease epidemic has not
reached its peak, and will be with us for decades
(Welch 2003).
In 2000, the Association of Occupational and
Environmental Clinics (AOEC) developed criteria
for medical screening programs for asbestosis and
related asbestos-related diseases; these principles
apply equally also to screening for silicosis and
related diseases. Medical screening is defined as a
search for previously unrecognized disease, when
finding the disease can lead to a benefit. In particu-
lar, occupational programs are designed to detect
work-related disease at an early stage, when treat-
ment or removal from exposure can improve the
outcome of that disease. Three types of prevention
can be differentiated:
 Primary prevention is reduction or elimination
of hazardous exposures.
 Screening is called secondary prevention, when
hazardous exposures have not been eliminated.
 Tertiary prevention is essentially medical care
and rehabilitation of disease, when it cannot be
reversed after diagnosis.
Some key principles should underlie all medical
screening programs:
 The test used should be selective, and chosen to
identify a specific disease.
 There must be some effective action that can be
taken if the screening test is positive, such as
removal from exposure or medical treatment.
 Adequate follow-up is critical, and further diag-
nostic tests must be available, accessible, and
acceptable to the individual screened. Follow-
up also entails action to reduce or eliminate the
hazard.
 Individuals who have been screened should
receive test reports and interpretations of those
results.
 The screening tests used should have good reli-
ability and validity.
 The benefits of the screening program should
outweigh the costs (Welch 2003).
The screening for asbestosis has several clear
public health and medical benefits:
 Identification of occupations and industries
where excess exposure still occurs, so that expo-
sure reduction can occur.
 Implementation of smoking cessation programs.
 Identification of individuals at heightened risk
from other occupational exposures (Welch
2003).
However, screening is only conducted as a pre-
liminary step in determining the presence of asbes-
tos-related disease. Therefore AOEC supports the
following statements:
 Screening on the basis of CR and work history
alone identifies possible cases but does not itself
provide sufficient information to make a firm
diagnosis, to access impairment or to guide
patient management.

 An appropriate screening program for asbestos-
related lung disease includes:
– Properly chosen and interpreted CR
– A complete exposure history
– Symptom review
– Standardized spirometry
– Physical examination
 Programs should also include:
– Smoking cessation interventions
– Evaluation for other malignancies
– Evaluation for immunization against pneumo
coccal pneumonia
– Timely physician disclosure of results to the
patient
– Appropriate medical follow-up
– Patient education (Welch 2003)
So far, screening using conventional methods
like CR and sputum cytology has mostly been con-
sidered ineffective; randomised trials have failed
to show a significant reduction in mortality rate.
This is most probably due to methodological prob-
lems and to the inadequacy of conventional CR
as a screening technique (Fontana et al. 1986;
Melamed et al. 1984). However, recent studies
using low-dose spiral CT techniques report more
encouraging results: the cancer detection rate
varied from 0.35% to 2.7%, with most tumours
being small, radically resectable, peripheral ade-
nocarcinomas (stage I–II) (Henschke et al. 1999;
Sone et al. 1998; Kaneko et al. 1996). Tiitola et
al. (2002) conducted a CT screening for lung cancer
in a high-risk population. A total of 602 workers
(38–81 years, 97% smokers) with asbestos-related
occupational disease were screened using spiral
CT and chest radiography and they detected suspi-
cious lung nodules in 18.4% of the study popula-
tion. Five lung cancers and one peritoneal meso-
thelioma were found. Kaneko et al. (1996) found
abnormalities in 17% of their study population, the
ELCAP-study (Henschke et al. 1999) in 23%, and
Yoshimura et al. (1999) in 22%. Recently, Das et
al. (2007) reported on a prevalence of 4.28% (i.e. 8
in 187) lung cancer in a high-risk asbestos-exposed
cohort using low-dose MDCT.
On the other hand, the great number of false posi-
tive findings is a fundamental problem in lung cancer
screening. An international standard for follow-up
examinations would be beneficial. Henschke et al.
(1999) classified nodules as benign, if no growth was
noted over 2 years. According to Yankelevitz et al.
(1999), however, malignant growth can be detected
Exogenous Exposition: Asbestos 271
on an early repeat CT within 30 days in tumours as
small as 5 mm.
To mention briefly the cost-effectiveness, Miet-
tinen (2000) found out that CT-based screening for
lung cancer, suitably specified, can be presumed to
save lives at a cost lower than the 10,000 USD per
saved life-year and can be effective enough, to jus-
tify its cost. If diagnostic algorithms are used which
have been applied in published feasibility studies,
the mean percentage of invasive diagnostic mea-
sures revealing benign lesions is about 34% and thus
below those obtained in, e.g., breast cancer screen-
ing trials. Currently, randomized controlled studies
involving low dose CT in about 100,000 subjects are
on the way. Around the year 2010 we will be able to
define whether or not lung cancer screening in high
risk populations including new techniques and stan-
dardized algorithms yields a decrease in mortality
(Nowak et al. 2005).
14.1.2.8
Conclusions and Recommendations
 Despite international and national actions, occu-
pational exposure to asbestos in industrialized
countries continues to be a major cause of mor-
bidity and mortality from both lung cancer and
mesothelioma. Furthermore, benign asbestos-
related diseases can result in loss of work ability,
loss of years of healthy life and quality of life for
workers and their families.
 Screening for asbestos-related diseases with
respect to imaging studies refers to the visual-
ization of different benign pleural and pulmo-
nary abnormalities and the above mentioned two
malignancies. And as a consequence, a method
has to be chosen, that can detect pleural effusion,
pleural plaques, small pulmonary nodules as well
as well as fine lung fibrosis and mesothelioma.
Currently, only thin-section spiral CT (slice thick-
ness of 1–2 mm, 120 kV, 120 mA but low-dose
seems to be possible, two window settings, and
matrix of 512 pixels) has an acceptable sensitivity
for all these abnormalities. MRI, PET and ultra-
sound can be worthy to answer special questions,
but cannot be recommended as screening tools.
CR is commonly used to monitor for pneumoco-
niosis among workers exposed to asbestos. In gen-
eral, its benefit for the early identification of lung
cancer has not been demonstrated due to its low
sensitivity and specificity (Tossavainen 2000).
272 R. Eibel and D. Nowak
 Medical screening: periodic use of standard
sputum cytology has been evaluated for the mass
screening for lung cancer and was shown to be of
limited value. Bronchoscopy, including autofluo-
rescence endoscopy, is impractical as a screen-
ing tool because of its cost, availability, and low
patient acceptance because of the invasiveness of
the procedure (Tossavainen 2000). Additional
use of serum markers such as mesothelin-related
peptides (Scherpereel et al. 2006) and osteo-
pontin (Pass et al. 2005) seems promising.
 Controlled screening programs for high-risk
asbestos-exposed workers should take into con-
sideration the following known risk factors or
risk markers of lung cancer:
– Cumulative exposure to asbestos of any fiber
type
– Latency time from first exposure to asbestos
(over 10 years of latency is needed before the
risk increases significantly)
– Cumulative exposure to tobacco (both current
and former smokers have increased risk; how-
ever, risk diminishes after smoking cessation)
– Age
– Presence of abnormal radiographic findings or
the impairment of lung function
– Exposure to other occupational lung carcino-
gens, such as radon, silica or polycyclic aro-
matic hydrocarbons (Tossavainen 2000).
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 Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 275

Exogenous Exposition 14
14.2 Heavy Smokers
14.2.1 CT Screening for Lung Cancer for High-Risk People
Claudia I. Henschke, Matthew Cham, and David F. Yankelevitz

CONTENTS 14.2.1.1
Background

14.2.1.1 Background 275 Screening for lung cancer in high-risk people has
been widely accepted for those exposed to asbestos
14.2.1.2 Screening for a Cancer: Its Essence 275
in the United States, Germany, France, and Finland
14.2.1.3 Evaluation of CT Screening for Lung (Straif and Silverstein 1997; Koskinin et al.
Cancer 276 1996; Frimat et al. 1999). The recommendations
thus far have been for screening with chest radi-
14.2.1.4 Diagnostic Performance 277
ography, although computed tomography (CT) is
14.2.1.4.1 Proportion Having a Positive Result of
the Initial CT Test 278 also being considered. In 2000, the Finnish Insti-
14.2.1.4.2 Proportion of Screen-Diagnosed tute of Occupational Health sponsored a meeting
Cases 281 to discuss the updating of these screening recom-
14.2.1.4.3 Proportion of Cases by Relevant mendations (Finnish Institute of Occupational
Prognostic Indicators 281
14.2.1.4.4 Proportion of Cases Resulting in a Health 2000). They invited the lead author of the
Diagnosis of Malignancy after a research study of 1000 high-risk people started in
Biopsy 281 the United States (Henschke et al. 1999, 2001) and
14.2.1.4.5 Summary of Diagnostic a mass screening study in Japan (Sone et al. 1998,
Performance 281
2001) to present their results. These two studies
14.2.1.5 Genuineness of Diagnoses 281 showed that CT is markedly superior to chest radi-
ography in detecting small, early lung cancers and
14.2.1.6 Prognostic Performance 282 it has long been established that resection of early
small lung cancers markedly improves the cure rate
14.2.1.7 Indication for Screening 282
over that of late stage lung cancer (Mountain 1997;
14.2.1.8 Summary 283 Inoue et al. 1998). Since then several studies in high-
risk occupationally exposed people have found CT
References 283 screening to be useful (Tiitola et al. 2002; Minniti
et al. 2005; Muravov 2005).
In this chapter we present the ELCAP paradigm
for the evaluation of the usefulness of CT screening
for a disease and the results to date.

C. I. Henschke, PhD, MD, FCCP 14.2.1.2

M. Cham, MD Screening for a Cancer: Its Essence
D. F. Yankelevitz, MD
Department of Radiology, New York Presbyterian Hospital –
Weill Cornell Medical Center, 525 East 68th Street, New It is commonplace to think of screening for a cancer
York, NY 10065, USA as the application of a single diagnostic test to an
276 C. I. Henschke, M. Cham, and D. F. Yanekelvitz
asymptomatic person and to think that this testing
is supposed to reduce mortality from the cancer.
The diagnostic test is viewed as an ‘intervention,’
and it is supposed to have ‘effectiveness’ in that it
should prevent the cancer’s fatal outcome. In our
view, it is this viewpoint and its consequent meth-
odology to screening research that has led to much
of the controversy surrounding screening, not only
in screening for lung cancer but for other cancers as
well (Jackson 2002; Miettinen et al. 2002a,b).
At variance with this view, the researchers of the
Early Lung Cancer Action Project (ELCAP) hold that
a sharp distinction is to be made between diagnos-
tic testing and the subsequent intervention which
follows upon the early diagnosis (Henschke et al.
1994, 2002). A diagnostic test provides informa-
tion about the person undergoing it but without an
associated intervention, the test has no effect on the
subsequent course of health. An intervention, by
contrast, is intended to change the course of health
for the better, to have effectiveness. For example, the
use of chest radiography did not change the typical
course of pulmonary tuberculosis; rather, the inter-
vention with streptomycin did (Hill 1990).
The ELCAP viewpoint defi nes screening as the
pursuit of early diagnosis, which starts with an
initial test and proceeds along a well-defi ned path
(screening regimen) to the diagnosis of cancer. The
diagnosis which results from this pursuit is early
in the meaning that, at the time of diagnosis, the
cancer is still in the latent, asymptomatic phase of
its course, and also it is hoped that it is still local-
ized and, thereby, curable. Ultimately, the aim is
to determine whether early intervention following
early diagnosis provides the hoped-for greater cura-
tive effectiveness relative to later intervention upon
prompting of symptoms, or to determine how often
the pursuit of early diagnosis leads to the prevention
of the cancer’s fatal outcome. To us, the real issue is,
thus, the quantitative determination of the number
of deaths that can be prevented. We call the ELCAP
study design a ‘diagnostic-prognostic’ design as it is
not simply a ‘cohort’ or ‘observational’ design but a
trial with two distinctive components, the diagnos-
tic one and the interventive one, each component
to be evaluated separately. As for the interventive
component, alternative designs, including random-
ized ones can be used, depending on the questions
which need to be answered.
Understanding of the ultimate usefulness of CT
screening requires understanding whether the vari-
ous subtypes of diagnoses resulting from the screen-
ing regimen at issue are genuine; and even the man-
agement of the diagnosed cases presupposes the
understanding of those matters, as in the end, the
ultimate usefulness – and adverse consequences – of
the screening depend on how these cases are actu-
ally managed. Specifically, we need to address the
genuineness of the screen-diagnosed cancer, that is
whether it would lead to death if not resected, partic-
ularly in cases of Stage I. Next we need to determine
how often such a genuine case is curable. In other
words, insofar as Stage I (pre-spread detection) is
achieved and early intervention is applied, we need
to determine how frequently death from an other-
wise fatal cancer is avoided; and on the community
level, by how much the mortality from the cancer is
reduced by such screening-and-intervening.
Recommendation for or against screening requires
knowledge inputs beyond the central one, the gain
in curability of lung cancer considered above – or
its corresponding reduction in case-fatality rate.
Principal among these further considerations are
the two that have critical bearing on the definition
of the indication for the screening: the person’s risk
for lung cancer (in the near future), and his/her life
expectancy (when spared of death from lung cancer).
These two inputs bear on when, if ever, to begin the
screening on a given person; and insofar as it has
been initiated, when to discontinue it, including its
cost. Indeed, the decision about screening for lung
cancer requires consideration of its benefits specific
to a particular person at a particular time.
14.2.1.3
Evaluation of CT Screening for Lung Cancer
The ELCAP report on baseline CT screening for
lung cancer (Henschke et al. 1999) led to consid-
erable public (Grady 1999) and professional inter-
est in the practice of CT-based screening for lung
cancer. Suddenly, screening for lung cancer became
a hot topic with researchers initiating projects to
study it, the public demanding it, and medical insti-
tutions offering it. The demand for information
on screening led us to hold the First International
Conference on Screening for Lung Cancer in 1999,
to which all those already performing screening
or wishing to start it were invited (I-ELCAP 1999).
These conferences were an outgrowth of the already
extensive role of ELCAP in helping other investiga-
 Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People
tor groups at the University of Muenster in Ger-
many (Diederich et al. 2002), Hadassah Medical
Center in Israel (Shaham et al., in press), Univer-
sity of South Florida (Moffitt Cancer Center) in the
United States, the Mayo Clinic in the United States
(Swensen et al. 2002), the University of Navarra
(Bastarrika et al. 2005) in Spain and Hirslanden
Lung Centre in Switzerland to initiate their research
projects patterned after the original ELCAP. By
2005, 13 such semi-annual conferences have been
held. These conferences led to the formation of the
International (I)-ELCAP consortium in 2000 whose
members have a shared set of principles, common
protocol, and centralized management system for
pooling of the data to answer the critical questions
about CT screening for lung cancer, including evalu-
ation and integration of new diagnostic approaches
as well as advances in alternative interventions for
these early lung cancers.
I-ELCAP’s goal is to assess the effectiveness of CT
screening in preventing deaths from lung cancer. It
asserts that to determine the effectiveness of screen-
ing, the particular regimen of screening as to how
early diagnosis of lung cancer is to be pursued must
be specified. The first task of I-ELCAP, thus, was to
define a potentially optimal regimen, and such a reg-
imen was adopted in 2001 (Henschke et al. 2002).
A particularly notable feature of the regimen is the
difference between the baseline and repeat screen-
ings in the definition of a positive result and the
algorithm for further work-up. In the repeat screen-
ings, the focus is on new nodules, thus growing by
definition, as the prior screen is available for com-
parison. At baseline, by contrast, such prior infor-
mation is not available and therefore it is not known
how long the nodule has existed and whether it is
growing or regressing. Although the fundamental
nature of the regimen of screening has remained
stable, it is continually updated based on emerging
information (Henschke et al. 2002, 2004; I-ELCAP
protocol – website: http://www.IELCAP.org). Poola-
bility of the data requires the use of a common regi-
men of screening, while the indications for screen-
ing (i.e., enrolment criteria) can be different for each
participating institution.
As of December 2005, 32,753 people have had
baseline screenings and they have had another
23,958 repeat screenings at 38 institutions partici-
pating in I-ELCAP throughout the world, including
the original ELCAP and its continued screenings
and its extension throughout New York State (NY-
ELCAP).
277
14.2.1.4
Diagnostic Performance
The I-ELCAP regimen starts with the initial low-
dose CT, and if the result is positive, other testing
follows along a well-thought out algorithm which
eventually leads to a (rule-in) diagnosis of lung
cancer. Assessment of growth has remained a criti-
cal part of the regimen (Yankelevitz et al. 1999,
2000; Kostis et al. 2003, 2004). Ultimately, the diag-
nosis of lung cancer derives from a biopsy of the sus-
picious nodule followed by the specimen’s reading
and interpretation. Growth and minimally-invasive
(i.e., percutaneous fine-needle aspiration) biopsy
are important components of the regimen as they
serve to limit unnecessary open surgical biopsy and
also serve to limit resection of slow-growing can-
cers which would not lead to death if left untreated.
Given the critical (and ultimate) role of pathology in
making the diagnosis, a separate pathology protocol
was developed (Vazquez et al. 2003; Vazquez et al.
[website: http://www.IELCAP.org]). Following this
protocol, all submitted slides were examined by a
five-member panel of pulmonary experts (Carter
et al. [submitted]) to determine their consensus
diagnosis according to the latest World Health Orga-
nization criteria (Travis et al. 2004).
The regimen provides recommendations for
the work-up, but the actual decision is left to each
screenee and his/her referring physician. In the I-
ELCAP approach, this does not compromise the
validity of the study as long as actions, results of
the tests, and interventions are documented for
each screenee. Adherence to the regimen, however,
does affect the performance of the regimen as it
determines the frequency of unnecessary biopsy or
surgery and the timeliness of the diagnosis which
ultimately determines how early (e.g., resectability,
stage) the cancer is diagnosed. Thus, for adequate
performance of any screening regimen, adherence
to it by the screenees and their referring physicians
is important and should be stressed in physician and
lay-community education.
Comparison of two regimens is provided by com-
paring the respective diagnostic distributions by
stage and size. Two different initial diagnostic tests
(e.g., CT and chest radiography) can be compared
by giving both tests to all participants as illustrated
by the original ELCAP of 1000 screenees (Henschke
et al. 1999). The ELCAP study (Henschke et al.
1999) as well as the Japanese study (Sone et al. 2001)
278 C. I. Henschke, M. Cham, and D. F. Yanekelvitz

clearly demonstrated the marked superiority of CT

imaging over chest radiography in identifying early
lung cancer as 85% of the earliest-stage cancers were
missed on the chest radiography. Based on this,
chest radiography was no longer performed in the
subsequent non-randomized studies.
Performance measures are useful when compar-
ing different regimens of screening. Such measures
should not depend on the risk indicators of the
participants (e.g., age, smoking history) but on the
regimen itself and we provide several such measures
below and have illustrated them in greater detail in a
previous publication (Henschke et al. 2004).

14.2.1.4.1
Proportion Having a Positive Result of the Initial
CT Test

At baseline the result of the initial CT is positive

if at least one solid or part-solid nodule 5.0 mm or
Fig. 14.2.1.2. High-resolution CT of a part-solid nodule
more in diameter or at least one nonsolid nodule
detected on baseline screening. Solid components are
8.0 mm or more in diameter is identified in lung centrally located surrounded by non-solid component.
parenchyma, or in an endobronchial location when Air-bronchograms are seen in solid component. Dia-
solid. When non-calcified nodules are identified but gnosis upon resection was adenocarcinoma, mixed
all of them are too small to imply a positive result, subtype
the result is semi-positive and calls for work-up only
in terms of the first annual repeat CT-ELCAP proto-
col – website: http://www.IELCAP.org

Fig. 14.2.1.1. High-resolution CT of a nonsolid Fig. 14.2.1.3. High-resolution CT of a part-solid nodule

nodule detected on baseline screening. Diagnosis with spiculations and pleural tag. Diagnosis upon resec-
upon resection was adenocarcinoma, mixed subtype tion was adenocarcinoma, mixed subtype
 Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 279

a b

Fig. 14.2.1.4a,b. CT of a nonsolid nodule (a), also shown in Figure 14.2.1.1 which changed into a part-solid (b) one after
4 years. This was resected and classified as an adenocarcinoma, mixed subtype

a b
Fig. 14.2.1.5a,b. CT showing growth of a nonsolid nodule. a The initial image. b The nodule 4 years later. Diagnosis upon
resection was adenocarcinoma, mixed subtype

On repeat screenings, again, the first concern with
the initial CT is to identify all non-calcified nodules,
but now regardless of size, and with special regard
for the nodules(s), if any that produced a semi-posi-
tive result on the initial CT at baseline; and now the
focus, among these, is on those that are showing
growth since the previous screen, of overall size or
the size of the solid component if previously part-
solid, or appearance of a solid component if previ-
ously nonsolidI-ELCAP protocol – website: http://
www.IELCAP.org. The result of the initial, low-dose
CT test is positive if at least one such nodule is iden-
tified.
Using these updated definitions, it occurred in
less than 15% of screenees on baseline and less than
6% on annual repeat screening.
280 C. I. Henschke, M. Cham, and D. F. Yanekelvitz

a b

c d

Fig. 14.2.1.6a–e. Contiguous high-resolution CT (HRCT) images are obtained of the small solid nodule in the left upper
lobe at the time of detection (a), and three months later (b). c,d The three-dimensional (3D) axial, sagittal, and coronal
views of the nodule. e Provides axes for comparison purposes and more clearly demonstrates growth. The calculated volume
doubling time was 120 days. Subsequent fi ne needle aspiration biopsy resulted in a diagnosis of adenocarcinoma, mixed
subtype. and this was confi rmed by histologic diagnosis at the time of resection
 Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People
14.2.1.4.2
Proportion of Screen-Diagnosed Cases
Screen-diagnosed cases are classified as baseline
or annual repeat cancers according to the screen-
ing cycle in which the nodule is first identified,
regardless of when the diagnosis is actually made.
A screening cycle starts with the performance of the
initial test including any diagnostic work-up and
ends before the next routinely scheduled rescreen-
ing. Any case of cancer diagnosed outside the regi-
men is called an interim-diagnosed cancer and is
attributed to the cycle of screening during which it
is diagnosed.
The proportion of screen-diagnosed cases was
more than 95% in the baseline cycle and 98% in
repeat cycles of screening.
14.2.1.4.3
Proportion of Cases by
Relevant Prognostic Indicators
The frequency distribution of the cases by relevant
prognostic factors (e.g., stage, size, histology) are
important performance measures. In terms of stage,
the critical determination as to treatment depends
on the pre-surgical stage, typically based on CT and
PET results, so it is the proportion of pre-surgical
Stage I diagnoses that is of particular interest. We
found that more than 80% of all lung-cancer diag-
noses, interim cases included, were of pre-surgical
Stage I on baseline and annual repeat screening.
Also, as expected, the median tumor size was larger
at baseline than on annual repeat.
14.2.1.4.4
Proportion of Cases Resulting in a
Diagnosis of Malignancy after Biopsy
Among the recommended biopsies according to the
regimen of screening, 94% resulted in a diagnosis
of malignancy. No lobectomies were performed for
benign disease. Thus the screening regimen turned
out to be quite successful in avoiding undue invasive
procedures, complications, and cost. On the other
hand, none of the biopsies performed outside of the
regimen’s recommendation resulted in diagnosis of
lung cancer.
281
14.2.1.4.5
Summary of Diagnostic Performance
The diagnostic performance of the I-ELCAP regimen
of screening demonstrated that further work-up can
be limited to a reasonable percentage of the cases and
result in 80% or more being of clinical Stage I and
that by following the regimen of screening, 94% of the
recommended biopsies resulted in a malignant diag-
nosis. A key performance parameter of the screening
regimen is the proportion of Stage I diagnoses, and
this proportion may be as high as 90% depending on
the adherence to the regimen of screening.
We also demonstrated that among cases of lung
cancer diagnosed in asymptomatic persons by CT
screening, there is a strong relationship between
tumor size and lymph-node status (I-ELCAP 2006).
14.2.1.5
Genuineness of Diagnoses
When a person with a screen-diagnosed case of lung
cancer dies of some other cause before having clini-
cal manifestations of lung cancer, the case is said to
be an ‘overdiagnosed’ case of lung cancer; and so is a
screen-diagnosed case that is so slow-growing that it,
even if left untreated, would not pose a risk for sur-
vival. While both are important topics to be addressed
in the context of screening, only the latter represents
overdiagnosis for us, the former being an issue of com-
peting causes of death. We address both topics, first
the proportion of screen-diagnosed cancers that are
genuine, that is, leading to death if not treated, and
secondly the issue of competing causes of death.
Potentially detracting from the apparent benefit
of CT screening is the possibility that a proportion
of the screen-diagnosed cases of lung cancer are free
of manifest metastases because they are growing so
slowly as to not lead to death if not resected. Protec-
tion against this was built into the regimen by requir-
ing assessment of growth prior to biopsy of nodules
less than 15 mm in diameter and by pathologic
review by a panel of expert pulmonary pathologists.
To supplement this, we also determined the propor-
tion of genuine clinical Stage I cases diagnosed as
a result of baseline screening as these are the most
suspect for being slow-growing. Among the cases
282 C. I. Henschke, M. Cham, and D. F. Yanekelvitz
presenting as solid nodules, all had doubling times
of less than 400 days, except for a carcinoid tumor
and the cases presenting as part-solid nodules and
nonsolid nodules, the percentage was 90% and 67%,
respectively (Henschke et al. 2006). It should be
noted that a cancer of 10 mm with a doubling time
of 400 days would lead to death from it in approxi-
mately 10 years. In the repeat cycles, the cancers are
typically aggressive ones as growth since the pre-
vious screen is integral in the concept of positive
result. For example, a newly-seen nodule of 3 mm
means that it has grown since the prior screen when
it was not visible. Assuming it had a diameter just
under the visibility threshold of 2 mm on the prior
screen, its slowest doubling time would be 200 days.
As newly seen nodules on repeat screening are typi-
cally 3 mm or larger in diameter when first identi-
fied, this means that these cancers are rapidly grow-
ing, aggressive, genuine cancers.
Further evidence was provided by the Pathology
Review Panel review of the pathologic specimens;
all diagnoses were confirmed to be genuine lung
cancers. Ultimately, evidence against overdiagno-
sis is provided by the untreated cases of lung cancer
(Henschke et al. 2003; Flehinger et al. 1992; Sobue
et al. 1992) or those in whom the recommended
biopsy and/or treatment was delayed. To date, all
those cases for which treatment was delayed, pro-
gressed, and those which were not treated, died.
Any decision about screening for a cancer needs
to consider the person’s risk of dying from causes
other than lung cancer. This is particularly relevant
for lung-cancer screening as smokers and former
smokers are also at higher risk of death from other,
competing causes, cardiovascular diseases in par-
ticular. To shed some light on the frequency of death
from a competing cause among persons who enter
into CT screening for lung cancer, we determined
the 5- and 10-year rates of death from causes other
than lung cancer in a high-risk older cohort of 2141
smokers and former smokers who had enrolled for
CT screening for lung cancer from 1993 to 2004
(Henschke et al. 2005); they were aged 60–75 years
and had a history of 30–100 pack-years of cigarette
smoking. Using Kaplan-Meier analysis, we found
that the 5- and 10-year survival rates conditional on
not dying from lung cancer were 96% (95% CI: 95%–
97%) and 91% (95% CI: 88%–93%), respectively.
Based on this analysis, older, high-risk smokers and
former smokers seeking and receiving CT screening
for lung cancer have quite a low 10-year risk of dying
from causes other than lung cancer, and early treat-
ment of screen-diagnosed cancer thus has a good
opportunity to be life-saving.
14.2.1.6
Prognostic Performance
The proportion of deaths that can be prevented by
CT screening can be estimated by the (proportion
of pre-surgical Stage I cases)×(cure rate of genuine
Stage I cases). This is a conservative estimate as it
assumes that all screen-diagnosed cases of higher
stage die. The estimated cure rate of genuine Stage I
cases of lung cancer is 95% and 96%, respectively for
baseline and repeat screening. Thus, the estimated
deaths that can be prevented are 87% × 95% = 83%
and 85% × 96% = 82%, respectively for baseline and
annual repeat screening (I-ELCAP 2005). Using,
very conservatively, the lower 95% confidence limits
for both of these two proportions, the correspond-
ing estimates for the probability of preventing an
otherwise fatal outcome of cancer for baseline and
annual repeat cycles are 76% and 68%, respectively
– still high when contrasted with the 5% (1–163,
510/172,570) or so (American Cancer Society
2005) in the absence of screening.
14.2.1.7
Indication for Screening
We performed a traditional cost-effectiveness anal-
ysis using the actual hospital costs of the original
ELCAP baseline screening and subsequent work-up,
it was found that CT screening is highly cost-effec-
tive, around $2500 per life-year saved, for smokers
and former smokers 60 years and older with a history
of at least 10 pack-years of smoking (Wisnivesky
et al. 2003; ). Others using actual data have found
similar results (Marshall et al. 2001a,b; Chirikos
et al. 2002), except for one model-based analysis
(Mahadevia et al. 2003) using unrealistic assump-
tions (e.g., a very high rate of overdiagnosis).
The decision about screening is really an indi-
vidual decision and thus should be based on the
benefit and risks to a specific person for a particu-
lar round of screening. Once this benefit and risks
is known, the individual then has to weigh the cost
 Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People
of the screening (typically $300) with its benefit in
potentially not dying of lung cancer.
The survival benefit of any contemplated round
of screening is determined by the product of the
following four probabilities: the probability P1 that
the round of screening will result in the diagnosis
of lung cancer, the probability P2 that of not dying
from some other cause in a sufficiently long period
of time, the probability P3 that the diagnosed case,
should there be one, would be genuine and of stage I
at the time of diagnosis and, finally, the probability
P4 that such a genuine case of lung cancer would be
curable by early treatment. The first of these prob-
abilities are specific to the individual at the time
while the last two depend on the regimen of screen-
ing, rather than the individual’s characteristics.
Using the I-ELCAP database, we are estimating
these probabilities (I-ELCAP 2005).
14.2.1.8
Summary
Critical for determination of the effectiveness of
screening is assessment of the diagnostic perfor-
mance of the regimen of screening and the con-
sequent curability of the screen-diagnosed cases.
Assessment of these performance measures provides
the information as to the proportion of deaths that
can be prevented by the screening.
Based on the results of CT screening efforts
throughout the world, it is clear that CT screening
provides for a significantly higher proportion of
Stage I diagnoses than screening using chest radi-
ography and thus also provides for a significantly
higher cure rate.
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 Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging 285

Exogenous Exposition 14
14.2 Heavy Smokers
14.2.2 Characterization of Lung Nodules Using Radiological Imaging
Christian Fink and Frank Berger

CONTENTS The broad clinical use of thin-section multi-

detector CT inevitably leads to detection of a large
number of pulmonary nodules. Previous lung
14.2.2.1 Introduction 285 cancer screening trials have shown that the major-
ity of all screened participants will have at least one
14.2.2.2 Morphological Characterization 285
non-calcified pulmonary nodule. At surgical biopsy
14.2.2.3 Characterization of Pulmonary Nodules approximately 50% of these indeterminate lung
Using Dynamic Imaging 286 nodules will turn out to be benign (Swensen 2000).
14.2.2.3.1 Dynamic Contrast-Enhanced CT 286 Therefore, non-invasive characterization of pulmo-
14.2.2.3.2 Dynamic Contrast-Enhanced MRI 288
nary nodules by imaging is of major importance in
14.2.2.4 Positron Emission Tomography (PET)/ the clinical work-up of incidentally detected pulmo-
CT and PET 289 nary nodules.

14.2.2.5 Conclusion 291

References 291

14.2.2.2
Morphological Characterization

14.2.2.1 A variety of morphological features of pulmonary

Introduction
A pulmonary nodule is defined as a focal round
or oval shaped pulmonary opacity which measures
less than 30 mm in diameter. A pulmonary nodule
is considered small if its largest diameter measures
10 mm or less. Also focal ground glass opacities are
classified as pulmonary nodules as they may rep-
resent small adenocarcinoma (Beigelman-Aubry
et al. 2007).
C. Fink, MD
Associate Professor, Section Chief Cardiothoracic Imaging,
Department of Clinical Radiology, University Hospital
Mannheim, Medical Faculty Mannheim – University of
Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim,
Germany
F. Berger, MD
Department of Clinical Radiology, University Hospitals –
Grosshadern, Ludwig-Maximilians-University of Munich,
Marchioninistrasse 15, 81377 Munich, Germany
nodules have been identified that together with
the clinical history are indicative of benignancy
or malignancy. For morphological characteriza-
tion of pulmonary nodules ideally a thin section
multi-detector CT with reconstruction of overlap-
ping slices is performed. Images should be recon-
structed in both, a high-resolution kernel (with
lung windowing) and a soft kernel (with medias-
tinal windowing), which are used for the evalua-
tion of the interface between the lung parenchyma
and bronchovascular structures as well as density
analysis of the lung nodule (Beigelman-Aubry et
al. 2007).
Based on their density pulmonary nodules are
classified as solid, non-solid, and mixed. Solid
nodules are most frequent. Non-solid nodules
have a density inferior to pulmonary blood vessels
and appear as focal areas of ground glass opacity.
Non-solid pulmonary nodules are most commonly
inflammatory or neoplastic. Typical examples for
286 C. Fink and F. Berger
malignant non-solid pulmonary nodules are adeno-
carcinoma and bronchioalveolar carcinoma.
Mixed nodules are characterized by a non-solid
ground glass opacity combined with a solid compo-
nent of soft tissue density. According to Yoon et al.
(2005) 90% of mixed nodules with a ground glass
component measuring 10 mm or less are malignant,
whereas only 30% of solid nodules of the same size
are malignant.
One of the most important imaging features that
can be used to distinguish benign pulmonary nod-
ules from cancer is calcification. However, up to
13% of lung cancers may show some calcification,
but this is true in only 2% of lung cancers smaller
than 30 mm in diameter (Grewal and Austin
1994; Mahoney et al. 1990). Eccentric calcification
should especially be considered as suspicious for
malignancy. A typical benign pattern of calcifica-
tion is a diffuse calcification which is typical for
old granulomatous disease. But also metastasis
from sarcomas, such as osteosarcoma or chondro-
sarcoma may be entirely calcified. Popcorn calci-
fication is typical feature of hamartoma. Unfor-
tunately, calcification is often not useful, as about
45% of benign nodules are not calcified (Winer-
Muram 2006).
The presence of fat within a pulmonary nodule is
another indicator for a benign lesion and suggests
the diagnosis of hamartoma. However, occasionally
also malignant lesions, such as a metastasis from
liposarcoma or renal cell carcinoma, may contain
fat (Muram and Aisen 2003).
The assessment of nodule margins is another
criterion which can be used for the differentiation
between benign and malignant lung nodules. A well-
defined nodule with smooth and regular margins is
more likely a benign lesion. However, about 20% of
malignant nodules may have well-defined and regu-
lar margins, the majority being pulmonary metas-
tasis (Erasmus et al. 2000). In contrast, irregular,
ill-defined or spiculated margins are more likely
malignant, although several benign lesions, such as
organizing pneumonia may have a similar appear-
ance (Beigelman-Aubry et al. 2007).
Cavitation of a pulmonary nodule is more fre-
quently a sign of malignancy, but may also be seen
in benign lesions, such as abscesses. Benign cavita-
tions tend to have more regular and thinner walls
than malignant lesions (Woodring et al. 1980).
Air bronchograms or bronchiolograms are more
commonly observed in malignant nodules than in
benign nodules (Zwirewich et al. 1991; Kui et al.
1996), and may be present in up to 55% of bronchio-
loalveolar cell carcinomas (Zwirewich et al. 1991).
The assessment of the size of a pulmonary nodule
is of major importance as the size of a nodule cor-
relates with the probability of cancer. Pulmonary
nodules measuring less than 5 mm only will be
malignant in 0.1%–1% of all cases. The prevalence of
malignancy ranges between 1% and 30% for nodules
measuring 5–10 mm and 30%–80% for nodules sized
over 10 mm (Winer-Muram 2006). If a pulmonary
nodule shows no detectable growth over a period
of 2 or more years this is commonly accepted as a
reliable indicator for benignity. As a consequence
serial follow-up studies are commonly performed
in incidentally detected nodules to rule out malig-
nancy. Especially in small nodules, however, manual
measurements are not very reliable (Jennings et
al. 2004). Another problem is that tumor growth
may be underestimated on two-dimensional mea-
surements. For example, if the diameter of a pul-
monary nodule increases by 26% this corresponds
to a volume increase of 100%. As a consequence
computer assisted diagnosis (CAD) tools with auto-
mated volumetry should preferably be used to assess
nodule growth (Marten et al. 2005) (Fig. 14.2.2.1).
A limitation of these algorithms is that adjacent
non-tumorous densities, such as inflammatory
changes, atelectasis, or scars may be included in the
measurement, thus resulting in an overestimation of
the nodule size. On the other hand, the ground-glass
component of a partly solid nodule, which has a high
frequency of malignancy, may not be detected by the
processing algorithm. For serial examinations of
tumor growth it has also to be taken into account
that tumors may undergo necrosis or cavitation, any
of which may decrease their size.
14.2.2.3
Characterization of Pulmonary Nodules
Using Dynamic Imaging
14.2.2.3.1
Dynamic Contrast-Enhanced CT
Due to tumor angiogenesis, blood flow and contrast
enhancement is usually greater in malignant than
in benign pulmonary nodules. Therefore, dynamic
contrast-enhanced CT of nodule enhancement has
been proposed for nodule differentiation.
 Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging
Fig. 14.2.2.1. Volumetry of a suspicious lung nodule of the right upper lobe using a dedicated computer-aided diagnosis
software tool (Lung Care, Siemens Medical Solutions, Forchheim, Germany)
The feasibility of dynamic contrast-enhanced
CT for the characterization of pulmonary nodules
has been demonstrated by a large number of studies
using different scanning protocols. A common find-
ing in all studies was that malignant nodules usually
showed a higher contrast-enhancement than benign
ones. This was also confirmed by a prospective, mul-
ticenter trial evaluating dynamic contrast-enhanced
CT for the differentiation of benign and malignant
pulmonary nodules (Swensen et al. 2000). In this
study absence of significant nodule enhancement
(d15 HU) was defined a negative test result for
malignancy. Of 550 studied pulmonary nodules
356 were eligible for the final analysis. Of these 171
turned out to be malignant, equivalent with a preva-
lence of 48%. The enhancement of malignant nod-
ules was found to be significantly higher than that
of benign nodules (38 vs 10 HU). With a threshold
of 15 HU the sensitivity and specificity of dynamic
contrast-enhanced CT was found to be 98% and 58%
(Swensen et al. 2000).
Unfortunately, if only the early enhancement
pattern (or wash-in phase) of pulmonary nodules
is analyzed some overlap can be expected between
the enhancement of malignant nodules and certain
benign nodules, such as active granulomas or benign
vascular tumors (Yi et al. 2004; Zhang and Kono
1997; Jeong et al. 2005). Therefore, some authors
have proposed to use both the wash-in and washout
287
characteristics of pulmonary nodules on dynamic
contrast-enhanced CT to distinguish benign from
malignant nodules. In a study by Jeong et al. 2005,
107 patients were examined with dynamic CT over
a time period of 15 min. Using a density change
of 25 HU or more during wash-in, and 5 to 31 HU
during wash-out as criteria for malignancy this
technique achieved a sensitivity, specificity, and
accuracy of 94%, 90%, and 92%, respectively.
Several studies have correlated the results of
dynamic contrast-enhanced CT to histological
parameters of tumor angiogenesis. In a study by
Yi et al. (Yi et al. 2004) in 54 indeterminate lung
nodules, a moderate positive correlation between
microvessel density and VEGF expression of lung
nodules with the peak enhancement on dynamic
contrast-enhanced CT was found. However, no sig-
nificant differences of the microvessel density of
benign and malignant lung nodules were observed.
In contrast, malignant lung nodules showed a sig-
nificantly higher VEGF expression.
Tateishi et al. (2002) evaluated the correlation
of tumor enhancement with VEGF expression and
microvessel density in 130 patients with histologi-
cal proven lung cancer. They found a significantly
higher peak enhancement of VEGF-positive tumors
than in VEGF-negative tumors. There was a signifi-
cant positive correlation (r= 0.65) between the peak
enhancement of VEGF-positive lung tumors with
288 C. Fink and F. Berger
the microvessel density. Neither the tumor enhance-
ment, nor VEGF or microvessel density showed a
correlation with the tumor size. Lymph node posi-
tive lung cancers showed a higher peak enhance-
ment, VEGF-expression and microvessel density
than lymph node negative cancers.
The correlation of angiogenesis, vascularization,
and contrast-enhancement can furthermore be uti-
lized for the assessment of tumor response to anti-
angiogenic therapy (Fig. 14.2.2.2).
14.2.2.3.2
Dynamic Contrast-Enhanced MRI
Apart from CT, dynamic contrast-enhanced MRI
has also been evaluated for the characterization
of indeterminate pulmonary nodules. Potential
advantages of dynamic MRI over CT are the excel-
lent contrast resolution, which may allow the detec-
tion of very discrete nodule enhancement, and the
smaller contrast agent bolus. In an early feasibil-
ity study, Hittmair et al. (1995) showed a stronger
and faster enhancement of malignant nodules than
benign neoplastic nodules using a 2D T1-weighted
spoiled gradient echo sequence (2D FLASH), which
was acquired before, during and up to 15 min after
injection of Gd-DTPA. However, similar to studies
using dynamic CT also a strong enhancement was
found in inflammatory or fibrous lesions.
In a subsequent study by Guckel et al. (1996) the
enhancement patterns of pulmonary nodules was
Fig. 14.2.2.2. Dynamic contrast-enhanced CT of pulmonary and mediastinal metastases from renal cell carcinoma. The
color-coded permeability map (right) shows a strong vascularization of the metastasis
compared using a dynamic snapshot gradient-echo
(GRE) sequence and a conventional T1-weighted SE
sequence. Malignant pulmonary nodules showed a
significantly higher enhancement on the dynamic
snapshot GRE images than benign lung nodules.
In contrast, static T1-weighted failed to show any
significant difference of the enhancement between
benign and malignant lung nodules.
In a more recent study Ohno et al. (2002) inves-
tigated the value of dynamic contrast-enhanced
MRI for the characterization of pulmonary nodules
using a 3D dynamic MRI technique. Concordant
to previous studies, malignant nodules showed a
significantly higher and faster enhancement than
benign nodules. Similar to the study of Hittmair et
al. (1995) the highest and fastest enhancement was
found in active inflammatory lung nodules. Over-
all, their technique had a sensitivity, specificity, and
accuracy of 100%, 70%, and 95%, for distinguish-
ing the malignant and active inflammatory nodules
from benign nodules.
Schäfer et al. (2004) evaluated 2D dynamic
contrast-enhanced MRI examinations in non-cal-
cified and fat-free solitary pulmonary nodules in
58 patients. In contrast to the study by Ohno et
al. (2002), both, the wash-in and wash-out char-
acteristics of pulmonary nodules were evaluated.
Malignant nodules showed a stronger enhancement
with a higher peak enhancement and a faster slope.
Significant washout (i.e. > 0.1% decrease of signal
intensity per second) was found only in malignant
lesions (Fig. 14.2.2.3). Sensitivity, specificity, and
 Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging
Fig. 14.2.2.3. Dynamic contrast-enhanced MRI in a patient
with adenocarcinoma of the right upper lobe. A strong and
fast contrast-enhancement of the tumor and subsequent
wash-out can be observed
accuracy for each criterion ranged between 52%–
96%, 75%–100%, and 75%–92%. When additionally
different curve types and morphologic criteria (e.g.
peripheral vs nodular enhancement) were taken in
account, the sensitivity increased to 100%.
In a study by Kim et al. (2004) contrast-enhanced
dynamic MRI and CT were compared in 23 patients
with solitary lung nodules. With both modalities,
malignant lung nodules showed a significantly
higher enhancement than benign lung nodules.
With a threshold for malignancy of 80% peak signal
intensity increase on dynamic MRI the sensitivity,
specificity, positive predictive value, negative pre-
dictive value, and accuracy of dynamic MRI were
100%, 67%, 62%, 100%, and 78%. In comparison,
using a threshold for malignancy of 20 HU density
increase on dynamic CT the sensitivity, specificity,
positive predictive value, negative predictive value,
and accuracy of dynamic CT were 87%, 60%, 54%,
90%, and 70%. In the two discordant cases of this
289
study (one tuberculoma and one adenocarcinoma)
dynamic MR imaging provided the correct nature
of the pulmonary nodules. Although dynamic MRI
in a direct comparison was slightly superior to CT
this was not statistically significant.
14.2.2.4
Positron Emission Tomography (PET)/CT
and PET
In an effort to improve the diagnostic accuracy of
imaging pulmonary lesions, PET with 18F-FDG has
been used (Devaraj et al. 2007). Malignant cells
have upregulated density of glucose transporters on
their cell surface, metabolism is elevated and they
proliferate rapidly. Comparable uptake of glucose
and the radiolabeled glucose analogue 18F-FDG in
malignant cells have permitted malignancy to be
detected by PET, which is considered an accurate,
noninvasive diagnostic test, with a sensitivity of
88%–96% and a specificity of 70%–90% for malig-
nant nodules (Herder et al. 2004).
Integrated PET/CT has many advantages over sol-
itary PET and CT. It provides more anatomic detail
and improved staging accuracy of non-small cell
lung cancer vs PET alone or CT alone (Fig. 14.2.2.4).
In a recent comparative study of dynamic helical
CT and integrated PET/CT in solitary pulmonary
nodules, the sensitivity, specificity, and accuracy for
predicting a malignant nodule on dynamic helical
CT and integrated PET/CT were 81%, 93%, 85% and
96%, 88%, 93%, respectively (Yi et al. 2006).
Pulmonary nodules with increased 18F-FDG
uptake should be considered malignant, although
false-positive results can be obtained in patients
with infectious and inflammatory processes such
as active tuberculosis, sarcoidosis and rheumatoid
nodules (Erasmus et al. 2000).
Lesions with low 18F-FDG uptake may be consid-
ered benign. However, false-negative results may be
seen in primary pulmonary malignancies such as
carcinoids, bronchioloalveolar carcinomas, adeno-
carcinomas with a predominantly bronchioloalveo-
lar carcinoma component, and malignant pulmo-
nary nodules of <10 mm in diameter (Lowe et al.
1998).
PET or PET/CT is suboptimal for the character-
ization of subcentimeter nodules because the spatial
resolution (currently ~7 mm) of those techniques is
290 C. Fink and F. Berger
insufficient for detecting malignant subcentimeter
nodules. Regarding radiologists` interpretation of
and management decision for these nodules, short-
term follow-up with length of intervals depending
on the likelihood of malignancy is recommended
(Munden and Hess 2001).
Fluorine-18 FDG PET yields false-negative results
in about 5% of all stage T1 lung cancers, but in only
3% of stage T1 lung cancers greater than 5 mm in
diameter (Lee et al. 2004).
The long-term survival of patients with a negative
PET scan for lung cancer suggests that these tumors
behave more indolently.
In a comparison of Fluorine-18 FDG PET and
nodule enhancement in CT, Christensen et al.
(2006) found in a series of 42 examined nodules
a sensitivity and specificity of 100% and 29% for
nodule enhancement CT vs 96% and 76% in FDG-
PET. Due to its much higher specificity and only
slightly reduced sensitivity, it must be concluded
that FDG-PET is preferable to nodule enhancement
CT in indeterminate pulmonary nodules. How-
Fig. 14.2.2.4. PET/CT scan of a patient with non-small
cell lung cancer of the left upper lobe (arrow), accompa-
nied by hypermetabolic mediastinal lymph node metas-
tases and contralateral pulmonary metastases of the right
upper lobe (small arrows)
ever, nodule enhancement remains useful due to its
higher negative predictive value and lower costs, and
taking the above described morphological criteria
for malignancy into account additionally improves
sensitivity.
Apart from FDG, other tracers might be of poten-
tial interest for the characterization of pulmonary
nodules. As the interest in antiangiogenesis therapy
is growing, the need for tumor perfusion measure-
ments is rising. In addition to the CT-or MRI based
techniques, measurement of tumor perfusion using
positron emission tomography and H215O poten-
tially is such a technique. When information of a
perfusion status of a tumor is needed, water labeled
with oxygen H215O may be used. Initial PET oncol-
ogy studies using H215O were performed in brain
tumors (Mineura et al. 1986). In tumors outside the
central nervous system, only a few studies have been
reported using a variety of different techniques. The
aim of the study of Hoekstra et al. (2002) was to
assess whether it is feasible to measure perfusion in
vivo in non-small cell lung cancer (NSCLC) using
 Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging
H215O and positron emission tomography. A total
of 15 dynamic H215O and [(18)F]2-fluoro-2-deoxy-
D-glucose ((18)FDG) studies were performed in 10
patients with stage IIIA-N2 NSCLC. Blood flow data
were correlated with simplified methods of analysis
(tumor:normal tissue ratio and standardized uptake
value) and with glucose metabolism. FDG data were
required for accurate definition of tumor and medi-
astinal lymph node metastases. There was large
intertumor variation in blood flow. Correlation of
simplified methods of analysis with quantitative
blood flow measurements was poor, but measure-
ment of blood flow in NSCLC using H(2)(15)O and
(18)FDG is feasible. It will be interesting to see in
future studies whether blood flow can be used for
response monitoring in antiangiogenic therapy and
how the PET- techniques compares to MR-or CT-
based quantitative perfusion measurements.
Recently, the thymidine analogue 3’-deoxy-
3’[18F]fluorothymidine (FLT) has been introduced
for imaging proliferation with positron emission
tomography (PET). FLT-PET has a high specificity
for the detection of malignant lung tumours. How-
ever, compared with FDG, FLT-PET is less accurate
for N-staging in patients with lung cancer and for
detection of lung metastases. FLT-PET therefore
cannot be recommended for staging of lung cancer
at this time (Buck et al. 2005).
Tumor hypoxia imaging with copper-labeled
diacetyl-bis(N(4)-methylthiosemicarbazone) or
[18F]fluoromisonidazole may provide a better
method of predicting which tumors will respond
best to conventional therapy, but these studies are
still in an experimental stage (Gagel et al. 2006).
14.2.2.5
Conclusion
Because of the large number of incidentally detected
pulmonary nodules at CT non-invasive character-
ization of pulmonary nodules by imaging is of major
importance for the clinical work-up. In addition to
a morphologic characterization of lung nodules and
volume analysis dynamic CT and MRI are alterna-
tive techniques for characterizing lung nodules. The
major advantage to 18F-FDG PET/CT is the broader
availability, lower costs and higher spatial resolu-
tion, potentially allowing a characterization of inde-
terminate lung nodules measuring less then ~8 mm.
291
Nevertheless, 18F-FDG PET/CT is an established
technique in the characterization of lung nodules.
Studies utilizing tracers to determine perfusion or
hypoxia of these tumors are still in an experimental
stage, but might proof useful in the future to guide
antiangiogenic or conventional therapy.
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 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 293

Exogenous Exposition 14
14.3 Screening for Endometrial Cancer in Asymptomatic Patients
Receiving Tamoxifen Therapy
Sandra A. Polin, Sandra J. Allison, and Susan M. Ascher

CONTENTS 14.3.1
Introduction

14.3.1 Introduction 293 Tamoxifen, the most commonly prescribed antineo-

plastic drug in the world, is a selective estrogen receptor
14.3.2 Background 293
modulator (SERM) with anti-estrogenic activity in the
14.3.3 Mechanism of Action 294 breast and estrogenic effects in other tissues including
the endometrium. It is widely used for the treatment of
14.3.4 Histopathologic Review 294 breast cancer as well as for chemoprevention of breast
14.3.4.1 Endometrial Polyps 294
cancer in high risk pre- and post- menopausal women.
14.3.4.2 Endometrial Hyperplasia 294
14.3.4.3 Endometrial Carcinoma 295 Tamoxifen has been shown to cause adverse effects
14.3.4.4 Other Uterine Changes 295 at the uterine level, of which endometrial carcinoma
14.3.4.5 Paradoxical Effects 296 is the most serious. In spite of more than 10 million
patient years of use for the treatment of early and
14.3.5 Screening Review 296
advanced breast cancer in pre- and post-menopausal
14.3.6 Imaging Review 298 women, significant controversy still exists regard-
14.3.6.1 Endovaginal Ultrasound 298 ing appropriate surveillance for endometrial cancer
14.3.6.2 Hysterosonography 299 in these patients (Machado et al. 2005; Neven and
14.3.6.3 Doppler 301
Vernaeve 2000; www.astrazeneca.com).
14.3.6.4 MR Imaging 302

14.3.7 Conclusion 305

References 306
14.3.2
Background

Large clinical trials in which tamoxifen was evaluated

S. A. Polin, MD
S. J. Allison, MD
Department of Radiology, Georgetown University Hospital,
3800 Reservoir Road NW, Washington DC 20007-2197, USA
S. M. Ascher, MD
Professor, Department of Radiology, Director, Division of
Abdominal Imaging, Georgetown University Hospital, 3800
Reservoir Road NW, Washington DC 20007-2197, USA
as adjuvant chemotherapy in women with breast car-
cinoma found (a) a statistically significant increase
in disease-free survival in estrogen receptor–positive
postmenopausal women, (b) an increase in overall
survival in estrogen receptor–positive postmeno-
pausal women, (c) a statistically significant decrease
in the incidence of contralateral breast cancer in
estrogen receptor–positive postmenopausal women,
and (d) beneficial effects in both estrogen receptor–
negative and premenopausal women (Forbes 1997;
Nayfield 1991; Osborne 1998).
In April 1998, the Breast Cancer Prevention Trial
halted a double-blind randomized clinical trial
294 S. A. Polin, S. J. Allison, and S. M. Ascher
14 months ahead of schedule when initial results
showed a 49% reduction in the development of breast
cancer in women at high risk who were randomly
assigned to receive tamoxifen (20 mg/day), as com-
pared with women at high risk who received a placebo
(Fisher et al. 1998). Based on these findings, on Sep-
tember 2, 1998, the Food and Drug Administration
advisory committee unanimously voted to recom-
mend approval of tamoxifen to reduce women’s risk of
developing breast cancer (Kolata 1998). The implica-
tions of the Breast Cancer Prevention Trial and Food
and Drug Administration decisions are underscored
by the fact that according to their criteria, more than
10 million U.S. women qualify for breast cancer che-
moprevention (Freedman et al. 2003).
14.3.3
Mechanism of Action
Tamoxifen is a nonsteroidal antiestrogen agent that
binds to estrogen receptors. This results in both anti-
estrogen action on breast tissue, as well as weak estro-
gen agonist effect in endometrial tissue, leading to a
spectrum of associated endometrial abnormalities The
abnormalities can be categorized into benign alterations
including endometrial polyps, endometrial hyperplasia,
endometrial cystic atrophy, adenomyosis, and uterine
fibroid growth, as well as malignant transformation into
endometrial carcinoma, uterine sarcoma, and malig-
nant mixed tumor of the uterus (De Muylder et al. 1991;
Neven et al. 1990; Gal et al. 1991; Fornander et al. 1989;
Lahti et al. 1993; Cheng et al. 1997; Kedar et al. 1994;
Cohen et al. 1994; van Leeuwen et al. 1994; Fisher
et al. 1994; Uziely et al. 1993; Ismail 1994; Barakat
1996; Cohen 1997; Corley et al. 1992). Tamoxifen also
exerts complex effects via mechanisms unrelated to the
estrogen receptor (Mourits et al. 2001).
14.3.4
Histopathologic Review
14.3.4.1
Endometrial Polyps
Endometrial polyps are the most common endo-
metrial pathology described in association with
tamoxifen exposure (Machado et al. 2005). The
incidence is higher in women treated with tamoxi-
fen than in untreated women: 8%–36% vs 0%–10%
(Lahti et al. 1993; Cheng et al. 1997; Kedar et al.
1994; Cohen et al. 1994; Barakat 1996; Corley et
al. 1992; Schlesinger et al. 1998). Although these
polyps may cause abnormal uterine bleeding, most
women are asymptomatic.
In the general population, endometrial polyps
typically measure 0.5–3.0 cm in diameter, and,
microscopically, contain a mixture of three ele-
ments in varying degrees: (a) stroma of dense
fibrous tissue, (b) thick-walled vascular chan-
nels, and (c) endometrial glands (Schlesinger et
al. 1998; Corley et al. 1992). Tamoxifen-related
polyps tend to be larger (mean diameter 5 cm)
and differ in their microscopic composition: a
combination of proliferative activity (cystic glan-
dular dilatation), aberrant epithelial differentia-
tion (metaplasia), and focal periglandular stromal
condensation (Schlesinger et al. 1998; Corley et
al. 1992; Ismail 1994). The importance of the peri-
glandular stromal condensation is unknown, but it
has been postulated that it may be associated with a
form of Müllerian adenosarcoma (Ismail 1994). In
addition, extensive stromal reaction (i.e., fibrosis)
may account for difficulties in resecting tamoxi-
fen-related polyps at hysteroscopy. Tamoxifen-
associated polyps have a reported increased rate
of malignant change. Cohen reported malignant
change in 3% of tamoxifen-treated women who
had postmenopausal breast cancer, compared with
0.48% in controls (Cohen et al. 1999). Schlesinger
et al. reported a 10.7% rate of malignant change in
polyps of tamoxifen treated patients (Schlesinger
et al. 1998).
14.3.4.2
Endometrial Hyperplasia
There is a significant increase in the incidence of
endometrial hyperplasia in postmenopausal breast
cancer patients treated with tamoxifen. The inci-
dence is 1.3%–20.0% in such patients, as compared
with the 0%–10% incidence in postmenopausal
breast cancer patients who are not receiving tamoxi-
fen (Gal et al. 1991; Lahti et al. 1993; Cheng et al.
1997; Cohen et al. 1994; Kedar et al. 1994; Barakat
1996; Corley et al. 1992; Berliere et al. 1998;
Karlsson et al. 1995; Kurman 1994). The diagno-
sis of endometrial hyperplasia is established on the
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy
basis of microscopic findings of a morphologically
abnormal proliferative-type endometrium. Some
authors insist that, in addition, there must be an
abnormal increase in endometrial volume (Kurman
1994).
Endometrial hyperplasia can be divided into
hyperplasia with cytologic atypia and hyperplasia
without cytologic atypia. These categories are fur-
ther subdivided into simple or complex depending
on the extent of glandular complexity and crowd-
ing. The nomenclature has prognostic significance:
In up to 23% of patients with atypical hyperplasia,
the hyperplasia progresses to carcinoma, com-
pared to only 2% in those without atypia (Kurman
1994).
14.3.4.3
Endometrial Carcinoma
Tamoxifen chemotherapy or prophylaxis increases
the relative risk of developing endometrial cancer
(Osborne 1998; Fisher et al. 1994, 1998; van
Leeuwen et al. 1994; Andersson et al. 1991; Uziely
et al. 1993). Studies have reported a 1.3- to 7.5-fold
increase in the relative risk of developing endome-
trial cancer (Osborne 1998; Fisher et al. 1994, 1998;
van Leeuwen et al. 1994; Ismail 1994; Barakat
1996), with data from major clinical studies indi-
cating tamoxifen use results in an approximately
twofold increase in the incidence rate of endome-
trial cancer (Early Breast Cancer Trialists’
Collaborative Group 1998; Curtis et al. 1996;
Assikis et al. 1996). This slight increase in endo-
metrial cancer risk led the International Agency for
Research on Cancer (IARC) to classify tamoxifen as
an endometrial carcinogen (IARC 1996).
The risk of developing endometrial cancer
increases with duration of treatment and cumula-
tive tamoxifen dose as well as with prior estrogen
replacement therapy, obesity, hypertension, and
the presence of endometrial pathologic conditions
before the initiation of tamoxifen (Fisher et al. 1998;
Osborne 1998; van Leeuwen et al. 1994; Barakat
1996; Ismail 1994; Vosse et al. 2002; Berliere et
al. 1998; Fong et al. 2003). The Early Breast Cancer
Trialists’ Collaborative Group reported the inci-
dence of endometrial cancer in patients treated
with tamoxifen approximately doubled in trials
of 1 or 2 years and approximately quadrupled in
trials of 5 years (Early Breast Cancer Trialists’
Collaborative Group 1998).
295
Several studies found that most cases of endome-
trial cancers occurring in tamoxifen treated patients
were of low grade and stage, with no differences in
stage, grade, or histologic subtype compared to
non-treated patients (Mignotte et al. 1998; Fisher
et al. 1994; van Leeuwen ea1994; Peters-Engl et
al. 1999; Barakat et al. 2000). However, other stud-
ies have found endometrial cancers in postmeno-
pausal patients treated with tamoxifen to be more
advanced with poorer prognoses than in non-treated
patients (Magriples et al. 1993; Wilder et al. 2004;
Deligdisch et al. 2000; Narod et al. 2001; Bergman
et al. 2000; Lasset et al. 2001). These studies have
shown an increase in unfavorable histologies (sar-
comas and Müllerian mixed tumors) resulting in
advanced stage at time of diagnosis and worse sur-
vival (Bergman et al. 2000; Cohen 2004; Narod et
al. 2001; Wickerham et al. 2002). Some studies have
found the endometrial cancer mortality rate among
tamoxifen treated patients significantly higher com-
pared to non-treated patients due to the unfavor-
able histology of the endometrial malignancy and
advanced stage at diagnosis (Bergman et al. 2000;
Cohen 2004; Narod et al. 2001; Deligdisch et al.
2000; Magriples et al. 1993; Ragaz and Coldman
1998).
14.3.4.4
Other Uterine Changes
Other uterine changes reported in association with
tamoxifen treatment include “tamoxifen” mucosa or
endometrial cystic glandular atrophy, adenomyosis,
and leiomyomas (Varras et al. 2003; Neven et al.
1998; Cohen et al. 1994, 1995; Ugwumadu et al.
1993).
At hysteroscopy, endometrial cystic atrophy is
described as smooth, white, hypervascularized,
and atrophic, with scattered protuberances that
represent cystic atrophy (Neven et al. 1998). This
“tamoxifen” mucosa with its protuberances differs
macroscopically from the atrophic mucosa seen
in postmenopausal women who are not receiving
tamoxifen. In the latter, the mucosa is characterized
as pale, thin, and without protuberances (Gompel
1994).
Endometrial cystic atrophy is diagnosed his-
tologically when multiple cystic spaces lined by
atrophic endometrium are present within a dense
fibrous stroma (McGonigle et al. 1998). In patients
treated with tamoxifen, the exact location of the
296 S. A. Polin, S. J. Allison, and S. M. Ascher
cysts is controversial. Some investigators report
that the cysts extend to the endometrial-myometrial
junction but clearly reside within the endometrium;
others have placed the cysts in the subendome-
trial location (McGonigle et al. 1998; Goldstein
1994; Achiron 1995). This is further complicated
by the fact that endometrial glands that extend into
the myometrium may also be called adenomyosis.
Whether the apparent increased incidence of adeno-
myosis in women treated with tamoxifen is a true
separate phenomenon or represents a spectrum of
tamoxifen-associated cysts („adenomyosis-like
changes“) is unknown (Cohen et al. 1995). Regard-
less of their location, the cysts seen in women treated
with tamoxifen do not appear to be premalignant
(McGonigle et al. 1998).
The leiomyomas observed in women treated
with tamoxifen do not differ histologically from
those found in untreated women (Dilts et al. 1992;
Lumsden et al. 1989). However, the presence of leio-
myomas, adenomyosis, and polyps may contribute
to the larger uterine volume reported in women
treated with tamoxifen (Cohen et al. 1995; Cheng et
al. 1997; Fornander et al. 1989; Lahti et al. 1993).
14.3.4.5
Paradoxical Effects
Interestingly, tamoxifen has apparent paradoxical
effects at the uterine level. Some portions of the
endometrium may be stimulated by tamoxifen,
while others undergo the effects of a more accel-
erated menopause. As a result, coexistent atrophy
and adenomyosis have been described in postmeno-
pausal women treated with tamoxifen (Cohen et al.
1994, 1995). These seemingly contradictory findings
can be explained, in part, by the existence of more
than one population of uterine receptors respond-
ing to tamoxifen and/or the possibility that growth
sites may lose their sensitivity to the antiestrogenic
effects of tamoxifen after an initial stimulatory
response (McGonigle et al. 1998).
14.3.5
Screening Review
The main purpose of a screening program is to
detect disease at an early more curable stage. Sev-
eral authors have concluded that there is no sig-
nificant benefit to screening asymptomatic women
treated with tamoxifen for endometrial cancer.
Neven reported that decreasing mortality from
endometrial cancer in tamoxifen users is unlikely
as most tamoxifen-associated endometrial lesions
are benign polyps without premalignant change and
the risk of developing endometrial cancer is small
(Neven and Vergote 1998). After reviewing the
literature, Cardosi and Fiorica (2000) determined
that routine endometrial surveillance is not war-
ranted in asymptomatic postmenopausal women
taking tamoxifen for the following reasons: the
majority of women with premalignant and malig-
nant endometrial lesions are symptomatic, random
endometrial sampling has a very low yield, and
screening sonography will lead to additional diag-
nostic procedures in more then 50% of women. Fung
et al. (2003) found a positive predictive value of only
1.4% when using an endometrial thickness of 9 mm
as the cutoff for detecting endometrial carcinoma.
They concluded that routine screening in asymp-
tomatic women on tamoxifen was not useful. In a
cost-benefit analysis of screening tamoxifen-treated
patients, Bakarat reported the decrease in mortality
for screening asymptomatic women on tamoxifen
for endometrial cancer would be only 0.03% of all
tamoxifen-treated patients (Barakat et al. 2000).
Since approximately 80,000 women begin tamoxi-
fen annually, the cost of screening for endometrial
cancer in women taking tamoxifen was felt to be
prohibitive (Barakat et al. 2000).
Other authors have concluded that there may be
a benefit to screening asymptomatic women. Uziely
et al. (1993) studied 95 patients with breast cancer
treated with tamoxifen who underwent endovaginal
US followed by endometrial biopsy. Histopathologic
changes were observed in 14 patients, 13 of whom
had been treated for more than 12 months and all
of whom had an endometrial thickness of more
than 5 mm. These changes included polyps in four
patients, hyperplasia in three patients, dysplasia
in three patients, and carcinoma in three patients.
The authors found a statistically significant corre-
lation between long-term tamoxifen administration
and endometrial proliferation and therefore rec-
ommended that women treated with tamoxifen for
more than 12 months undergo annual endovaginal
US and endometrial biopsy. Sinawat (2002) stud-
ied 37 asymptomatic postmenopausal breast cancer
patients who had taken 20 mg/day of tamoxifen for
at least 6 months. He found the prevalence of endo-
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy
metrial cancer to be 5.26% and suggested a reliable
surveillance method for endometrial abnormality
should be offered to all asymptomatic postmeno-
pausal breast cancer patients undertaking long term
tamoxifen treatment.
Some authors have attempted to identify a subset
of patients who are at high risk for developing
tamoxifen related endometrial pathology in whom
screening may prove to be beneficial. In a prospec-
tive study by Berliere et al. (1998), 264 women with
breast cancer were evaluated for endometrial abnor-
malities before initiating tamoxifen therapy. Women
with endometrial thickness > 4 mm underwent out-
patient hysteroscopy with endometrial biopsy. Of the
264 women, 46 (17.4%) had asymptomatic baseline
endometrial lesions. Of these 46 women, one had
atypical hyperplasia and one had endometrial ade-
nocarcinoma in situ. The other 44 women had endo-
metrial polyps, submucosal myomas, and hyperpla-
sia without atypia. After 3 years, the authors found
an equal incidence of benign endometrial lesions
but a significantly higher incidence of hyperplasia
with atypia and adenocarcinoma in the group with
baseline abnormalities (11.7% vs 0.7%). The authors
concluded that they had prospectively identified a
group of women at high risk of developing endo-
metrial cancer on tamoxifen treatment. They also
observed a high percentage of asymptomatic lesions
and they recommended that regular endometrial
surveillance of tamoxifen treated women, even in
the absence of symptoms, should be performed.
In breast cancer patients, the adverse effect of
developing endometrial cancer is outweighed by
improved survival and lower incidence of contra-
lateral breast cancer (Jaiyesimi et al. 1995; Early
Breast Cancer Trialists’ Collaborative
Group 1998). However, the risk/benefit ratio from
tamoxifen as a preventive therapy against breast
cancer is unclear. Data from the Breast Cancer Pre-
vention Trial suggest that the benefits of tamoxi-
fen therapy outweigh the real, but small 2.5-fold
increased risk of developing endometrial cancer
(Fisher et al. 1998). However, when stratified by age,
the risk of endometrial cancer increased to four-
fold in women over 50 years of age (Early Breast
Cancer Trialists’ Collaborative Group 1998;
Ferrazzi and Leone 2004). After reviewing the
literature, Machado et al. (2005) felt that screen-
ing asymptomatic women may be appropriate in (a)
all patients on tamoxifen as chemoprophylaxis, to
improve the risk/benefit ratio in these patients and
in (b) long-term users of tamoxifen.
297
Some of the studies that found no significant
benefit to screening asymptomatic patients noted
that endometrial cancers occurring in breast cancer
patients were of similar stage and prognosis as those
occurring in women who had not undergone tamox-
ifen treatment. Because endometrial cancer in the
general population has a generally good prognosis,
the authors concluded early detection would prob-
ably not improve outcome significantly (Barakat
et al. 2000). However, as previously discussed, addi-
tional studies are suggesting that endometrial can-
cers occurring in tamoxifen treated patients have
more aggressive histologies, with higher mortality
rates, raising the possibility that there may indeed
be a benefit to screening (Cohen 2004; Bergman et
al. 2000).
Adding to the controversy is a lack of consensus
on the means to carry out surveillance. Endometrial
biopsy, a safe but invasive procedure, is generally not
recommended in asymptomatic women on tamoxi-
fen due to its low yield. This is because tamoxifen
induced endometrial lesions are usually subepithe-
lial and focal in nature resulting in false negatives
(Suh-Burgmann and Goodman 1999; Marconi
et al. 1997; Hann et al. 2003; Barakat et al. 2000).
Hysteroscopy is superior to blind endometrial sam-
pling but is too aggressive for screening asymptom-
atic women on tamoxifen (Develioglu et al. 2004).
Screening with endovaginal US, an inexpensive,
readily available, noninvasive method, is limited by
a significant false positive rate and lack of consensus
on the appropriate cutoff for normal endometrial
thickness in women treated with tamoxifen.
Additionally, there is no consensus on the dura-
tion of and interval for screening. While studies
have found that endometrial thickening returns
to normal after cessation of tamoxifen treatment
(Gerber et al. 2000; Love et al. 1999), some authors
assert that the risk of endometrial carcinoma may
remain after cessation of therapy (Bergman et al.
2000).
Currently, the American College of Obstetricians
and Gynecologists does not recommend screening by
endometrial biopsy or transvaginal ultrasound for
asymptomatic women. They recommend all women
undergo annual gynecologic exam and that women
be educated about their increased risk of endome-
trial cancer. Women are encouraged to promptly
report any abnormal uterine bleeding. Any abnor-
mal vaginal symptoms should then be investigated
(ACOG 2001). The American College of Obstetricians
and Gynecologists also states the use of tamoxifen
298 S. A. Polin, S. J. Allison, and S. M. Ascher
for chemoprevention should be limited to 5 years
(ACOG 2002). However, physician surveys have indi-
cated that physicians favor surveillance of asymp-
tomatic breast cancer patients treated with tamoxi-
fen. One study of breast cancer patients showed
that 42% of tamoxifen users reported regular sur-
veillance for uterine abnormalities (Althuis et al.
2000). Therefore, radiologists must become familiar
with the imaging features of the uterus in women
receiving tamoxifen and the relative strengths and
weaknesses of the various imaging modalities with
respect to evaluation of the uterus.
14.3.6
Imaging Review
14.3.6.1
Endovaginal Ultrasound
US is the first-line imaging modality for evaluation
of the endometrium. The normal postmenopausal
endometrium appears as a single echogenic line
and should not exceed 5 mm as a bilayer thickness
(Goldstein et al. 1990; Granberg et al. 1991). In
general, women undergoing tamoxifen treatment
have a thicker endometrium as compared with
that in control subjects (9–13 mm vs 4.0–5.4 mm)
(Cheng et al. 1997; Lahti et al. 1993; Kedar et
al. 1994; Cohen et al. 1994). In postmenopausal
women undergoing estrogen replacement therapy,
the normal endometrium may measure up to 8 mm
in thickness. However, the upper limit for normal
endometrial thickness on endovaginal US in asymp-
tomatic women receiving tamoxifen remains con-
troversial (Fong et al. 2003; Levine et al. 1995).
Various authors have recommended cut-off
values ranging from 4 to 10 mm. In a prospective
study, using an endometrial thickness of 5 mm as
the upper limit of normal, Cohen et al. (1993) found
the sensitivity of endovaginal US in relation to posi-
tive histologic findings was 91%, and the specific-
ity was 96%. In a prospective study by Fong et al.
(2001, 2003), an endometrial thickness of 6 mm
was found to be the optimal endometrial thickness
for diagnosing endometrial abnormalities with a
sensitivity of 85.1% and specificity of 55.7%. The
combination of transvaginal ultrasound and hys-
terosonography further increased the specificity to
77.1% without a significant decrease in sensitivity
(78.7%). Kedar et al. (1994) reported that endome-
trial thickness greater than 8 mm on ultrasound
had a 100% positive predictive value for endome-
trial disease. A study by Franchi et al. (1999) found
that the proportion of women with abnormal histo-
logic findings was higher among those with endo-
metrial thicknesses greater than 9 mm, compared
with those with endometrial thickness 9 mm or less
(60% vs 6.1%). A study by Ito et al (2001) also advo-
cated 9 mm as the optimal cutoff for endometrial
thickness. A retrospective study by Develioglu
et al. 2004 reported the optimal cutoff of endo-
metrial thickness at ultrasonography was 9.5 mm
with a sensitivity of 89% and specificity of 78% for
endometrial pathology. Gerber et al. (2000) recom-
mended a 10-mm cutoff to try to reduce the false
positive rate of ultrasonography and the resulting
unnecessary aggressive tests.
These statistics should be interpreted with cau-
tion. Positive histologic findings (e.g., endometrial
proliferation and simple hyperplasia) may be clini-
cally unimportant. Moreover, a thicker endometrium
on the US image does not necessarily correlate with
specific pathologic endometrial findings (Cohen et
al. 1993). Additionally, while using a lower cut-off
value for endometrial thickness should improve the
sensitivity of endovaginal US for detecting endo-
metrial carcinoma, achieving 100% sensitivity is
still limited. In a case report, Renard et al. (2002)
noted a case of endometrial cancer in an asymptom-
atic patient with breast cancer with an endometrial
thickness of 3 mm.
Regardless of the cutoff value for detecting endo-
metrial abnormalities, the most common endome-
trial transvaginal US pattern seen in women treated
with tamoxifen is a thickened endometrium with
cystic spaces described as a “Swiss cheese” pattern
(Fig. 14.3.1) (Lahti et al. 1993; Cheng et al. 1997;
Kedar et al. 1994; Uziely et al. 1993; Cecchini et
al. 1996; Hulka and Hall 1993; Hann et al. 1997;
Atri et al. 1994; Love et al. 1999; Mourits et al.
1999). The findings of a thickened endometrial com-
plex, with or without cystic changes, is often non-
specific and may be caused by endometrial polyps,
submucosal leiomyoma, cystic atrophy, endometrial
hyperplasia, or carcinoma (Fong et al. 2003). Cer-
tain sonographic findings may improve specificity.
A distinct hyperechoic line partially or completely
surrounding the endometrial complex favors a focal
intracavitary process such as a polyp or submucosal
fibroid (Fong et al. 2003; Baldwin et al. 1999). Sub-
mucosal fibroids may be hypoechoic or heterogenous
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy
Fig. 14.3.1. a,b Sagittal endovaginal ultrasound images
from two different patients show the most common endo-
metrial fi nding in women undergoing tamoxifen treatement:
a thickened endometrium punctuated by cysts. c Trans-
verse ultrasound images from a third patient with similar
fi ndings. Calipers denote an intramural fibroid (Fig. 14.3.1a
reprinted with permission from Ascher et al. 2000)
and often demonstrate acoustic attenuation (Atri et
al. 1994; Fong et al. 2003). Sonographic findings of
adenomyosis include uterine enlargement, asym-
metric thickening of the anterior or posterior uter-
ine wall, increased myometrial echotexture, het-
erogeneous poorly circumscribed areas within the
myometrium, and myometrial or subendometrial
cysts. These findings can result in a false-positive
appearance of thickened endometrium at trans-
vaginal ultrasound (Fong et al. 2003). Endometrial
carcinomas are often either diffusely or partially
echogenic (Atri et al. 1994; Fong et al. 2003). While
poorly defined endometrial thickening is usually
suggestive of malignancy, this is not a helpful diag-
nostic feature in women treated with tamoxifen due
to underlying adenomyosis (Fong et al. 2003).
14.3.6.2
Hysterosonography
Hysterosonography has increasingly been used
to improve the ability to diagnose intrauterine
299
c
pathologic conditions and to resolve discrepancies
between endometrial thickening on endovaginal US
images and insufficient material or nondiagnostic
results at endometrial biopsy (Wolman et al. 1996;
Cohen et al. 1993; Dubinsky et al. 1997; Shipley et
al. 1994; Langer et al. 1997; Lev-Toaff 1996; Cul-
linan et al. 1995). Specifically, hysterosonography
is an attractive adjunct to endovaginal US because
it more clearly defines endoluminal lesions that are
pedunculated or sessile and can be used to better
determine whether an abnormality is endometrial
or subendometrial (Fig. 14.3.2).
The potential utility of hysterosonography in
imaging of tamoxifen-related changes was noted
in a 1994 case report (Bourne et al. 1994) in which
a patient treated with tamoxifen was described as
having an atrophic endometrium at endometrial
biopsy despite a thickened endometrium (1.9 cm)
on endovaginal US images. Hysterosonography
demonstrated a large polyp, which was confi rmed
and excised at hysteroscopy. Later, Goldstein
(1994) described five women with a thick, “irregu-
lar, bizarre, heterogeneous” endometrium on endo-
300 S. A. Polin, S. J. Allison, and S. M. Ascher

a c

b d

Fig. 14.3.2a–d. Hysterosonography as adjunct to endovaginal ultrasound. a Sagittal endovaginal ultrasound demonstrates
a thickened endometrium. b Sagittal hysterosonogram shows an endometrial polyp accounting for the endometrial thicken-
ing. c In the same patient, a small fibroid (calipers) abuts the endometrium and a submucosal component cannot be excluded.
d Hysterosonogram shows the fibroid (calipers) is intramural without a submucosal component

vaginal US images. At hysterosonography, anechoic who underwent hysterosonography followed by hys-

areas were noted in the subendometrial proximal
myometrium, not in the endometrium as originally
interpreted on the basis of endovaginal US images.
At endometrial biopsy, all patients had an inactive
endometrium. On the basis of these findings, albeit
from a small sample, the author cautioned against
over-interpreting a “thickened” endometrium on
endovaginal US images that have not been enhanced
with fluid.
Achiron et al. (1995) also investigated the dis-
crepancy between a thickened endometrium at
endovaginal US and benign results at sampling in
patients with breast cancer treated with tamoxifen.
They evaluated 20 women with cystic thickening
(> 5 mm) of the endometrium at endovaginal US
teroscopy and endometrial curettage. In 8 patients,
hysterosonography delineated free-floating echo-
genic masses (polyps); the remaining 12 patients had
endometrial or subendometrial cysts. At inspection
and sampling, polyps were confirmed in the first
group, whereas 11 of the 12 women in the second
group had scanty, senile cystic atrophy. The remain-
ing patient had benign proliferative endometrial
changes. The authors concluded that to increase
specificity, postmenopausal women treated with
tamoxifen who demonstrate thickening of the endo-
metrium on endovaginal US images should undergo
hysterosonography.
Tepper et al. (1997) found that 68 of 114 patients
with breast cancer treated with tamoxifen had an
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy
endometrial thickness of more than 8 mm at trans-
vaginal ultrasound. Hysterosonography revealed
hyperechoic or polypoid masses in 22 patients,
and histologic results confi rmed the presence of
benign endometrial polyps (12 patients), polyps
with simple or complex hyperplasia (4 patients),
leiomyomas (2 patients), and no tissue obtained
(4 patients). In the remaining 46 patients, hystero-
sonography did not reveal any intracavity pathol-
ogy. Correlative hysteroscopy and biopsy revealed
complex hyperplasia (2 patients), simple hyperpla-
sia (5 patients), and atrophic endometrium or no
tissue (39 patients). There were no false negative
hysterosonographic diagnoses. The authors con-
cluded that hysterosonography has high sensitivity
(100%) and a high positive predictive value (95.5%)
in patients receiving tamoxifen who have an endo-
metrial thickness of more than 8 mm at endovagi-
nal US.
In a retrospective study of 51 patients treated
with tamoxifen, Hann et al. (2003) found a sig-
nificantly higher sensitivity of hysterosonography
(100%) versus endometrial biopsy (4%) for the diag-
nosis of endometrial polyps. She concluded that
sonohysterography should be considered for evalu-
ation of abnormal uterine bleeding or thickened
endometrium even if endometrial biopsy results
are negative.
At hysterosonography, polyps appear as
smoothly marginated echogenic masses with or
without cystic areas. Polyps often have a narrow
attachment to the endometrium but may be broad-
based (Fig. 14.3.3). Submucosal fibroids appear as
Fig. 14.3.3. Routine endovaginal ultrasound dem-
onstrated nonspecific thickening of the endome-
trium. Transverse hysterosonogram improved the
specificity of endovaginal sonography by showing
an echogenic mass with smooth margins and a
narrow attachment to the endometrium consistent
with a polyp
301
round structures arising from the myometrium,
commonly with wide attachment to the myome-
trium, although they are occasionally peduncu-
lated (Fong et al. 2003). Hysterosonographic fea-
tures of adenomyosis include small cysts which
appear in the inner myometrium (Fong et al. 2003).
Diffuse smooth thickening of the endometrium
suggests hyperplasia, however, hyperplasia may
also appears as irregular asymmetric endometrial
thickening (Laifer-Narin et al. 1999). An irregu-
lar heterogenous mass or irregular focal thicken-
ing of the endometrium is suggestive of endome-
trial carcinoma (Fong et al. 2003).
14.3.6.3
Doppler
In an attempt to increase the specificity of sonogra-
phy for detecting endometrial pathology, Doppler
studies of the endometrium of women on tamoxifen
have been performed. Several studies have shown
lower impedance of the uterine and endometrial
flow compared with control groups (Achiron et al.
1995; Kedar et al. 1994; Sladkevicius et al. 1994;
Develioglu et al. 2004). However, in the majority
of these studies Doppler indices have been unable to
differentiate between benign and pathologic etiolo-
gies (Achiron et al. 1995; Sladkevicius et al. 1994;
Develioglu et al. 2004). In certain cases, color Dop-
pler US can improve the specificity of sonography by
showing the feeding artery in the pedicle of a polyp
(Atri et al. 1994) (Fig. 14.3.4).
302 S. A. Polin, S. J. Allison, and S. M. Ascher
Fig. 14.3.4. Color Dopppler US shows the feeding artery in
the pedicle of a polyp on this transverse image from a hys-
terosonogram. The corresponding ultrasound was shown in
Fig. 14.3.1c
14.3.6.4
MR Imaging
Despite the proven effectiveness of MR imaging for
demonstrating endometrial abnormalities (Lipson
and Hricak 1996; Hricak et al. 1992), little has been
written in the MR imaging literature about uter-
ine findings in women undergoing treatment with
tamoxifen (Reinhold and Ascher 1997). Ascher
et al. (1996) reported on the MR imaging appear-
ance of the uterus in 35 postmenopausal patients
with breast cancer who were undergoing tamoxifen
treatment, and they correlated the imaging findings
with histopathologic results. The authors noted two
imaging patterns: (a) an endometrium with homo-
geneously high signal intensity on T2-weighted MR
images (mean thickness, 0.5 cm) associated with
contrast material enhancement of the endometrial-
myometrial interface and a signal void lumen on
gadolinium-enhanced images in 18 patients and
(b) an endometrium with heterogeneous signal
intensity on T2-weighted MR images (mean thick-
ness, 1.8 cm) associated with enhancement of the
endometrial-myometrial interface and latticelike
enhancement traversing the endometrial canal on
gadolinium-enhanced images in 17 patients. Other
imaging findings included endometrial-myometrial
and subendometrial cysts, Nabothian cysts, leiomy-
omas, and adenomyosis (Ascher et al. 1996; Silva
et al. 1998). Ten patients with the former pattern had
an atrophic or proliferative endometrium at histo-
pathologic analysis (Fig. 14.3.5). Of 17 patients with
the latter pattern, 12 had polyps, 1 of which had a
focus of endometrial carcinoma (Fig. 14.3.6).
Gadolinium enhancement improves the defini-
tion of the endometrial process. Specifically, an
enhancing stalk is seen in many of the polyps, allow-
ing the diagnosis to be established with confidence
(Fig. 14.3.7). In the one polyp that was malignant,
MR imaging allowed accurate exclusion of deep
myometrial invasion. The ability of MR imaging
to help accurately predict myometrial invasion
has been established in the general (untreated)
postmenopausal population, and these findings
should hold true for women receiving tamoxifen
(Fig. 14.3.8) (Hricak et al. 1987, 1991; Ito et al.
1994; Delmaschio et al. 1993). Although larger
studies are needed to determine if MR imaging can
help reliably distinguish the various endometrial
pathologic conditions associated with tamoxifen
use, Ascher et al. (1996) concluded that MR imag-
ing may (a) help identify those patients who should
undergo a sampling procedure vs those who can be
followed up noninvasively with MR imaging and (b)
lead to a more aggressive intervention (dilation and
curettage vs endometrial biopsy) if a nondiagnostic
or normal result is obtained in a patient with abnor-
mal MR imaging findings.
In another study (Ascher et al. 1995) MR imag-
ing was compared with endovaginal US for uterine
evaluation in 28 women with breast cancer treated
with tamoxifen. Histopathologic correlation was
obtained in 21 patients. Histopathologic results
included polyps (8 patients, 1 with superficial carci-
noma), cystic atrophy (10 patients), and proliferative
change (3 patients). For the correlation of imaging
findings with histopathologic results, MR imaging
had 100% sensitivity, 61.5% specificity, 76.2% accu-
racy, 61.5% positive predictive value, and 100% neg-
ative predictive value, whereas endovaginal US had
87.5% sensitivity, 7.7% specificity, 38.1% accuracy,
36.8% positive predictive value, and 50% negative
predictive value. There was no statistically signifi-
cant difference between the two modalities in terms
of mean endometrial thickness. Of interest, tamoxi-
fen-associated cysts were noted on MR images in
eight of 12 patients with a false-positive endovagi-
nal US diagnosis, including 7 of 10 patients with
cystic atrophy. These cysts may be responsible for
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 303

Fig. 14.3.5. a Sagittal endovag-

inal ultrasound shows a retro- a
verted uterus with a thickened
endometrial complex mea-
suring 6 mm (calipers) with
small cystic spaces. b Sagittal
T2-weighted fast spin-echo
MR image shows a thin, high-
signal-intensity endometrium
and cysts. c The corresponding
sagittal gadolinium-enhanced
spoiled gradient-echo MR image
shows enhancement of the endo-
metrial-myometrial interface.
The endometrial lumen is a
signal void. Endometrial-myo-
metrial cysts are visible. Cystic
atrophy was diagnosed at sam-
pling (Fig. 14.3.5b,c reprinted
with permission from Ascher
b
et al. 1996) c

a b

Fig. 14.3.6. a Sagittal T2-weighted fast spin-echo MR shows significantly thickened endometrium with heterogeneous signal
intensity. b The corresponding sagittal gadolinium-enhanced spoiled gradient-echo MR image shows latticelike enhance-
ment travsersing the endometrial canal and was found to represent a benign endometrial polyp. The corresponding ultra-
sound is shown in Fig, 14.3.1a. (Reprinted with permission from Silva et al. 1998)
304 S. A. Polin, S. J. Allison, and S. M. Ascher

a
b

Fig. 14.3.7a–c. A 71-year-old woman with breast cancer who received

tamoxifen for 42 months. a Sagittal endovaginal ultrasound shows a
thickened, heterogeneous endometrium (calipers) with large cystic
spaces. b Sagittal T2-weighted fast spin-echo images of the uterus
show a widened endometrial canal with heterogenous signal intensity.
c Corresponding contrast enhanced sagittal-T1-weighted fat-suppressed
spoiled gradient-echo images shows enhancing tissue traversing the
endometrial canal. An enhancing stalk originating from the posterior
endometrium is well demarcated, allowing the diagnosis of polyp to be
established with confidence. (Reprinted with permission from Ascher
c et al. 1996)

a
Fig. 14.3.8. a Saittal endovaginal ultrasound shows a thickened
hetrogenous endometrium (calipers). b T2-weighted fast spin-
echo MR image shows a heterogeneous mass distending the
endometrial canal. The junctional zone remains intact allowing
exclusion of deep myometrial invastion. At hysterectomy, superfi-
cal endometrial carcinoma was found without evidence of myo-
metrial invasion b
 Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 305

Fig. 14.3.9a–c. Endovaginal US and MR imaging evaluation

of endometrial-myometrial cysts. a Transverse endovagi-
nal US image shows small cysts flanking the endometrial
echo complex. This appearance may lead to a spuriously
widened endometrial measurement. b Sagittal T2-weighted
fast spin-echo MR image demonstrates a retroverted uterus
with a normal thin homogeneously high signal intensity
endometrium. The actual location of the cysts is at the
endometrial-myometrial junction. c Sagittal gadolinium-
enhanced T1-weighted spoiled gradient-echo MR image
also demonstrates the cysts at the endometrial-myometrial
junction, consistent with cystic atrophy- a common fi nding
in undergoing tamoxifen treatment. (Reprinted with per-
mission from Ascher et al. 2000)

b c

spurious endometrial thickening on endovaginal US
scans. The authors (Ascher et al. 1995) concluded
that both modalities are sensitive for the detection
of endometrial abnormalities, although neither is
very specific.
14.3.7
Conclusion
Significant controversy still exists regarding appro-
priate surveillance for endometrial cancer in asymp-
tomatic women treated with tamoxifen.
Earlier studies which concluded there is no sig-
nificant benefit to screening asymptomatic women
also noted that most cases of endometrial cancers
occurring in tamoxifen treated patients were of
similar prognosis to non-treated patients. However,
other studies are finding that endometrial cancer
mortality rates among tamoxifen treated patients
are significantly higher compared to non-treated
patients due to an increase in unfavorable histolo-
gies (Bergman et al. 2000; Cohen 2004; Narod et
al. 2001; Deligdisch et al. 2000; Magriples et al.
1993; Ragaz and Coldman 1998). In light of these
findings, further studies may be necessary to evalu-
ate if screening may be able to improve the mortality
in this population.
In breast cancer patients undergoing tamoxi-
fen treatment, it is clear that the adverse effect of
developing endometrial cancer is outweighed by
improved survival and lower incidence of contra-
306 S. A. Polin, S. J. Allison, and S. M. Ascher
lateral breast cancer (Jaiyesimi et al. 1995; Early
Breast Cancer Trialists’ Collaborative
Group 1998). However, in healthy women, the risk/
benefit ratio from tamoxifen as a preventive therapy
against breast cancer is unclear. Authors have sug-
gested that women treated with tamoxifen for che-
moprophylaxis undergo screening to improve their
risk/benefit ratio (Machado et al. 2005). Addition-
ally, some authors have recommended women with
baseline endometrial abnormalities and women
undergoing long term tamoxifen treatment may
benefit from screening as they are at higher risk for
developing endometrial cancer (Machado et al.
2005; Berliere et al. 1998).
Currently, the American College of Obstetricians
and Gynecologists does not recommend screening
by endometrial biopsy or transvaginal ultrasound
for asymptomatic women. However, a significant
proportion of tamoxifen patients do receive regu-
lar surveillance for endometrial changes (Althuis
et al. 2000) and radiologists must become familiar
with the appearance of the uterus in women receiv-
ing tamoxifen and have a strategy to evaluate these
patients.
To aid in that process, we offer an imaging algo-
rithm based on results in published reports. Endo-
vaginal US should be the first-line imaging modality
for evaluation of the uterus in asymptomatic women
undergoing tamoxifen therapy. We conservatively
use 5 mm as the upper limit for normal endometrial
thickness in asymptomatic women treated with
tamoxifen. A pretreatment uterine assessment with
endovaginal US is recommended to identify any pre-
existing abnormalities. Asymptomatic women can
then be screened annually with endovaginal US from
1 to 2 years after the start of tamoxifen. The strength
of endovaginal US is in the normal findings. In cases
where the endovaginal US image is nondiagnostic or
is suggestive of an abnormality, hysterosonography
can provide additional information. That is, hys-
terosonography can be used to image polyps and
endometrial-myometrial and subendometrial cysts
with confidence and can help direct sampling pro-
cedures when necessary. Although the role of MR
imaging in this patient population is less clear, MR
imaging can demonstrate both endometrial and
myometrial pathologic conditions. MR imaging
may be appropriate (a) in patients with an equivocal
or abnormal endovaginal US scan who are unable to
undergo hysterosonography due to cervical stenosis
and (b) at centers that do not offer hysterosonogra-
phy (Ascher et al. 2000).
Acknowledgement. The authors acknowledge Aki
Kido, for assisting with the images.
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 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk 311

Genetic Disposition 15
15.1 Breast Cancer – Screening in Women with an Inherited Risk
Thomas Schlossbauer, Karin Hellerhoff, and Claudia Perlet

CONTENTS 15.1.1
Introduction

15.1.1 Introduction 311 Although all women are at high risk for breast
cancer, various studies have demonstrated that
15.1.2 Women at Increased Risk –
Standardized Risk Evaluation 312 certain subgroups have a significantly increased
15.1.2.1 Patient’s Perspective 312 probability of developing this disease compared
15.1.2.2 Family History 312 to their same-age counterparts. In the early 1990s,
15.1.2.3 BRCA1 and BRCA2 Testing 312 two genes (BRCA1 and BRCA2) have been identi-
15.1.2.4 Clinical Relevance of Breast Cancer
fied in which mutations are associated with an up
Susceptibility Gene Detection 314
15.1.2.5 Additional Risk Factors 314 to 85% lifetime risk for developing breast cancer. It
15.1.2.6 Radiation Exposure in Screening and is estimated that more than 50% of BRCA1 muta-
Radiation Therapy 314 tion carriers have already developed the disease by
age 50 (Easton et al. 1995). In addition, BRCA1
15.1.3 Radiological Screening in High Risk
Populations 314 and BRCA2 genes are associated with an increased
15.1.3.1 Who Should Participate in Intensified risk for ovarian cancer. Other genetic predisposi-
Screening Programs? 314 tions for breast cancer might exist, but have not
15.1.3.2 Intensified Radiological Screening 315 yet been discovered. Therefore, evaluation of family
15.1.3.3 MRI Screening 315
history for breast and ovarian cancer is of signifi-
15.1.3.4 High-frequency Ultrasound 318
cant importance for the detection of individuals at
15.1.4 Breast Biopsy 318 moderate or high risk. Mammography is the cur-
rent standard screening method for early diagnosis
15.1.5 Primary Preventive Measures 320 of breast cancer. However, women at high-risk tend
15.1.5.1 Bilateral Preventive Mastectomy 320
15.1.5.2 Preventive Salpingo-Ovaraectomy 320
to develop cancer at a younger age, when their tissue
is more dense and the detection of small in-situ and
15.1.6 Summary 320 invasive cancer is more challenging. In this context,
additional imaging modalities and shorter screen-
References 321 ing intervals might contribute a potential benefit.
Nevertheless, in this age group, breast tissue shows
an increased sensibility for radiation. Different
recent studies support the application of contrast-
enhanced MRI in high-risk screening. The diagnos-
tic value of high-frequency ultrasound is currently
under evaluation. Besides imaging, an adapted
clinical surrounding is of significant importance
T. Schlossbauer, MD for intensified care of high-risk individuals. Radiol-
K. Hellerhoff, MD ogy and gynaecology departments should establish
C. Perlet, MD
Department of Clinical Radiology, University Hospitals –
intensive interdisciplinary cooperation and should
Grosshadern, Ludwig-Maximilians-University of Munich, consult a human genetics specialist for individu-
Marchioninistrasse 15, 81373 Munich, Germany alized risk assessment. Mammography-, ultra-
312 T. Schlossbauer, K. Hellerhoff, and C. Perlet
sound-, and MR-guided biopsy should be available
for evaluation of suspicious lesions, to allow his-
topathologic minimally invasive intervention. To
date, broadly accepted guidelines for screening of
high-risk patients have not yet been established.
However, different expert recommendations for
high risk breast cancer screening and patient care
are available and will be summarized in the follow-
ing sections.
15.1.2
Women at Increased Risk –
Standardized Risk Evaluation
Different predisposing factors have been identified.
The most important general risk factors are age and
gender. Less than 1% of breast cancer cases occur
in males. The overall risk of developing the disease
increases with age.
15.1.2.1
Patient’s Perspective
Primary motivations for individuals who seek out
preventive services include: family history, risk of
passing a mutation onto one’s children, recommen-
dations on screening options, and preventive sur-
gery (Struewing et al. 1995). For the most part,
women overestimate their risk for breast cancer or
BRCA mutations (Lerman et al. 1996). Most women
responding to surveys, including women at average
and moderate predisposition, report a strong desire
for genetic testing (Bowen et al. 2004). However,
only those with a high-risk family history would
potentially benefit. Concerns about cancer, scientific
advances, insufficient understanding of testing and
interventions, and advertising from medical com-
panies and health care professionals result in an
increased demand for genetic testing and accord-
ingly for intensified diagnostic imaging. No studies
describe diagnostic or mortality outcomes related
to genetic counselling. However, there is a signifi-
cant number of studies describing psychological and
behavioural outcomes. Decreased measures of psy-
chological distress have been reported. Particularly,
decreased breast cancer worry after the test result
has been transmitted, is one of the most important
benefits (Nelson et al. 2005).
15.1.2.2
Family History
After controlling for age, the greatest increase in risk
has been associated with a family history of breast
and/or ovarian cancer. Within family history, the
number of persons affected, the age at onset, and
the type of cancer are important variables. A family
history of early onset breast cancer (age less than
40) is present more frequently in young patients
compared to older individuals with breast cancer.
Also, a positive familial history of breast cancer
(any age) is more frequent in young than in older
affected individuals. Therefore, intense surveillance
of women with close relatives diagnosed with early
onset breast cancer is recommended (Lynch et al.
1988). The likelihood of inherited breast cancer
risk is higher when the biologic relationship of the
affected relative is closer (e.g. first-degree relative
like mother or sister), compared to a second-degree
relative (e.g. grandmother or aunt).
There are various models for assessing the indi-
vidual risk of developing breast cancer. The British
National Institute of Clinical Excellence (NICE) has
provided criteria for standardized risk evaluation
based on family history (NICE Guidelines 2004).
Patients are assigned to three groups (standard: life-
time risk < 17%, moderate: lifetime risk 17%–30%,
high risk: lifetime risk > 30%). Criteria to assign
individuals to the moderate or high-risk group are
summarized in Table 15.1.1
The NICE guidelines recommend screening
women at moderate breast cancer risk by annual
mammography from age 40 until 50 years. Women
at high risk are recommended to continue annual
screening beyond the age of 50 years. The American
Cancer Society (ACS) recommends mammography
based screening for women aged 40–49 years irre-
spective of predicted breast cancer risk with adap-
tation for high risk gene carriers. However, recent
studies have supported the use of MRI screening
in high-risk populations. Potential benefits of MRI
screening in moderate-risk populations and the use
of additional ultrasound screening are currently
under evaluation.
15.1.2.3
BRCA1 and BRCA2 Testing
Two breast and ovarian cancer susceptibility genes
have been identified, named BRCA1 and BRCA2.
 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk
Table 15.1.1. Criteria for classification of women into moderate and high risk for developing breast cancer. Guidelines of
the National Institute of Clinical Excellence
Moderate risk
 One fi rst degree relative diagnosed with breast cancer
< 40 years
 One fi rst degree relative + one second degree relative or
two fi rst degree relatives diagnosed with breast cancer
at any age
 Two second degree paternal relatives with breast cancer
 Three second degree relatives maternal relatives diag-
nosed with breast cancer at any age
 One fi rst degree male relative diagnosed with breast
cancer at any age
 One fi rst degree relative with bilateral breast cancer
 One fi rst or second degree relative with breast cancer +
one fi rst or second degree relative with ovarian cancer at
any age (one must be fi rst degree)
These genes show an autosomal dominant mode of
inheritance (Parmigiani et al. 1998). Mutations of
BRCA1 and BRCA2 genes are associated with an
increased risk for breast and ovarian cancer and
are widely spread in the general population (Miki
et al. 1994; Wooster et al. 1995). Certain specific
BRCA mutations are clustered among ethnic groups,
such as Ashkenazi Jews, and generally in the popu-
lations of Belgium, the Netherlands, Iceland, and
Sweden. Genetic testing should be considered in
patients with suspicious family histories. Family
history characteristics that suggest a genetic breast
cancer risk are summarized in Table 15.1.2 (Isaacs
et al. 2000). The diagnostic value and drawbacks of
genetic testing have to be discussed in detail with
the affected person and only those who have signed
informed consent should be enrolled.
Genetic risk can be inherited equally from mater-
nal and paternal side. There may be no apparently
affected first-degree relatives. Any woman with a
BRCA1 or BRCA2 mutation should be considered
at high risk. If mutation testing is not available, or
has been done but is non-informative, or if testing
was refused by the affected individual, family his-
tory (Table 15.1.1) characteristics have to be used for
genetic risk evaluation. Individuals with pedigree
high-risk criteria should be enrolled in intensified
screening, even if genetic testing gives a negative
result. BRCA1 and BRCA2 mutations are likely to be
responsible for only about half of hereditary breast
313
High risk
 Two fi rst, or one fi rst + one second degree relative both
diagnosed with breast cancer < 50 years
 Three fi rst degree + second degree relatives diagnosed
< 60 years
 Four fi rst + second + third degree relatives diagnosed
at any age
 One ovarian + one breast cancer diagnosed < 50 years
 Two ovarian and one breast cancer at any age
 One ovarian + two breast cancers < 60 years
 One bilateral breast cancer case both sides < 50 years
 Male breast cancer at any age + breast cancer < 50 years
or two breast cancer cases under 60 years
 Close family members Ashkenazi Jewish families with
breast cancer < 40 years or ovarian cancer
 Family patterns including Li-Fraumeni or hereditary
non-polyposis colonic carcinoma
Table 15.1.2. Increased probability of BRCA 1/2 mutation in
respective family histories
Two or more relatives with breast or ovarian cancer
Breast cancer occurring before age 50 in an affected rela-
tive
Relatives with both, breast and ovarian cancer
One or more relatives with two cancers (breast and ovarian
cancers or two independent breast cancers)
Male relatives with breast cancer
A family history of breast or ovarian cancer and Ashkenazi
Jewish heritage
cancers. Other genes, maybe with multi-factorial
heredity, have not yet been identified.
The American Society of Oncology (ASCO)
has provided an update on its general guidelines
for genetic testing for cancer (ASCO 1996). These
guidelines help to determine who would ben-
efit from testing and recommendations have been
accepted by those who provide genetic counselling
and testing services. Risk assessment is likely to
offer the greatest benefit for women aged less than
40. Patient education should consist of a compre-
hensive discussion of the benefits, limitations, and
risks of undergoing genetic testing. To date, there
is a lack of information regarding post-test disclo-
sure. The optimal manner in which the post-test
314 T. Schlossbauer, K. Hellerhoff, and C. Perlet
disclosure should be performed has not yet been
established. Isaacs et al. (2000) have described a
model for counselling which includes a post-test
disclosure session. The scheduled session should at
fi rst include the results of genetic testing, and sub-
sequently stress on medical management options
and coping strategies. Patients with known high-
risk status need personal guidelines for intensi-
fied clinical and radiological observation. In addi-
tion, a plan to disseminate results to other family
members, which also could potentially be affected,
should be provided.
15.1.2.4
Clinical Relevance of Breast Cancer
Susceptibility Gene Detection
For the most part, testing for breast cancer suscepti-
bility genes are detected after genetic counseling due
to a positive family history of breast or/and ovar-
ian cancer. Clinically significant BRCA mutations
are estimated to occur in 1 of 300 to 500 persons
in unselected populations (Antoniou et al. 2000).
These mutations increase a women’s lifetime risk
for breast cancer to 60%–85%. The lifetime risk
for ovarian cancer varies between 18% and 56%
(BRCA1) and 14% and 27% (BRCA2), depending on
the presence or absence of a family history for the
disease (Sogaard et al. 2006). Mutation carriers
develop breast cancer significantly earlier compared
to non-carriers (Antoniou et al. 2003). Further-
more, BRCA1 and BRCA2 mutations are associated
with the occurrence of prostate cancer, and BRCA2
mutations are related to an increased risk for pan-
creatic and stomach cancer and melanoma (Liede
et al. 2004).
In BRCA1 mutation carriers, the risk for devel-
oping breast cancer increases continuously begin-
ning at the age of 25, reaching a maximum between
45 and 49 years. Yearly incidences vary around 4%
(Kuhl 2006). In cases of previous breast cancer epi-
sodes, mutation carriers are at high risk to develop
a second carcinoma in the contra-lateral breast
(40%–60%).
BRCA associated cancer demonstrates distinc-
tive histological features compared to non-heredi-
tary carcinomas, meaning a significantly higher
frequency of rapidly growing G3 cancers and pre-
dominantly no expression of oestrogen receptors.
Medullary or atypical-medullary differentiation is
more frequent.
15.1.2.5
Additional Risk Factors
Additional factors enhancing breast cancer predis-
position have been identified, and thus may warrant
earlier or more frequent screening. These factors
include previous treatment with chest irradiation
(such as for Hodgkin’s lymphoma), a personal his-
tory of breast cancer, or a family history of dis-
eases known to be associated with hereditary breast
cancer such as Li-Fraumeni or Cowdens Syndrome.
These non-frequent syndromes might be respon-
sible for only about 2% of hereditary breast cancers
(Parmigiani et al. 1998).
15.1.2.6
Radiation Exposure in Screening and Radiation
Therapy
BRCA1 and BRCA2 represent damaged tumor sup-
pressor genes. Breast tissue in high risk patients may
be more sensitive to radiation exposure, as iden-
tification and repairing of double-strand damages
might be impaired. Double-strand damages are pre-
dominantly induced by ionising radiation. However,
there is no evidence that post-operative radiotherapy
induces higher incidences of local relapses in high
risk patients compared to same-age non-high risk
individuals (Kirova et al. 2005). Contrariwise, it
has been discussed whether the higher sensitivity to
radiation exposure in high-risk patients has a posi-
tive effect on the efficacy of radiotherapy (Veronesi
et al. 2005).
15.1.3
Radiological Screening in High Risk
Populations
15.1.3.1
Who Should Participate in Intensified Screening
Programs?
The diagnostic accuracy of BRCA1 or BRCA2 muta-
tion testing is 97%. However, other breast cancer
predisposing mutations have not yet been identi-
fied. Due to these unknown gene loci, the estimated
effective diagnostic accuracy for breast cancer gene
testing is only at about 50%. In cases of a nega-
 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk
tive BRCA1 or BRCA2 test result, the test is classi-
fied “non-informative”, and the individual risk for
developing breast cancer will be calculated from
pedigree criteria. The threshold to include patients
into an intensified screening program is determined
between 15% to 30% lifetime risk, according to
different international criteria. Software tools for
standardised risk evaluation based on individual
analysis of family history are available (“Cyrillic”,
“BRCA-PRO”). Risk assessment should be performed
by a human genetics specialist.
15.1.3.2
Intensified Radiological Screening
Different imaging modalities could potentially be
included into an intensified screening process, e.g.
mammography, high-resolution ultrasound, and
contrast-enhanced breast MRI. Recommendations
for specific imaging techniques and screening inter-
vals are predominantly based on incidence analyses
at different age groups. Women at increased risk
might benefit from additional screening strategies
beyond those offered to women at average risk. The
evidence currently available is insufficient to justify
strict recommendations for a specific modality or
screening interval (Smith et al. 2003). Based on the
limited available information and expert opinion,
general recommendations have been developed by
the ACS in 2003 (Smith et al. 2006). These guidelines
include the fact that women at increased risk should
talk with their doctors about the benefits and limi-
tations of starting mammography checks earlier,
having additional tests (for example, breast ultra-
sound, or MRI), or having more frequent exams.
Screening in each individual should be based on
shared decision-making after a review of poten-
tial benefits, limitations, and dangers of different
screening strategies and the degree of uncertainty
about each. Generally, in patients with elevated risk,
screening should be initiated at the age of 30 (or
5 years prior to the first cancer episode in family
history) and intervals should not exceed 1 year.
In cases of a documented high-risk situation (e.g.
mutation carriers, high-risk family history), inter-
vals should not exceed 6 months (Pichert et al.
2003). Figure 15.1.1a–d shows mammograms of a
65-year-old high-risk patient (BRCA2, father with
breast cancer) who had breast-conserving therapy
(left side) because of an invasive ductal carcinoma
3 years ago. Mammograms do not show a suspicious
315
lesion. Routine annual MRI screening (Fig. 15.1.1e–
g) shows a round, well-defined retromamillar lesion
in the right breast. Histological evaluation after sur-
gical excision of the lesion confirmed an invasive
ductal carcinoma.
Based on an analysis among 192 BRCA mutation
carriers, recommendations for intensified screen-
ing in high-risk populations were provided (Kuhl
et al. 2000). A significantly increased sensitivity and
equal specificity of contrast-enhanced breast MRI
compared to mammography was found. Results jus-
tify annual MRI screening within high-risk popu-
lations. Similar studies were conducted in differ-
ent countries (including the U.S. and Canada), and
study results could be reproduced several times.
Sensitivity for the detection of breast cancer is
approximately twice as high in MR screening com-
pared to mammography. Based on these findings,
intensified screening in high-risk groups includes
annual mammograms starting at an age of 30 years,
annual contrast-enhanced MRI, and periodic high-
frequency ultrasound once every 6 months.
15.1.3.3
MRI Screening
Screening MRI is not recommended for women at
average risk. In these individuals, MRI is recom-
mended solely for generally accepted indications,
e.g. staging in patients with known malignancy, his-
tory of breast cancer and postoperative scarring, and
searching for cancer of unknown primary. The high
sensitivity of the method would lead to the detection
of a large number of false positive lesions which sub-
sequently require invasive evaluation. However, in
individuals with an increased risk for breast cancer,
MRI represents a valuable screening method. In
these populations, sensitivities for the detection of
cancer between 71% and 100% have been reported
(Lehmann 2006). The relatively low detection rates
of mammography (sensitivities between 0% and
40%) and ultrasound (sensitivities between 13% and
40%) in high-risk populations underline the value of
MRI in this particular surrounding. During a clini-
cal evaluation conducted with BRCA1 and BRCA2
mutation carriers, 9.3% of women developed in situ
or invasive cancer within a 36 months period under
observation. Figure 15.1.2a,b shows right mammo-
grams of a 40-year-old high-risk patient (BRCA1)
with mastectomy because of left breast invasive
breast cancer 4 years ago. No suspicious lesion
316 T. Schlossbauer, K. Hellerhoff, and C. Perlet

a b c d

e f g

Fig. 15.1.1. a–d Digital mammograms of a 65-year-old patient 3 years after breast conserving therapy. Residual parenchyma
in anterior localisation. No suspicious lesion could be detected. Corresponding 3D T1-weighted fast low-angle shot sequence.
e Pre-contrast image. f Fourth repetition after contrast injection (0.1 mmol/kg) shows a round-shaped retromamillar lesion
with homogenous enhancement. g Subtraction

could be detected. Additional routine MR screen-
ing (Fig. 15.1.2c,d) depicts two focal lesions with
pronounced contrast enhancement. Subsequent
histological evaluation confirmed a bifocal invasive
ductal cancer.
The positive predictive value of suspicious con-
trast-enhancing lesions in MRI depends on the expe-
rience of the reader. A high correlation of the experi-
ence of readers and the positive predictive value for
malignancy has been reported (Warner et al. 2001).
Similar results were found regarding sensitivity of
MRI screening. MRI findings in each patient need
to be compared with previous studies and findings
from clinical evaluation, mammography, and ultra-
sound in order to improve diagnostic accuracy. The
MR-mammographic detection of in-situ carcinoma
is particularly challenging. Typical signs of malig-
nancy, like intense contrast enhancement and signal
 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk 317

a b

c d

Fig. 15.1.2. a,b Mammograms of the right breast of a 40-year-old patient with previous mastectomy of the left breast because
of ductal invasive cancer. Mammograms show dense parenchyma (ACR3) and no focal lesion. c,d Corresponding contrast-
enhanced dynamic MRI (subtraction images) shows two suspicious lesions with an intense homogenous enhancement in
the right breast. Histological evaluation confi rmed a bifocal ductal invasive carcinoma

intensity time curves with a washout phenomenon
in the post-initial phase are missing in 40%–60% of
in-situ lesions. Of in-situ carcinomas, 10% do not
show the contrast enhancement pattern character-
istic for malignant tumors, but a delayed enhance-
ment with a spotty, linear, segmental or ductal shape
(Hwang et al. 2003).
Figure 15.1.3 displays the sinistral breast MRI of a
58-year-old high-risk patient with previous left side
breast conserving therapy because of ductal invasive
cancer. Excision biopsy was made 1 year ago because
of a palpable lesion 12 months ago. There was an
additional excision biopsy 9 months ago, again
because of a palpable lesion. Both lesions showed a
benign histology. In mammography, besides post-
operative changes, no focal lesion was visible. Cur-
rent MRI shows a small lateral round-shaped lesion
(Fig. 15.1.3a,b). Histological evaluation after MR-
guided biopsy showed an invasive ductal carcinoma
(Fig. 15.1.3c).
318 T. Schlossbauer, K. Hellerhoff, and C. Perlet

a b c

Fig. 15.1.3a–c. Sinistral breast MRI of a 58-year-old high-risk patient with previous left side breast conserving therapy
because of ductal invasive cancer. Excision biopsy 1 year ago because of a palpable lesion 12 months ago. Additional exci-
sion biopsy 9 months ago, again because of a palpable lesion. Both lesions showed a benign histology. In mammography,
besides postoperative changes, no focal lesion was visible. Current MRI shows: a,b a small lateral round-shaped lesion; c
histological evaluation after MR-guided biopsy showed an invasive ductal carcinoma

Figure 15.1.4a–d shows mammograms of a 45-
year-old patient with known BRCA1 mutation. In
the left breast extensive polymorphic microcalci-
fications are present in the inner quadrants. MRI
(Fig. 15.1.4e–g) shows a homogenous enhancement
of the parenchyma of the left breast which affects
all four quadrants. The right breast does not show
a substantial enhancement. Histological evaluation
confirmed a ductal in-situ carcinoma with invasive
components.
the shortcomings of mammography, and it causes
a substantial number of false positive diagnoses.
A combination of MRI and mammography screen-
ing with ultrasound does not result in a substan-
tial improvement of diagnostic accuracy. However,
high-frequency ultrasound is recommended as the
imaging modality of choice every 6 months to close
the gap between the annual mammography and MRI
screening intervals in high-risk individuals. To date,
a substantial diagnostic outcome, i.e. earlier detec-
tion of interval-carcinomas, has not been reported.

15.1.3.4
High-frequency Ultrasound

High-frequency ultrasound of the breast should 15.1.4

be performed with 7.5–13.5-MHz probes. The
entire breast (both sides) have to be examined sys-
tematically with a special focus on regions which
might have shown a suspicious lesion in a previous
examination (i.e. MRI or mammography). Suspi-
cious lesions should be documented and archived
according to ACR guidelines (American College
of Radiology 1993, 2003). Detection rates of up to
43% have been reported when using solely ultra-
sound for high-risk screening (Kuhl et al. 2005).
However, compared to MRI, the performance of
ultrasound in early detection of cancer in high-risk
individuals is poor (Warner et al. 2001). If ultra-
sound is used in combination with mammography,
it can only partially help to compensate for some of
Breast Biopsy
Image-guided biopsy in risk-populations does not
substantially differ from that in regular patient pop-
ulations. However, as the diagnostic threshold for
potential malignancy is generally set to a lower level,
prompt accomplishment of interventions should be
provided in order to reduce psychological distress
for affected individuals. As shorter screening inter-
vals in risk-groups potentially produce false positive
results more frequently, minimal-invasive biopsy
methods should be favoured over image-guided
wire localisation and subsequent surgical biopsy.
In cases of false positive findings, unnecessary
surgical interventions can be avoided. In cases of
 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk 319

a b

c d

Fig. 15.1.4. a–d Polymorph microcalcifications in the inner quadrants (see text). e–g Corresponding MRI study. Ductal
carcinoma in situ with invasive components. Homogenous contrast enhancement in sinistral residual parenchyma. 3D T1-
weighted fast low-angle shot sequence. e Pre-contrast image. f Fourth repetition after contrast injection. g Subtraction

true positive findings in image-guided biopsy, ade-
quate planning of subsequent surgical procedures
can be achieved. Techniques in use include fine-
needle aspiration cytology, core-needle biopsy, and
vacuum-assisted core-biopsy (Vargas et al. 2000).
For guiding the biopsy, the imaging method should
be employed in which the target lesion is most read-
ily detected. Compared to core-needle and vacuum-
assisted biopsy, fine-needle aspiration techniques
have become less important, as the first mentioned
methods provide more representative specimens
for histological evaluation and the sampling error
is reduced. For MR-guided and mammography-
guided interventions, vacuum-assisted techniques
should be preferred (Perlet et al. 2002). Its main
advantage concerns the acquisition of a larger tissue
volume. This allows one to reduce sampling error,
which is important for the histopathologic diagnosis
of small in situ malignancies or borderline lesions.
Furthermore, tissue shift by bleeding is avoided by
continuous suction and errors due to tissue shift
may be compensated by removing a sufficiently large
320 T. Schlossbauer, K. Hellerhoff, and C. Perlet
area of tissue (1.5–2 cm in diameter). Finally, cor-
rect biopsy can be proven by direct visualization of
lesion removal on the postinterventional images.
MR-guided vacuum-assisted biopsy in high-risk
patients has a high diagnostic value and allows to
greatly reduce the number of surgical interventions
(Perlet et al. 2006; Viehweg et al. 2006). In 97
cases, only 24% of focal enhancing lesions showed
a malignant histology. In MR-guided interventions,
success rates of up to 98% have been reported. MRI
guided biopsy should be conducted between days 7
and 15 after the fi rst day of menstrual cycle in order
to avoid hormone induced contrast enhancement.
Additionally, hormone replacement therapy should
be interrupted approximately 4 weeks prior to each
breast MRI. By now, several biopsy devices for MR-
guided intervention have been developed and most
aids available provide medial and lateral access.
Similar to MR-guided interventions, there is no
technical difference in performing mammography
and ultrasound-guided biopsies between high-risk
and average-risk populations. If initial ultrasound
did not show a pathologic finding, but subsequent
MRI evaluation leads to the detection of a suspi-
cious lesion, ultrasound should be repeated. In cases
which finally show a morphologic correlate under
the knowledge of the MRI result, ultrasound-guided
biopsy should be performed. Potential advantages
of ultrasound-guided biopsy include lower costs,
higher acceptance by affected individuals, and a
less time consuming procedure compared to MRI-
guided biopsy.
15.1.5
Primary Preventive Measures
15.1.5.1
Bilateral Preventive Mastectomy
Primary prevention of inherited breast cancer can
be obtained through prophylactic bilateral mas-
tectomy. Various studies have shown a significant
reduction of cancer risk (Meijers-Heijboer et al.
2001; Rebbeck et al. 2004). Quality guidelines for
preventive mastectomy have been introduced by the
European Society of Mastology (EUSOMA) in 1992.
Guidelines include recommendations regarding
counselling measures, surgery, and breast recon-
struction (Petit and Greco 2002). Outcome goals
Table 15.1.3. Outcome measures for prophylactic mastec-
tomy (PM) according to EUSOMA
Final cosmetic result of the reconstructed breast follow-
ing PM should be excellent (with complete satisfaction on
behalf of the woman), in at least 75% of cases
Minor complications (e.g. infection, persistent pain, lim-
ited skin necrosis, etc.) should be expected in less than 10%
of cases
Asymmetry of the breast with modification in shape (and
consistency) and contracture of peri-prosthetic capsula
should occur in less than 20% and 10%, respectively
Of women undergoing PM, 100% should be completely
informed by the plastic surgeon, of the type of operation,
they are undergoing and the possible complications should
be explained in detail
Of women undergoing PM, 95% should be followed up with
an annual physical examination carried out by a breast and
plastic surgeon
When the correct positioning of the implant is to be
assessed, ultrasound examination should be adopted in
100% of cases
If a possible rupture of the implant is suspected, MRI
should be prescribed in 100% of cases
and procedures for diagnostic evaluation to ensure
quality of treatment are summarized in Table 15.1.3.
Follow-up examinations should include ultrasound
if implant dislocation is suspected. MRI should be
performed for the evaluation of implant rupture.
15.1.5.2
Preventive Salpingo-Ovaraectomy
In high-risk populations, preventive salpingo-ova-
rectomy leads to a significant reduction of both,
breast and ovarian cancers (Kauff et al. 2002). Pre-
ventive treatment with Tamoxifen might represent
another option, however further research has to be
conducted on this topic.
15.1.6
Summary
Recent study results indicate that MRI screening in
addition to mammography, ultrasound and clini-
cal evaluation significantly improves sensitivity for
the detection of in-situ and invasive breast cancer
 Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk
in high-risk individuals. MRI should be part of the
annual breast cancer screening in these patients.
Each MRI study has to be evaluated by experienced
readers, in order to identify subtle lesions (e.g. in-
situ carcinomas) which frequently do not fulfi l the
standard MRI criteria of malignancy. Assessment
of suspicious lesions should be performed without
delay in order to minimize psychological distress
of patients. Compared to surgical evaluation, ultra-
sound-, mammography-, or MR-guided biopsy rep-
resent cost-effective and time-saving alternatives
with comparable diagnostic accuracies. Screening of
high-risk individuals should be embedded into a spe-
cialized clinical surrounding with close cooperation
of radiologist, gynaecologist, and human genetics
specialist. Each of the screening methods has limita-
tions, and there are potential harms associated with
false-positive findings. Women should be informed
about the benefits and limitations of screening. Mul-
tiple international studies have demonstrated that
MRI is a powerful tool for the early detection of
breast cancer in high-risk individuals. Results could
be independently reproduced. However, to date, the
impact of intensified screening on survival remains
unclear. Further studies need to be conducted to
evaluate if the earlier detection of malignant lesions
finally leads to higher survival rates.
The authors of this section support annual mam-
mography and breast MRI, and additional high-fre-
quency ultrasound every 6 months in patients who
fulfi l high-risk criteria. Screening should be initi-
ated approximately 5 years prior to the first case in
family history (e.g. mother diagnosed with breast
cancer at the age of 35, daughter starts screening at
30 years of age).
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 Genetic Disposition: Practical Aspects and Results of Screeening for Medullary Thyroid Carcinoma 323

Genetic Disposition 15
15.2 Practical Aspects and Results of Screeening for
Medullary Thyroid Carcinoma
Friedhelm Raue and Stefan Delorme

CONTENTS cal features of neuroendocrine tumors. In 75% of

15.2.1 Introduction 323
15.2.2 Natural Course of Disease 323
15.2.3 Therapeutic Modalities 323
15.2.4 Screening and Diagnosis of MTC
patients, the disease is sporadic, whereas in the
remaining, there is a hereditary mutation of the
RET proto-oncogen, which also predisposes to
pheochromocytomas, and, to a lesser extent, to
parathyroid adenomas (multiple endocrine neopla-
sia type 2, MEN 2) (Leboulleu et al. 2004; Cohen
EG et al. 2004; Gimm et al. 2001).
324

15.2.5 Calcitonin 324

15.2.6 RET Mutations in MEN 2 Patients 325

15.2.2
15.2.7 Imaging Methods of Medullary Thyroid Natural Course of Disease
Carcinoma 3264

15.2.8 Conclusion 327 The natural history of medullary thyroid carcino-

References 327
15.2.1
Introduction
Of all malignant thyroid tumours, 7%–10% are
medullary carcinomas. Medullary thyroid carci-
noma (MTC) is a rare calcitonin-secreting tumor
of the parafollicular or C-cells of the thyroid. As
the C-cells originate from the embyonic neural
crest, MTC often have the clinical and histologi-
mas is distinctly different from that in other solid
tumours, with a slow progression, and therefore a
course of disease which may extent over more than
20 years. There is, however, a broad variability, and
patients are seen in whom the disease is rapidly and
relentlessly progressive, despite treatment. Local
lymph node metastases are often seen at the time of
diagnosis. They are mostly located in the central and
lateral compartment of the lower neck, the supracla-
vicular regions, and the mediastinum. Metastases in
the suprahyoid neck (e.g., at the mandibular angle)
do occur but are less common. Haematogenous, dis-
tant metastases occur later in the clinical course,
and may be preferentially located in the lung, liver,
and bone (Raue and Frank-Raue 2005).

F. Raue, MD
Professor, Endocrine Practice, Brückenstrasse 21, 69120 15.2.3
Heidelberg, Germany Therapeutic Modalities
S. Delorme, MD
Professor, Department of Radiology, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, To date, the only established treatment modality
Germany is surgical removal of the thyroid and regional
324 F. Raue and S. Delorme
metastases. The only chance of cure is surgery.
The lymphadenectomy, which under optimal cir-
cumstances is carried out in the same session as
total thyroidectomy, should be a modified, radi-
cal one, depending on the tumor stage. It should
include preservation of the jugular vein and the
sternocleidomastoid muscle, and can be limited
to the central compartment, and, when the central
compartment is involved, dissection of the lateral
compartments is indicated. Neither is there a role
for a classical, radical neck dissection, which is a
mutilating procedure, nor for radioiodine therapy
or postoperative radiotherapy. The latter is par-
ticularly obsolete, since it increases the likelihood
of complications if resection of metachroneous
metastases are attempted in the later course. The
value of chemotherapy is unproven, and radio-
therapy is reserved for palliation. Octreotide treat-
ment may be of help in patients with advanced
metastasizing medullary thyroid carcinoma, how-
ever, it has not been demonstrated that octreotide
reduces the tumor mass or improves the patient
survival rate; clinical studies with tyrosinkinase
inhibitors are on the way. Partial thyroid resec-
tion is inadequate, especially in hereditary MTC,
because the tumour may be multicentric, and
diffuse C-cell hyperplasia, a precancerous condi-
tion, is often present. Persistent and/or recurrent
tumours are frequent, but biochemical cure can
only be achieved in a minor portion of patients;
therefore reoperation of lymph node metastases is
possible in the later course of the disease, but the
indication is palliative. It is not proven whether
repeated resections, attempting to achieve radical
removal of the tumour burden, is advantageous for
the patients, given the risk of local complications
in pre-operated areas.
The most important prognostic factor is the pres-
ence or absence of lymph node (or even distant)
metastases (tumour stage) at the time of diagnosis
or surgery. Once lymph nodes are involved, cure
rate decreases, and no patient with more than 10
metastatic lymph nodes has so far been biochemi-
cally cured. In these patients it appears that those
are better in whom an oncologically radical thyroid-
ectomy and lymph node dissection was carried out
in a single session, compared to those who had to
undergo multiple resections until radical removal of
cancer was achieved. Unfortunately, there are still
patients in whom this is the case, because primary
surgery was inadequate (Gimm et al. 2001; Vitale
et al. 2001).
15.2.4
Screening and Diagnosis of MTC
The way MTC is detected and diagnosed has
changed within the last decade by using specific
strategies: calcitonin screening in patients with thy-
roid nodules and screening with molecular methods
for RET proto-oncogene mutations in patients with
apparently sporadic MTC and in family members
at risk for MTC. By earlier identification of patients
with MTC, the presentation changed from clinical
tumours to pre-clinical disease resulting in a high
cure rate of affected patients with much better prog-
nosis (Raue and Frank-Raue 2005).
15.2.5
Calcitonin
The primary secretory product of MTC is calcito-
nin (Calcitonin), a peptide hormone consisting of 32
amino acids and with a molecular mass of 3400. Cal-
citonin serves as a tumor marker, and measurement
of monomeric Calcitonin with two-site assays remains
the definitive test for prospective diagnosis of MTC.
The test is widely available, accurate, reproducible,
and cost-effective. The sensitivity and specificity can
be increased by stimulation of Calcitonin release using
pentagastrin. 0.5 ug pentagastrin/kg body weight are
administered as an intravenous bolus over 5–10 s, and
Calcitonin measurements are made at 2 and 5 min.
Abnormal elevation of Calcitonin is a reliable pre-
dictor of C-cell hyperplasia or MTC. Either basal
or stimulated plasma Calcitonin levels are elevated
in virtually all patients with MTC. Basal Calcitonin
concentrations usually correlate with tumor mass
and are almost always high in patients with palpable
tumors (Cohen R et al. 2000). Elevated plasma Calci-
tonin levels following surgery to remove the tumor are
indicative of persistent or recurrent disease.
Measurement of serum calcitonin has been part
of the routine evaluation of patients with thyroid
nodules, up to three percent of patients with thyroid
nodules have pathological serum Calcitonin concen-
trations (Elisei et al. 2004; Karges et al. 2004). The
prevalence of MTC was 50% when basal Calcitonin
level were elevated more than 30 pg/ml and stimu-
lated Calcitonin above 100 pg/ml, and 100% when
basal Calcitonin levels were more than 200 pg/ml
 Genetic Disposition: Practical Aspects and Results of Screeening for Medullary Thyroid Carcinoma
measured with specific and sensitive two-site assays.
This procedure allows early diagnosis and early sur-
gery of MTC, reducing the significant mortality asso-
ciated with this malignant tumour. It is well known,
that basal plasma Calcitonin can also be elevated
during normal childhood and pregnancy in differ-
ent malignant tumors, Hashimoto’s thyroiditis and
chronic renal failure. Patients with these conditions,
however, usually have blunted or absent stimulatory
responses to Calcitonin secretagogues. Provocative
Calcitonin stimulation tests thus help to sort out these
false-negative and false-positive conditions. There
are a number of other substances, including carcino-
embryonic antigen (CEA), PDN-21 (katacalcin), chro-
mogranin A, neurone-specific enolase, somatostatin,
ACTH, that are produced by MTC and which may
help to differentiate it from other tumors.
Routine Calcitonin measurement has been sug-
gested for the work-up of patients with thyroid nod-
ular disease (Fig. 15.2.1), followed by a pentagastrin
stimulation test in all cases of detectable basal Cal-
citonin levels more than 30 pg/ml. Stimulated calci-
tonin levels of more than 100 pg/ml is highly suspi-
Thyroid nodule
Serum calcitonin determination
normal elevated
<10 pg/ml >10 pg/ml
pentagastin stimulation test
stimulated Calcitonin
30-100 pg/ml >100pg/ml
re-evaluate after suspected MTC
6 months
total thyroidectomy
histologically confirmed MTC
RET- gene analysis
Negative positive
SporadicMTC MEN 2 /familial MTC
Family screening with
specific RET-mutation
Fig. 15.2.1. Screening for sporadic and familial medullary
thyroid carcinoma (MTC)
325
cious for MTC, more than 200 pg/ml indicate MTC
in nearly 100%. This procedure allows the preopera-
tive diagnosis of unsuspected MTC at a relative early
stage where the tumor is limited to the thyroid and a
definitive cure by surgical treatment is possible.
15.2.6
RET Mutations in MEN 2 Patients
The MEN 2 gene was localised to centromeric chro-
mosome 10 by genetic linkage analysis in 1987. Point
mutations of the RET proto-oncogene were iden-
tified in 1993 in MEN 2A, MEN 2B and FMTC in
six closely located exons (Kouvaraki et al. 2005).
Analysis of RET in families with MEN 2A and
FMTC revealed that only affected family members
had germline missense mutations. This has brought
major advances in our understanding of the molecu-
lar genetic basis of medullary thyroid cancer and
has significantly changed the clinical management
of these families with hereditary tumors.
The RET gene has 21 exons and encodes a recep-
tor tyrosine kinase that appears to transduce growth
and differentiation signals in several developing tis-
sues including those derived from the neural crest. It
is expressed in cells, such as C-cells, the precursors
of medullary thyroid carcinoma, and in pheochro-
mocytomas. The RET gene codes for a receptor that
has a large extracellular cysteine-rich domain which
is involved in ligand binding, a short transmembrane
domain, and a cytoplasmic tyrosine kinase domain
which is activated upon ligand-induced dimerization.
Recent studies have provided evidence for an
activating effect of receptor mutations associated
with MEN 2/FMTC. It was demonstrated that muta-
tion of the extracellular cysteine at codon 634 causes
spontaneous receptor dimerization, enhanced
phosphorylation, and cell transformation without
ligand binding (autophosphorylation). Mutation of
the intracellular tyrosine kinase (codon 918) has no
effect on receptor demerization but causes enhanced
phosphorylation of a different set of substrate pro-
teins and also results in cellular transformation.
Point mutations in the RET proto-oncogene have
been identified in 92%–100% of MEN 2 and FMTC
families in exon 8, 10, 11, 13–16 (Berndt et al. 1998;
Frank-Raue et al. 1996; Kouvaraki et al. 2005). In
the majority of these families, germline point muta-
tions are found tightly clustered in five cysteine
326 F. Raue and S. Delorme
codons in a cysteine-rich region of the extracellular
domain of the RET protein (Exon 10: codons, 609,
611, 618, 620; exon 11: 630, 634). In 87% of MEN 2A
families cysteine codon 634 is affected, and is par-
ticular the most common mutation of this codon,
associated with pheochromocytoma and parathy-
roid gland involvement with MEN 2A families.
Therefore individuals with this mutation should be
annually screened for endocrinopathies like pheo-
chromocytoma and parathyroid tumors.
Mutations in exon 13 (768, 790, 791 ), exon 14 (804,
844) and exon 15 (883, 891) of the RET gene were
detected especially in families with hereditary MTC
without other endocrinopathies (FMTC=familiar
MTC) (Kouvaraki et al. 2005).
In 95% of families with MEN 2B a mutation in
codon 918 in exon 16 was found. Approximately
23%–60% of sporadic MTCs have a codon 918
somatic (present in tumor only) mutation identical
to the germline mutation found in MEN 2B.
In hereditary MTC DNA –based diagnosis of
MEN 2 has replaced measurement of stimulated CT
levels in the identification of gene carriers. Detec-
tion of the RET mutation carriers in kindreds with
hereditary MTC allows for early intervention with
prophylactic thyroidectomy and alters the course of
MTC, reducing both disease-related morbidity and
death.
The optimal treatment strategy is to prevent
hereditary MTC by performing early thyroidec-
tomy before malignant transformation occurs. The
timing of surgical intervention in patients being
evaluated for prophylactic thyroidectomy and the
extent of surgery in patients with established MTC
are based on the specific RET mutation risk group
(Brandi et al. 2001; Machens et al. 2003; Frank-
Raue et al. 2006).
15.2.7
Imaging Methods of Medullary Thyroid
Carcinoma
The role of imaging methods in the work up of MTC
is to localize the tumor, its burden and the exten-
sion of the disease. In patients with thyroid nod-
ules thyroid ultrasound, 99mTc thyroid scan (when
indicated) and calcitonin determination is done. At
ultrasound, MTC shows a hypoechogenic pattern,
often with calcification (Fig. 15.2.2); in thyroid scan
Fig. 15.2.2. Ultrasound longitudinal section (14 MHz linear
transducer) over the left thyroid lobe. Medullary thyroid
carcinoma (straight arrows) with low echogenicity, its irreg-
ular contour, and small internal microcalcifications (curved
arrow)
a hypofunctional cold nodule is seen, not different
from other forms of thyroid malignancies (Saller
et al. 2002). When MTC is suspected because of
elevated basal and/or stimulated calcitonin a fine
needle aspiration biopsy is indicated, confirming
the malignancy. Calcitonin levels may be elevated
and hence indicate the presence of persistent or
recurrent disease while imaging technique fail to
identify these lesions. Preoperatively a cervical
ultrasound, as well as a cervical and mediastinal
CT scan help to define the involvement of cervical
and mediastinal lymph nodes, suspicious lesions in
the lung and the relationship between the tumor
and the upper aerodigestive tract. Ultrasound of the
liver and/or CT scan may also be helpful in detecting
hepatic lesions. Lymph node metastases are most
commonly seen in the lower cervical groups, i.e.,
medial and lateral to the common carotid artery
and the internal jugular vein, in the jugulum, and
behind the claviculae. The suprahyoid groups sub-
mandibular, retromandibular, and submental are
less frequently involved. As always, the differentia-
tion between reactive and metastatic lymph nodes
is difficult and possibly better with ultrasound than
with CT. Compared to inflammatory nodes, metas-
tases have a more roundish contour, lack an echo-
genic hilum, have a characteristic “pepper-and-salt”
texture (which makes them appear brighter than
reactive nodes), and are strikingly hypervascular,
even if small (Fig. 15.2.3).
Wherever lymph nodes are well accessible with
ultrasound, CT has no advantage at all, except for
 Genetic Disposition: Practical Aspects and Results of Screeening for Medullary Thyroid Carcinoma
Fig. 15.2.3. Ultrasound transverse section in the right su-
praclavicular fossa, with a 14 MHz linear transducer angu-
lated straight downwards. Lymph node metastasis due to
medullary thyroid carcinoma behind the clavicle (arrows),
with marked hypervascularization. IJV=internal jugular
vein, SCA=subclavian artery
permitting a more reliable follow-up, e.g., for RECIST
assessments. The region behind the clavicles is more
difficult to assess using CT, due to beam hardening
artifacts at the bone-tissue interface. In the medias-
tinum, naturally, CT is necessary; presently there is
no advantage of MRI over CT.
Imaging and disease localization in the follow
up of patients with persistent or recurrent MTC are
conventional techniques like ultrasound, computed
tomography, MRI or radionuclide imaging with 131-
I-MIBG, 111-In-octreotide or 99m-Tc-DMSA. How-
ever, the vast majority of patients with metastatic
disease will have a positive CT scan. How to select
patients with a negative CT scan to undergo soma-
tostatin receptor scintigraphy is not clear. Scanning
may be more useful in localizing residual or recur-
rent disease after primary therapy. In patients sus-
pected to harbor skeletal metastases, MRI may be
superior to other imaging modalities for identifying
these lesions. New molecular targeting approaches
like anti CEA immunoscintigraphy, CCK-B/gastrin
receptor scintigraphy, DOTATOC scintigraphy, FDG-
PET offer a novel and promising tool, as they might
be also used for therapeutic options (Hoegerle et
al. 2001; Behr and Becker 2005).
In patients with slightly elevated calcitonin levels
after surgery of medullary thyroid carcinoma indi-
cating the presence of persistent disease, imag-
ing techniques often fail to identify the suspected
lesions. However, the decision for a curative reopera-
tion does not depend on the result of imaging meth-
327
ods, but rather on the tumour stage and adequacy of
previous operations. If adequate operation of central
and/or lateral lymph node compartments was done,
it is likely that cure rate will not improve in patients
with tumour extension beyond the thyroid capsule
or with more than 10 lymph node metastases.
15.2.8
Conclusion
Prognosis of MTC has greatly improved by family
screening for germline mutation in RET proto onco-
gen in hereditary cases leading to earlier diagno-
sis and treatment and by calcitonin screening in
patients with thyroid nodules. Imaging methods are
useful in localizing tumor burden in proven MTC
but are not sensitive and specific enough for screen-
ing in patients at risk.
References
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cancer. In: Biersack H-J, Grünwald F (eds) Thyroid Ccan-
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Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grußen-
dorf M, Raue F, Ritter MM, Höppner W (1998) A new hotspot
for mutations in the RET proto-oncogene causing familial
medullary thyroid carcinoma and multiple endocrine neo-
plasia type 2A. J Clin Endocrinol Metab 83:770–774
Brandi ML, Gagel R, Angeli A et al. (2001) Guidelines for
diagnosis and therapy of MEN type 1 and type 2. J Clin
Endocrinol Metab 86:5658–5671
Cohen EG, Shaha AR, Rinaldo A, Devaney KO, Ferlito A
(2004) Medullary thyroid carcinoma. Acta Otolaryngol
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L, Miccoli P, Iacconi P, Basolo F, Pincera A, Pacini F (2004)
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noma. Cancer 91:1797–1800

Predisposing Diseases
16.1 Chronic Hepatitis and Liver Cirrhosis
Gerald U. Denk and Ulrich Beuers
CONTENTS
16.1.1 Chronic Hepatitis B and D 329
16.1.2 Chronic Hepatitis C 330
16.1.3 Hemochromatosis 330
16.1.4 Wilson’s Disease 331
16.1.5 α1-Antitrypsin Deficiency 331
16.1.6 Autoimmune Hepatitis 332
16.1.7 Primary Biliary Cirrhosis 332
16.1.8 Primary Sclerosing Cholangitis 332
16.1.9 Alcoholic Liver Disease 332
16.1.10 Non-alcoholic Steatohepatitis 333
16.1.11 Chronic Liver Disease and Hepatocellular
Carcinoma 333
References 334
Liver cirrhosis is the final stage of a chronic hepato-
pathy characterized by widespread fibrosis, nodule
formation and destruction of the lobular and vas-
cular architecture of the liver. Alcohol abuse and
chronic viral hepatitis are the main causes of liver
cirrhosis. Other less frequent causes are inherited
(e.g., hemochromatosis, Wilson’s disease, α1-anti-
trypsin deficiency) and autoimmune disorders (e.g.,
G. U. Denk, MD
Department of Medicine II , University Hospitals – Grosshadern,
Ludwig-Maximilians-University of Munich, Marchionini-
strasse 15 , 81377 Munich, Germany
U. Beuers, MD
Professor, Department of Gastroenterology and Hepatology,
Academic Medical Center, University of Amsterdam,
Meibergdreef 9, P.O. Box 22700, 1100 DE Amsterdam,
The Netherlands
Predisposing Diseases: Chronic Hepatitis and Liver Cirrhosis 329
16
autoimmune hepatitis, primary biliary cirrhosis,
primary sclerosing cholangitis) and vascular liver
diseases. Any cirrhosis of the liver irrespective of its
origin represents a risk factor for developing hepa-
tocellular carcinoma, the most frequent primary
malignancy of the liver. The following chapter pro-
vides an overview of the most frequent hepatopa-
thies causing cirrhosis of the liver.
16.1.1
Chronic Hepatitis B and D
Hepatitis B is one of the most frequent infections
world-wide. According to the World Health Orga-
nization two billion people have been infected and
more than 350 million suffer from chronic infec-
tion. In the Western world transmission of the
hepatitis B virus mostly occurs via sexual contact
and intravenous drug abuse. Pre- and perinatal
transmission of the hepatitis B virus from infected
mothers to the embryo is very common with up
to 95% of cases worldwide, but is not a frequent
route of infection in the Western world. Between
5% and 10% of infected adults and 90% of infected
newborns become chronic carriers of the virus
with an increased risk for developing cirrhosis and
hepatocellular carcinoma. According to the Robert
Koch Institute (Berlin, Germany) the risk for devel-
oping cirrhosis in HBe antigen positive carriers is
8%–10% per year and 2%–5.5% per year in HBe
antigen negative carriers. The risk for developing
hepatocellular carcinoma is increased by a factor
of 100 in patients with chronic infection with the
hepatitis B virus with an incidence of 0.5% per year
and 2.5% per year in case of known cirrhosis in
comparison with the normal population (Bruix
and Sherman 2005).
330 G. U. Denk and U. Beuers
Also the hepatitis D virus (HDV) is prevalent all
over the world. An infection with this virus is pos-
sible only in the presence of the hepatitis B virus.
Both, simultaneous infection with hepatitis B
virus and hepatitis D virus (coinfection) as well
as sequential infection of chronic carriers of the
HBs antigen (superinfection) may occur. Coinfec-
tion presents clinically like an acute infection with
hepatitis B virus; the risk for developing chronic
hepatitis is not increased. In contrast, superinfec-
tion is associated with a more progressive course
with an increased risk for developing liver cirrho-
sis. Besides standard liver biochemistry, serologi-
cal markers are essential for the diagnosis of hep-
atitis B and D. Acute infection with the hepatitis B
virus is characterized by anti-HBc IgM, HBs anti-
gen, and HBV-DNA in serum. Persistence of HBs
antigen and HBV-DNA for more than 6 months is
indicative of chronification of the infection. Acute
infections with the hepatitis B virus are not treated
specifically because of the low frequency of chroni-
fication in symptomatic patients. Only in fulminant
hepatitis B with liver failure, that occurs in less than
1% of cases, lamivudine should be administered.
For treatment of chronic hepatitis B, several thera-
peutic options are currently available and experts
differ in their view of primary drug therapy. Inter-
feron α can be used successfully for the treatment
of high-replicative HBe antigen-positive patients
with a sustained response, defi ned as sustained
loss of HBe antigen, in 30%–40% of patients. In
addition, pegylated interferon α has been licensed
for the treatment of chronic hepatitis B since 2005
and has recently been shown to be superior to lami-
vudine in HBe antigen-positive patients. Alterna-
tively, lamivudine or – in case of lamivudine resis-
tance – adefovir can also be used successfully for
the treatment of HBe antigen-positive patients.
Further treatment options are awaited in the near
future (Perrillo 2005).
16.1.2
Chronic Hepatitis C
Nowadays intravenous drug abuse is the most
important risk factor for infection with the hep-
atitis C virus. Sexual transmission in stable long-
term relations is quite rare (ca. 2%–6%) with the
exception of coinfection with the human immune
deficiency virus. Pre- and perinatal transmission
of the hepatitis C virus from infected mothers to
the fetus/newborn occurs in less than 5% of cases
and is dependent on the viral load of the mother.
So far six genotypes of the hepatitis C virus have
been described with varying geographic distribu-
tion. The natural course of hepatitis C is character-
ized by a high rate of chronification in up to 85% of
cases. Spontaneous elimination of the virus is rare.
Liver cirrhosis is expected in 20% of patients with
chronic infection after 20–30 years. The risk for
developing hepatocellular carcinoma is between 2%
and 8% per year in patients with manifest cirrhosis
(Bruix and Sherman 2005). Anti-HCV antibodies
and HCV-RNA in serum are diagnostic markers of
chronic and acute infection with the hepatitis C
virus, respectively. In case of chronic infection, i.e.
after more than 6 months, serum HCV-RNA should
be quantified and the genotype of the virus should
be determined. In chronic hepatitis C, pegylated
interferon α in combination with ribavirin for 48
weeks (genotype 1) or 24 weeks (genotype 2, 3) is
the standard therapy resulting in sustained virus
control – i.e. no detection of HCV-RNA in serum
for more than 6 months after therapy – in 50%
of the treated patients. While successful elimina-
tion of the hepatitis C virus is achieved in only
40%–50% of cases with genotype 1, HCV elimina-
tion is observed in more than 80% of cases with the
genotypes 2 and 3. Treatment of acute hepatitis C
is controversially discussed. An immediate start
with pegylated interferon and ribavirin and start
after observation for 3 months both revealed high
sustained rates of viral clearance. A comparison of
these treatment strategies is currently the subject
of a large randomized multicenter study (Dienstag
and McHutchison 2006).
16.1.3
Hemochromatosis
Hemochromatosis is one of the most frequent auto-
somal-recessive disorders in Europe (up to 1:200). In
Central and Western Europe, up to 95% of patients
with hemochromatosis present with mutations
of the HFE gene leading to enhanced resorption
and systemic accumulation of iron with consecu-
tive damage of liver, pancreas, heart, and kidneys
(hemochromatosis type 1). Less common defects

involve the genes for hemojuvelin, hepcidin, the
transferrin receptor 2, and ferroportin 1 (hemo-
chromatosis type 2a, 2b, 3, and 4) (Pietrangelo
2004). Having developed liver cirrhosis, patients
with hemochromatosis have a markedly increased
risk (20-fold) for hepatocellular carcinoma with an
annual incidence of 3%–4% (Bruix and Sherman
2005). Typical symptoms for patients with advanced
hemochromatosis are fatigue, skin pigmentation,
impotence, amenorrhoea, arthralgia, abdominal
pain, and diabetes. In men, first symptoms typi-
cally occur after the age of 40, in women after the
menopause. Patients typically present with elevated
serum liver enzymes and elevated blood glucose.
Serum iron is an insensitive parameter that is not
necessarily elevated. When a transferrin saturation
> 50% and a serum ferritin > 300 ng/mL (> 200 ng/
mL in women) are observed, molecular genetic test-
ing for HFE gene mutations (Cys282Tyr homocygos-
ity, Cys282Tyr/His63Asp compound heterocygosity)
is recommended. Native magnetic resonance imag-
ing of the liver, the pancreas and the cardiac muscle
is a useful and non-invasive technique for detection
of abnormal iron storage in these organs confirm-
ing the diagnosis. Liver histology with quantitative
determination of hepatic iron and determination
of the hepatic iron index is helpful in patients older
than 40 and with the suspicion of liver cirrhosis
and/or serum ferritin higher than 1000 ng/mL for
assessing the individual prognosis. Lifelong ther-
apy consists of regular phlebotomy (Hb > 10 g/dL)
to keep the serum ferritin lower than 50 ng/mL.
In the first 1–2 years when phlebotomies (500 ml)
are needed at weekly intervals, serum ferritin and
transferrin saturation should be controlled every
3 months, thereafter at least once a year when 4–12
phlebotomies are performed per year. Patients with
cirrhosis have a high risk for hepatocellular car-
cinoma and should undergo regular surveillance
(see below).
16.1.4
Wilson’s Disease
Wilson’s disease is a rare (prevalence 3/100,000)
autosomal-recessive disorder characterized by an
impaired transport of copper from the liver into
bile resulting in copper accumulation in liver, brain
and other tissues. The major signs and symptoms
Predisposing Diseases: Chronic Hepatitis and Liver Cirrhosis 331
of the mostly young patients reflect liver damage
and/or neurological and psychiatric involvement.
In about 5%, Wilson’s disease presents with acute
liver failure and hemolysis. Wilson’s disease can be
diagnosed when two of the following four condi-
tions are fulfi lled: (1) a Kayser-Fleischer corneal
ring, (2) reduced coeruloplasmin serum level (less
than 0.2 g/L), (3) increased urine copper excretion
(more than 100 µg in urine collected over 24 h), and
(4) markedly elevated copper content of the liver
(more than 250 µg copper per g dry liver tissue).
In addition, total copper in serum that is 95% coe-
ruloplasmin-bound in healthy persons is reduced
in patients with Wilson’s disease in the presence
of often elevated transaminases. In contrast, the
serum alkaline phosphatase level can be reduced
down to undetectable levels in acute liver failure
in Wilson’s disease. Life-long medical therapy is
indispensible and consists in: (1) increasing the
urine copper excretion by chelator substances like
D-penicillamine or trientine until total body copper
is normalized (< 60 µg copper in urine/24 h), and (2)
impairing intestinal copper uptake by administra-
tion of zinc acetate or zinc sulfate after total body
copper has normalized (regular control of urinary
copper excretion!). Acute liver failure is treated by
high urgency liver transplantation (Brewer and
Askari 2005).
16.1.5
α1-Antitrypsin Deficiency
α1-Antitrypsin deficiency is an inherited autoso-
mal co-dominant disorder (prevalence 1/2000 to
1/5000) with more than 100 known alleles. Typical
signs and symptoms include early-onset emphy-
sema, pulmonary infections, and indicators of liver
disease. α1-Antitrypsin is a protease inhibitor that
protects the lung against proteolysis by neutrophilic
elastase and that is synthesized predominantly in
the liver. The most frequent mutation affects the
SERPINA1 gene and gives rise to the Z allele. In
homocygotes for this mutation, one aminoacid
substitution in the α1-antitrypsin molecule causes
its retention in the hepatocytes. This may fi nally
lead to cirrhotic transformation of the liver. The
concomitant lack of α1-antitrypsin in serum pre-
disposes to emphysema of the lung (Stoller and
Aboussouan 2005).
332 G. U. Denk and U. Beuers
16.1.6
Autoimmune Hepatitis
Autoimmune hepatitis (AIH) is an infrequent type
of chronic hepatitis (prevalence 17/100,000) which
leads to progressive inflammatory destruction
of liver tissue. AIH affects mainly women (80%).
Before immunosuppressive treatment was estab-
lished, up to 50% of patients died within 3 years.
The diagnosis of AIH is based on the presence of
elevated serum transaminases, elevated immuno-
globulin G, characteristic histologic fi ndings of a
moderate to severe “interface hepatitis” with dense
lymphocellular portal and periportal infi ltrates and
piecemeal necroses, autoantibodies, and exclusion
of other viral, toxic, metabolic, or autoimmune liver
diseases (Krawitt 2006). Based on the serum auto-
antibody profi le, two types of autoimmune hepa-
titis are distinguished. The more frequent type 1
(> 80% of cases) affects patients at all ages and is
characterized by the presence of antinuclear (ANA),
anti-smooth muscle (ASMA) and/or soluble liver
antigen (SLA) antibodies in serum. Type 2 mainly
affects girls and young women and is characterized
by the presence of liver kidney microsomal (LKM1)
antibodies. Insufficient treatment response is more
often observed in AIH type 2 than AIH type 1
(Krawitt 2006).
Patients with AIH typically present with distinctly
elevated serum transaminases and increased immu-
noglobulin G levels. Clinical signs and symptoms
are nonspecific (fatigue, anorexia, nausea, jaundice,
hepatosplenomegaly). AIH is associated with extra-
hepatic autoimmune disorders like autoimmune
thyreoiditis, rheumatoid arthritis, or coeliac disease
in 30%–50% of cases.
The established therapeutic concept consists in
immunosuppressive treatment with corticosteroids
and azathioprine. Initially, prednisolone (up to
60 mg daily) is administered for the fi rst 2 weeks.
An adequate treatment response is expected, oth-
erwise the diagnosis of AIH should be questioned.
Subsequently, azathioprine (1–1.5 mg/kg daily)
is added and corticosteroids are reduced slowly
every week down to an individual maintenance
dose (titration in dependence on disease activity).
Therapy with azathioprine and low-dose corticoste-
roids or monotherapy with azathioprine (or pred-
nisolone) should be continued for at least 4 years. In
most cases, however, life-long treatment is needed
(Krawitt 2006).
16.1.7
Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is the most common
cholestatic liver disease with a prevalence of 25–
42 per 100,000 (Kaplan and Gershwin 2005). Of
the patients, 90% are female, mostly middle-aged.
The underlying pathomechanisms seem to be of
autoimmunological character. The natural course
of PBC is characterized by a chronic progressive
portal inflammation of interlobular and septal bile
ductules resulting in complete biliary cirrhosis after
10–15 years without treatment. Typical symptoms
comprise pruritus, fatigue, and sicca syndrome. In
addition to elevated markers of cholestasis, most
patients present with antimitochondrial antibodies
(AMA, subclass M2) and elevated immunoglobulin
M levels in serum. The only established conservative
therapy is oral administration of ursodeoxycholic
acid, the therapy of decompensated liver cirrho-
sis consists in liver transplantation (Kaplan and
Gershwin 2005). The incidence of hepatocellular
carcinoma in patients with advanced primary bili-
ary cirrhosis (stages III and IV) is comparable with
patients suffering from cirrhosis due to chronic
hepatitis C (Caballeria et al. 2001).
16.1.8
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a rare chronic
cholestatic disorder of unknown origin affecting
intra- and extrahepatic bile ducts (Withington et
al. 2005). Its prevalence is 9–13 per 100,000 with
a preference of the male gender (2:1). The disease
is associated with chronic inflammatory bowel
disease, especially ulcerative colitis (70%–90% of
all patients), and the typical age of manifestation
is between 25 and 40 years. PSC carries a risk of
developing cholangiocellular carcinoma of 1.5% per
year. Clinical symptoms are nonspecific similar to
PBC. Patients with PSC present with elevated serum
markers of cholestasis, atypical antineutrophilic
cytoplasmatic antibodies with perinuclear fluores-
cence pattern (atypical pANCA; in 70% of patients),
and onion skin fibrosis around the bile ducts in liver
biopsy specimens. The established diagnostic gold
standard is endoscopic retrograde cholangiography

(ERC) which reveals irregular strictures and dilata-
tions of the intra- and/or extrahepatic bile ducts.
High quality Magnetic Resonance Cholangiopan-
creaticography (MRC) is increasingly replacing ERC
as a diagnostic procedure. Ursodeoxycholic acid has
been shown to improve serum liver tests and liver
histology and to decrease the risk of colon and chol-
angiocellular cancer in PSC and is, therefore, rec-
ommended at daily doses of 15–20 mg/kg. In addi-
tion, high-grade stenoses are treated by endoscopic
dilatation. Liver transplantation must be considered
in late stage disease when cirrhosis has developed
(Rust and Beuers 2005).
16.1.9
Alcoholic Liver Disease
Alcoholic liver disease is one of the leading causes of
chronic hepatopathy and comprises alcoholic fatty
liver (up to 90% of alcoholics), alcoholic hepatitis
(up to 10%–35%), and alcoholic liver cirrhosis. It
is known that there is a correlation between the
amount of the alcohol daily consumed and the risk
of developing alcoholic liver cirrhosis but no exact
threshold is known. Typically, only a relatively small
portion of alcoholics, drinking daily > 60 g of alco-
hol in men and > 20 g in women, will develop alco-
holic liver cirrhosis (Willner and Reuben 2005).
Alcoholic liver cirrhosis is an established risk factor
for developing hepatocellular carcinoma (Bruix and
Sherman 2005). In a study by Hassan et al. (2002)
alcoholic liver disease was the risk factor for 32% of
all hepatocellular carcinomas.
16.1.10
Non-alcoholic Steatohepatitis
Non-alcoholic steatohepatitis is a hepatopathy of
unknown origin that is histopathologically very
similar to alcoholic hepatitis despite absent alco-
hol abuse. The typical age of manifestation is
40–60 years. Women are affected more often than
men. Risk factors for non-alcoholic steatohepatitis
include disorders of the metabolic syndrome com-
plex (obesity, diabetes mellitus, hyerlipidemia) and
certain drugs such as amiodaron, diltiazem, pro-
Predisposing Diseases: Chronic Hepatitis and Liver Cirrhosis 333
tease inhibitors, steroids, or tamoxifen. Diagnosis
is based on exclusion of active alcohol abuse, pres-
ence of elevated serum transaminases, an enhanced
echogenicity in liver ultrasonography, and typi-
cal liver histology with balloon-like degeneration
of hepatocytes, nuclear vacuoles, Mallory bodies,
and inflammatory infi ltration. Therapy consists in
weight reduction and adequate treatment of diabe-
tes or hyperlipidemia. Potentially hepatotoxic drugs
should be avoided. The natural course of non-alco-
holic steatohepatitis is not well-known, the inci-
dence of cirrhosis is estimated to be up to 30% of
cases (Göke et al. 2005).
16.1.11
Chronic Liver Disease and Hepatocellular
Carcinoma
Hepatocellular carcinoma (HCC) is the third most
common cause of cancer-related death and the
fifth most common cancer worldwide. The annual
incidence of HCC has been rising in the Western
world during the last decades with 10–30 new cases
per 100,000 citizens (Spangenberg et al. 2004).
Chronic viral hepatitis, alcoholic liver disease, and
hemochromatosis represent the main risk factors
for developing HCC. In addition, any chronic hepa-
topathy and liver cirrhosis is accompanied by an
increased risk for this tumor. The risk rate depends
on etiology, duration, and activity of the respective
hepatopathy. The risk to develop HCC is highest in
patients with cirrhosis due to chronic hepatitis C
(60% life-time risk, LR), chronic hepatitis B (50%
LR), hemochromatosis (40% LR), and alcoholic liver
disease (30% LR) (Spangenberg et al. 2004). Early
diagnosis of HCC is crucial: potentially curative
therapeutic strategies like surgical resection, liver
transplantation, and percutaneous ablation can suc-
cessfully be applied only in early stages of HCC.
Surveillance for HCC is recommended in patients
with liver cirrhosis due to chronic hepatitis B and C,
alcohol abuse, genetic hemochromatosis, and pri-
mary biliary cirrhosis (Bruix and Sherman 2005).
In addition, cost-efficacy analyses led to the recom-
mendation of regular surveillance in hepatitis B car-
riers without cirrhosis who are: (1) Africans above
20 years, (2) Asian males above 40 years, (3) Asian
females above 50 years, (4) with a family history
of HCC. In addition, hepatitis B carriers with high
334 G. U. Denk and U. Beuers
HBV-DNA levels and ongoing hepatic inflammation
remain at risk to develop HCC. Patients with cirrho-
sis due to α1-antitrypsin deficiency, non-alcoholic
steatohepatitis, and autoimmune hepatitis may also
be at an increased risk to develop HCC. However,
there are insufficient published data available so far
to recommend regular surveillance in these cases
(Bruix and Sherman 2005).
Serum α-fetoprotein (AFP) has long been used as
a diagnostic test for HCC although its sensitivity and
specificity are limited. At serum levels above 20 ng/mL,
sensitivity for HCC is only 60% (Trevisani et al.
2001). Thus, AFP alone should not be used for screen-
ing unless ultrasound is not available (Bruix and
Sherman 2005). AFP levels above 200 ng/mL can be
helpful in patients with a lesion in a cirrhotic liver.
Surveillance for HCC should be performed
using ultrasonography (Bruix and Sherman
2005). Abdominal ultrasound achieves a sensitivity
between 65% and 80% and a specificity greater than
90% for detection of HCC when used as a screening
tool (Bruix and Sherman 2005). However, nodu-
lar cirrhosis often makes differentiation of hepatic
lesions by ultrasound difficult, and ultrasonography
is an operator-dependent technique. Screening at 6-
to 12-month intervals has been recommended based
on tumor doubling times, and a 6-month interval is
used by most experts (Bruix and Sherman 2005).
Contrast-enhanced MRI of the liver represents the
gold standard for detection and differentiation of
hepatic masses in liver cirrhosis, but has not yet
been accepted as a routine screening procedure due
to its enormous costs. Besides diagnostic imaging
and serum AFP, histopathology is helpful for the
diagnosis of HCC.
The diagnostic workup depends primarily on the
size of a hepatic lesion detected. Lesions > 2 cm in
diameter in cirrhotic livers with typical features of
HCC such as hypervascularity and washout in the
portalvenous phase in dynamic imaging or an ele-
vated serum AFP above 200 ng/mL do not have to
be biopsied for diagnosis of HCC. However, biopsy
should be performed if the vascular profi le on imag-
ing is not characteristic or if the lesion is detected in
a non-cirrhotic liver.
Lesions 1–2 cm in diameter detected in cirrhotic
livers should be analyzed by two dynamic imaging
techniques such as MRI, dynamic CT, or contrast
enhanced ultrasonography. When the lesion pres-
ents with typical signs of HCC, the diagnosis of HCC
can be made. In case of a nonspecific pattern or con-
flicting results, a biopsy should be obtained.
Lesions < 1 cm should be followed with ultra-
sound at intervals of 3–6 months. In case the lesion
does not grow over a period of up to 2 years, it is
improbable that the nodule represents a HCC. The
patient can then return to routine surveillance
(Bruix and Sherman 2005).
References
Brewer GJ, Askari FK (2005) Wilson’s disease: clinical man-
agement and therapy. J Hepatol 42(Suppl 1):S13–21
Bruix J, Sherman M (2005) Management of hepatocellular
carcinoma. Hepatology 42:1208–1236
Caballeria L, Pares A, Castells A et al. (2001) Hepatocellular
carcinoma in primary biliary cirrhosis: similar incidence
to that in hepatitis C virus-related cirrhosis. Am J Gastro-
enterol 96:1160–1163
Dienstag JL, McHudchison JG (2006) AGA technical review
on the management of hepatitis C. Gastroenterology
130:231–264
Göke B, Kolligs F, Rust C (2006) Interner Klinikleitfaden
Gastroenterologie, Hepatologie, Endokrinologie, Stoff-
wechsel. Eigenverlag, München
Hassan MM, Hwang LY, Hatten CJ et al. (2002) Risk fac-
tors for hepatocellular carcinoma: synergism of alcohol
with viral hepatitis and diabetes mellitus. Hepatology
36:1206–1213
Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis.
N Engl J Med 353:1261–1273
Krawitt EL (2006) Autoimmune hepatitis. N Engl J Med
354:54–66
Perrillo RP (2005) Current therapy of chronic hepatitis B:
benefits and limitations. Sem Liver Dis 25(Suppl 1):
20–28
Pietrangelo A (2004) Hereditary hemochromatosis – a new
look at an old disease. N Engl J Med 350:2383–2397
Rust C, Beuers U (2005) Medical treatment of primary bil-
iary cirrhosis and primary sclerosing cholangitis. Clin
Rev Allerg Immunol 28:135–145
Spangenberg HC, Thimme R, von Weizsäcker F et al. (2004)
Hepatozelluläres Karzinom. Internist 45:777–785
Stoller JK, Aboussouan LS (2005) Alpha1-antitrypsin defi-
ciency. Lancet 365:2225–2236
Trevisani F, D´Intino PE, Morselli-Labate AM et al. (2001)
Serum alpha-fetoprotein for diagnosis of hepatocellu-
lar carcinoma in patients with chronic liver disease:
inf luence of HBsAg and anti-HCV status. J Hepatol
34:570–575
Willner IR, Reuben A (2005) Alcohol and the liver. Curr Opin
Gastroenterol 21:323–330
Worthington J, Cullen S, Chapman R (2005) Immunopatho-
genesis of primary sclerosing cholangitis. Clin Rev
Allergy Immunol 28:93–103
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 335

Predisposing Diseases 16
16.2 Autoimmune Disease, AIDS and Transplanted Patients
Johannes R. Bogner and Michael Fischereder

CONTENTS ● Practical aspects and results of screening in

immunodeficient patients
● Prevalence of infections, bone disease and
16.2.1 Introduction 335 malignancy in immunodeficient patients
● Specific considerations in autoimmune dis-
16.2.2 Autoimmune Disease 335
16.2.2.1 General Recommendations 336 ease, AIDS and transplanted patients
16.2.2.2 Disease Specific Screening
Recommendations 336

16.2.3 AIDS 337

16.2.3.1 General Considerations 337
16.2.3.2 Pulmonary Disease 337
16.2.3.3 Abdominal Disease 338 16.2.1
16.2.3.4 Central Nervous System 338 Introduction
16.2.3.5 Bone Disease 338
16.2.3.6 Fever of Unknown Origin 339
The rationale of radiological screening in autoim-
16.2.4 Transplanted Patients 339 mune disease, AIDS and transplanted patients can
16.2.4.1 General Considerations 339 be based on detection of co-morbid conditions asso-
16.2.4.2 Preexisting and Recurrent ciated with either the underlying disease or, in case
Malignancy 340
of autoimmune disease and transplantation, the
16.2.4.3 De Novo Malignancy 341
16.2.4.3.1 Kidney Transplantation 341 pharmacologic regimens with which such patients
16.2.4.3.2 Heart Transplantation 343 are treated, i.e. immunosuppressants. In either case,
16.2.4.3.3 Liver Transplantation 344 physiologic mechanisms of immune - surveillance
16.2.4.3.4 Stem Cell Transplantation 344 are affected with a subsequent increase in the risks
16.2.4.4 Complications at the Site of
Anastomosis 344
for infection and malignancy. However, depending
16.2.4.5 Immunological Rejection 345 on the underlying cause of immunodeficiency, dif-
16.2.4.6 Osteoporosis 345 ferent forms of opportunistic infections or tumours
may arise, thus explaining the necessity of specific
References 346 screening strategies.

16.2.2
Autoimmune Disease

The term autoimmune disease refers to a rather large

J. R. Bogner, MD, Professor
M. Fischereder, MD, Professor
Medical Policlinic, University Hospitals – Innenstadt,
Ludwig-Maximilians-University of Munich, Pettenkofer-
strasse 8a, 80336 Munich, Germany
and heterogeneous group of diseases in the patho-
genesis of which some degree of immune phenom-
ena are postulated. Virtually all organ systems can
be affected by auto-immune diseases either alone or
336 J. R. Bogner and M. Fischereder

Table 16.2.1. Autoimmune diseases with potential benefit from radiological screening

System Disease Comorbid condition

Gastrointestinal • Primary sclerosing cholangitis • Hepatocellular carcinoma

• Celiac disease • Lymphoma
Renal • Systemic lupus erythematodes • Serositis
• Vasculitis • Lymphoma
• Granulomatous disease (ENT, lung)
Rheumatologic • Systemic lupus erythematodes • Serositis Lymphoma
• Sjogren syndrome (salivary glands) • Lymphoma
• Rheumatoid arthritis • Lymphoma
• Tuberculosis
Endocrine • Lymphocytic thyroiditis • Lymphoma

in combination. The pattern of organ involvement
and comorbidity are as complex as is the underlying
pathophysiology. For the purpose of this chapter, it
appears most reasonable to use rather a pragmatic
than pathophysiologic approach. As most of these
diseases are rather rare, little evidence based recom-
mendations on the utility of screening are available.
Table 16.2.1 summarizes co-morbid conditions, the
detection of which may either aid in the diagnosis
of the autoimmune disease (such as serositis in sys-
temic lupus or granulomas in vasculitis) or which
represent a potentially fatal complication of a spe-
cific autoimmune disease.
16.2.2.1
General Recommendations
Some general recommendations can be given for
radiological screening examinations that apply to
the entire group of patients. Foremost, prior to the
institution of immunosuppressive therapy, active
infection, past exposure to tuberculosis or malig-
nant disease has to be ruled out.
From this point of view obtaining a screen-
ing chest X-ray at the time of diagnosis is recom-
mended. The utility for the reduction of symptom-
atic pulmonary infections has been well evaluated
in patients with rheumatoid arthritis (Carmona et
al. 2005). During treatment with a biological agent,
i.e. a TNF-antagonist, the risk for reactivation of
tuberculosis risk was fourfold higher vs treatment
without a TNF-antagonist (Askling et al. 2005).
Likewise the incidence of adverse events also cor-
related with the intensity of immunosuppressive
therapy in these patients and SIR for lymphomas
were 2.5, 5.1 and 11.5 for patients respectively.
(Smedby et al. 2006).
Systemic corticosteroid therapy is known to
reduce bone mineral density BMD (Sambrook 2005;
Blake and Fogelman 2002). Since various different
treatment regimens are available, the identification
of patients at risk appears warranted. Randomized
studies on the utility are also missing, but expert
opinion, which has also been incorporated in guide-
lines suggests BMD measurement especially if risk
factors such as:
● Oestrogen deficiency
● Corticosteroid therapy > 7.5 mg/day
● Maternal family history of hip fracture
● Body mass index < 19 kg/m²
● Anorexia nervosa
● Malabsorption syndrome
● Primary hyperparathyroidism
● Chronic renal failure
● Post transplantation
● Hyperthyroidism
● Cushing syndrome
● Radiologic evidence of osteopenia
● Previous osteoporotic fracture
● Thoracic kyphosis are present (Blake 2002 and
Fogelman)
16.2.2.2
Disease Specific Screening Recommendations
As summarized in Table 16.2.1, a number of autoim-
mune diseases are associated with an increased risk
of malignancy:
● Hashimoto’s thyroiditis is associated with thyroid
lymphoma (Pedersen and Pedersen 1996).
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients
● Primary sclerosing cholangitis carries a 10%–
15% lifetime risk of cholangiocarcinoma (Rosen
et al. 1991).
● In primary Sjogren syndrome (SS) a 5.8% NHL
prevalence has been reported. The SIR is increased
to 18.8. In 19 of 21 patients with lymphomas these
were located in the head or neck (Tonami et al.
2003; Smedby et al. 2006; Zintzaras et al. 2005).
● There is a moderate risk of lymphoma in patients
with SLE with a SIR of 7.4 (Smedby et al. 2006).
● A mildly elevated risk of lymphoma was observed
in patients with rheumatoid arthritis, i.e. a SIR of
3.9 (Smedby et al. 2006).
However, no studies are available to demonstrate
an improvement in clinical outcome with the intro-
duction of radiological screening. Therefore, despite
the increased malignancy rates general screening
has not been advocated thus far.
16.2.3
AIDS
16.2.3.1
General Considerations
HIV infection is a chronic disease that mandates
medical attention over years and decades. Since the
introduction of highly active antiretroviral therapy
(HAART) the course of HIV infection can be pro-
longed. Thus, late stages of immunodeficiency can
be prevented, at least in patients who adhere to ther-
apy and routine control visits. Nevertheless, there
is still a high number of patients who present with
high grade immunodeficiency, either because their
therapy is not working any longer or because they
were not aware of having contracted HIV.
16.2.3.2
Pulmonary Disease
These patients definitely do have a high risk of
opportunistic infections. Moreover, also those on
successful HAART are at risk for opportunistic
tumours or other neoplastic disease. For this reason
we usually include imaging studies in baseline visits
of HIV patients, even if they do not present with
specific symptoms or signs on physical examina-
337
tion. These studies comprise a plain chest X-ray
and an ultrasound examination of the abdominal
organs (liver, spleen, kidneys and exclusion of large
perivascular lymph node mass). The rationale for
this type of baseline screening is derived from three
arguments:
● HIV-patients show an increased incidence of pneu-
monia in case of deterioration of their immune
system and even those who are under HAART
may have higher incidence of bacterial disease as
compared to the general age matched population.
In order to assess the presence of new infiltrates or
changes in hilus pattern it is important to compare
a film with previous studies (Hopewell 1988).
● HIV-patients develop pulmonary hypertension
significantly more frequently (Pellicelli et al.
2004). In this scenario it is also of help if there
is a study that was performed months or years
before the onset of symptoms.
● HIV-patients have a higher risk to develop non-
Hodgkin’s lymphoma (NHL) and other malig-
nant diseases in the regions of chest or abdomen.
These could be timely found by a screening study.
Again, comparison with a baseline study greatly
facilitates this task.
However, the usefulness of this kind of screening
has not been investigated in substantial patient pop-
ulations and there is no direct study on cost effec-
tiveness or diagnostic yield. In our clinical practice
there are numerous cases showing the advantage
of providing a screening baseline chest X-ray and
abdominal ultrasound. Furthermore, it is question-
able whether a extensive randomised multi-center
study on cost effectiveness and usefulness of this
screening will be feasible.
In order to assess the utility of serial chest X-ray
studies in HIV patients, Schneider et al. 1996 per-
formed a prospective study in 1065 patients: patients
received chest X-ray investigations at intervals of 3, 6
and 12 months. Medical history, physical examina-
tion and laboratory parameters were also part of the
visits. Of the 5263 chest X-ray fi lms in asymptomatic
patients, 98% turned out to be normal. Only 2% of
these screening fi lms showed pathology. A new pul-
monary pathology was identified within 2 months
following a screening radiograph in 55 subjects.
Only 11 of these subjects had abnormal radiographs,
i.e. the sensitivity of the radiograph was 20%. The
sensitivity was similarly low at baseline, within each
transmission category, and in subjects whose CD4
lymphocyte counts were less than 200/µl. The types
338 J. R. Bogner and M. Fischereder
of pulmonary diseases that occurred were similar
in the subjects with normal and abnormal screen-
ing radiographs. The authors conclude that serial
screening chest radiography in asymptomatic HIV-
infected adults is unwarranted because the diagnos-
tic yield is too low (Schneider et al. 1996).
16.2.3.3
Abdominal Disease
In asymptomatic HIV disease a typical immunologic
finding on histology is the hyperplasia of germinal cen-
tres in lymphatic organs, e.g. lymph nodes or spleen.
Enlargement of lymph nodes or spleen therefore is a
typical sign of HIV infection. However, at late stages
when most of the germinal centres are destroyed,
lymphatic organs become lymphocyte-depleted. In
parallel, spleen size returns to normal or small. Sple-
nomegaly or hepato-splenomegaly are indicative of an
opportunistic infection or opportunistic tumour if it
is encountered in a patient in the stage of immuno-
logic destruction and depletion (e.g. stage Centers of
Disease Control (CDC) “3”, e.g. less than 200 CD4/µl).
Thus, imaging studies with ultrasound and/or CT of
the abdomen contribute to the question of spleen size
(Gerber and Hohlfeld 2003).
16.2.3.4
Central Nervous System
The central nervous system (CNS) is afflicted by
HIV infection in two forms: HIV can result in HIV
encephalopathy as a direct effect of CNS-infection
and replication. On the other hand, opportunistic
infections and tumours are indirect manifestations
of HIV due to low T-cell immune function (Castillo
1994; Lizerbram and Hesselink 1997).
The question whether cerebral CT is of use in HIV
patients who present with headache and no other
neurological symptoms or signs was evaluated by
Graham and co-workers. They reviewed 204 CT scan
results and CD4 counts in 178 patients with this con-
stellation. For analysis, scans were considered posi-
tive or negative and were grouped according to CD4
counts of less than 200/µl, 200–499/µl, and equal to
or greater than 500/µl. Of the scans, 128/204 (62.7%)
were negative, and 76/204 (37.3%) were positive. Of
the positive scans, 58 (76.3%) showed atrophy only
and 18 (23.7%) showed mass lesions or white matter
lesions. All cases that were positive for mass lesions
or white matter lesions occurred in patients with
CD4 counts less than 200/µl. The authors’ conclu-
sion is that performing CT of the head in patients
with CD4 counts equal to or greater than 200/µl is of
questionable value considering the low prevalence
of positive CT findings (Graham et al. 2000).
A direct comparison of CCT and MRI reveals higher
sensitivity for MRI; Post et al. (1988) performed a
comparison of CCT and MRI in 22 patients: MRI was
more sensitive in detection of demyelinating lesions.
In another study 119 MRI studies were evaluated in
a multicentric design. 95 patients were asymptomatic
and 24 were symptomatic. The results were correlated
with clinical data. MR images regarded as positive
included those showing atrophy and/or white matter
lesions. On the basis of these criteria, 96 subjects had
normal MR images and 23 had abnormal images.
There was a significant difference (p < 0.001) between
the asymptomatic group (12 of 95 [13%] with abnor-
mal scans) and the symptomatic group (11 of 24 [46%]
with abnormal scans). In the asymptomatic group,
positive MR images showed fewer, smaller, and/or less
extensive abnormalities. The researchers concluded
that MR imaging can show indirect evidence of HIV
infection early in the disease, but abnormalities will
be minor and seen only in a small minority of neuro-
logically asymptomatic subjects. Another conclusion
was that the appearance of clinically recognizable
neurological disease correlates with the MR imag-
ing findings of increasingly severe brain atrophy and
white matter lesions (Post et al. 1991). However, MRI
may be negative despite neurological disease. The
results of this study indicate that routine screening
with cranial MR imaging of neurologically asymp-
tomatic HIV-seropositive individuals would yield a
very low number of positive findings.
However, all studies on imaging in HIV patients
are affected by the problem, that studies performed
in the pre HAART era may not be valid nowadays.
This is due to the fact that the spectrum of disease
manifestations has been changing since 1995 (intro-
duction of saquinavir as the first protease inhibi-
tor) and a new differential diagnosis called immune
reconstitution syndrome has become prevalent after
the commencement of HAART.
16.2.3.5
Bone Disease
Also adding to the complications of HIV infection
under treatment there is a number of reports on
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients
osteoporosis and aseptic bone necrosis (Miller et
al. 2002). Whether a screening with plain X-ray fi lms
or a routine bone densitometry would be cost effec-
tive is still not clear. In a series of 339 asymptomatic
patients, 4.4% showed osteonecrosis of the femoral
head on MRI scans (Miller et al. 2002).
Besides the radiological imaging techniques
based on X-ray and magnetic resonance imaging,
scans based on the use of radioisotopes have been
studied and used in the screening of symptomatic
HIV patients.
16.2.3.6
Fever of Unknown Origin
In patients with symptoms suggestive of systemic
disease like night sweats, prolonged fever and
weight loss, in whom localization of the underly-
ing pathological process is not accomplished with
conventional radiological imaging, positron emis-
sion tomography (PET) is a useful diagnostic tool
(Lorenzen et al. 2001; O’Doherty et al. 1997).
In one study PET use was investigated in 80 HIV
patients: in patients with NHL localisation the
extent of the disease could be determined more
precisely. In patients with opportunistic infections
(Cryptococcus neoformans, Pseudomonas aerugi-
nosa, Mycobacterium tuberculosis, Mycobacterium
avium intracellulare) PET was successful in finding
a suitable site for taking biopsy or microbiologic
samples (O’Doherty et al. 1997).
Moreover, PET was suggested for use in patients
with fever of unknown origin (without HIV infec-
tion) (Lorenzen et al. 2001).
In contrast, gallium-scanning, which was mainly
used in the late 1980s and 1990s is no longer recom-
mended, PET and MRI not being widely available
(Gomez et al. 1996; Lee et al. 1999; Moser et al.
Table 16.2.2. Radiological screening of patients with AIDS
System
Gastrointestinal
Renal
Pulmonary
Neurologic
Skeletal
339
1990; Santin et al. 1995; Tatsch et al. 1988, 1990).
Gallium-scanning was sensitive and predictive in
localisation and differential diagnosis of opportu-
nistic infections like atypical mycobacterioses, PcP
and other parasitic diseases.
The screening recommendations for patients with
are summarized in Table 16.2.2.
16.2.4
Transplanted Patients
16.2.4.1
General Considerations
Over the past decades, the half-life of organ trans-
plants has substantially increased, mostly due to
more sophisticated pharmacologic therapy. This
results in longer exposure to more potent immu-
nosuppression. Clinical consequences are a pre-
disposition to infections, malignant tumours and
osteoporosis. The management of potential allograft
recipients includes therefore screening procedures
prior to transplantation in order to detect preexist-
ing diseases that prohibit transplantation as well as
screening after the procedure.
Although infections are more prevalent, they
usually can be either suspected on clinical grounds
or are detected during routine preoperative evalua-
tion. Therefore, the potential benefit of radiological
screening has not been proven for the management
of infectious complications so far.
The increased malignancy rate observed in trans-
plant recipients is certainly of multifactorial aetiol-
ogy. For one, it is influenced by standard risk factors
such as smoking, exposure to ultraviolet radiation,
certain viral infections, gender and age. Further-
Study Recommendation
Abdominal ultrasound Recommended
Abdominal CT No data available
Abdominal ultrasound Recommended
Chest X-ray Controversial
Chest CT No data available
CT/MRI Not recommended
Osteodensitometry No data available
340 J. R. Bogner and M. Fischereder
more, transplant specific issues, e.g. the degree and
duration of immunosuppressive therapy, use of
agents with a higher risk of secondary malignan-
cies, e.g. cyclophosphamide, calcineurin inhibitors
or lymphocyte depleting antibodies, or preexisting
malignancy are relevant (Morath et al. 2004). As
a consequence, current recommendations for radio-
logical screening of transplanted patients are based
on the general population and are extended with
some specific additions highlighted below.
Although world wide the numbers of organ trans-
plants are increasing, one has to keep in mind that
the field of transplantation is still relatively young
and total patient numbers are rather low, especially
if specific organs are considered. Thus, evidence
from large, randomised studies on the benefit of
various screening strategies is rather limited. By far
the largest number of patients has received a renal
transplant and most of the information presented in
this chapter is based on experiences in this cohort or
adapted from general recommendations for screen-
ing examinations. However, organ-specific recom-
mendations are included when available.
16.2.4.2
Preexisting and Recurrent Malignancy
When increased rates of cancer following solid organ
transplantation are discussed, it must not be over-
looked that a fair number of patients have malig-
nant disease before or when they are evaluated for
the transplant waiting list. This is due to the fact
that solid organ transplantation may be a valuable
therapy for certain tumours, e.g. hepatoblastoma or
hepatocellular cancer as well as the general preva-
lence of malignancy in this age group. Most com-
monly, cancers are detected either in the intestine,
breast or urinary system. Overall, 3% of dialysis
patients developed cancer during a follow-up of
2.5 years (Maisonneuve et al. 1999). In other words,
a large number of patients is affected and up to 9% of
patients on dialysis carry a diagnosis of malignancy
at initiation of dialysis.
Unless transplantation is intended to treat a
tumour, freedom from malignancy and infection at
the time of transplantation is of greatest importance
in order to avoid accelerated clinical deterioration
due to the decreased immunosurveillance. This pre-
requisite results in current recommendations for the
screening of potential transplant candidates prior
to their acceptance on a waiting list. These recom-
mended examinations also cover the detection of
clinically relevant infection, namely previous tuber-
culosis, and are summarised in Table 16.2.3.
However, the diagnosis of malignancy or infec-
tion does not necessarily preclude solid organ trans-
plantation. After identification and appropriate
therapy of such tumours, patients can be accepted
on the waiting list provided freedom from cancer or
infection has been demonstrated. This approach has
resulted in a total of 1297 renal allograft recipients
transplanted with preexisting tumours who had
been reported to an international registry by 1997
(Penn 1997). The recurrence rates of the respective
cancer after transplantation were
● Breast cancer 23%
● Renal cancer 27%
● Sarcoma 29%
● Bladder cancer 29%
● Skin cancer 53%
● Myeloma 67%
● Thyroid cancer 8% (Penn 1997)
Results from the Australian and New Zealand reg-
istry, ANZDATA, of 11894 renal transplant recipients
indicate that 210 recipients had a history of cancer
prior to transplantation and in only 11, i.e. 5%, did
a recurrence occur. Similar to the results from the
international registry, the recurrence was more
likely for renal cancer (2/37), bladder cancer (1/24)
and prostate (1/5). As expected, the recurrence rate
for melanoma was also rather high (2/19), whereas
breast cancer (0/23) and colon cancer (0/23) did not
recur (Chapman et al. 2001). However, it has to be
kept in mind that these patients were subjected to
selection bias, reflected in the lower prevalence com-
pared to the dialysis population. Most likely these
data are also influenced by reporting bias. Thus, in
an individual patient, the risk of recurrence may be
higher, depending on tumour stage and grade.
On the other hand, recurrence rates per se give little
information on the clinical relevance of such a recurrent
cancer. This is nicely illustrated by the clinical course
of prostate cancer after transplantation. In 19 of 90
transplant recipients (17.7%) prostate cancer recurred
after transplantation but mortality due to recurrent
carcinoma was low: PCA related death rate was 7.8%,
overall mortality 28.8% (Woodle et al. 2005).
Not surprisingly, recurrence rates are higher if
transplantation is performed for the treatment of
cancer. In 135 children, liver transplantation was
performed for hepatoblastoma and in 41 children
for hepatocellular carcinoma. Respective 1-, 5-, and
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 341

Table 16.2.3. Radiological screening examinations prior to transplantation

System Study Candidates

Gastrointestinal Abdominal ultrasound All patients

Abdominal CT Hepatocellular carcinoma
Polycystic kidney disease
Renal Abdominal ultrasound All patients
Pulmonary Chest X-ray All patients
Chest CT Hepatocellular carcinoma
ENT Sinus X-ray History of ENT disease
Breast Mammogram Women > 50 years
Dental Panorex Avital teeth

10-year patient survival was 79%, 69%, and 66% for
hepatoblastoma and 86%, 63%, and 58% for hepa-
tocellular carcinoma. The primary cause of death
for both groups was metastatic or recurrent disease,
accounting for 54% of deaths in the hepatoblastoma
group and 86% in the hepatocellular carcinoma
group (Austin et al. 2006).
Although such registries supply valuable infor-
mation on tumour recurrence in the post-transplant
course of these high risk patients, the actual preva-
lence of preexisting malignancy in transplant recip-
ients can not be extracted. The prevalence of malig-
nancy in transplant recipients was addressed in a
cross-sectional study which evaluated 380 patients
evaluated for renal transplantation. In this cohort,
10% of patients had a preexisting malignancy. 20
of 45 tumours were located in the urinary system
(Fischereder and Jauch 2005).
This observation is supported by another study
of 260 renal transplant recipients who underwent
unilateral nephrectomy at the time of transplanta-
tion. In these patients, abnormalities detected were
acquired renal cystic disease, a condition frequently
associated with renal cell cancer, in 85 kidneys
(33%), renal adenomas in 35 kidneys (14%) and renal
cell cancer in12 patients (4%) (Denton et al. 2002)
16.2.4.3
De Novo Malignancy
The state of decreased immunosurveillance, as well
as specific side effects of immunosuppressive drugs,
result also in a dramatic increase of certain de novo
tumours after transplantation. A survey among
transplant centres in Northern Italy found that 172
out of 3521 renal transplant patients developed malig-
nant disease, i.e. 39 Kaposi sarcoma, 38 lymphopro-
liferative diseases and 95 carcinomas (17 renal cell
cancer, 11 non-basalioma skin cancer, 10 colorectal
cancer, 8 breast cancer, 7 gastric cancer, 7 lung cancer,
6 bladder cancer, and 3 mesothelioma) (Pedotti
et al. 2003). This observation is confirmed when
standardised incidence ratios, SIR, are calculated
(Table 16.2.4) (Kasiske et al. 2004). The highest rela-
tive increase is present in skin and renal cancer with
an almost 90-fold increase in incidence. Except for the
high relative increase in renal cancer, the frequencies
of de novo malignancies following other solid organ
transplants are comparable (Fung et al. 2001). As
in the general population, bronchogenic carcinoma
is associated rather with a history of smoking than
with any particular for of transplant (De Perrot et
al. 2003). While skin or oral cancer is readily identi-
fied on routine physical examination, renal cancer
requires a more sophisticated screening strategy.
16.2.4.3.1
Kidney Transplantation
On rare occasions, renal cell cancer may also arise
from the transplant. A survey among 27 German
transplant centres including 10.997 recipients of
the years 1990–1998 identified 16 cases of de novo
renal cell cancer (0.15%) within the graft. The
latency since transplantation was 3–12 years, the
tumour size at diagnoses ranged from 2 to 2.8 cm
(Wunderlich et al. 2001). The Cincinnatti Tumor
Register has compiled 31 cases up to 1996 with a
latency of 9–258 months. Most cases were identified
on routine ultrasound screening of the transplant
which should be performed at least once annually
(Kasiske et al. 2000). Treatment was either trans-
plant nephrectomy or partial nephrectomy (Lamb et
342 J. R. Bogner and M. Fischereder
Table 16.2.4. SIR of malignant tumours in solid organ transplant recipients. Standardized incidence rates are given for
various tumours expressed as cases per 100,000 patients (for the general population) and year or cases per 100,000 patient
years (transplant recipients). Data based on Kasiske et al. 2000 unless stated
Tumor General population
Prostate 162.0
a 134.1
Breast
Colon 48.5–66.4
Skin 14.3–24.0
Uterine cervix 9.4
a 8.4–16.0
Kidney
Non-Hodgkin lymphoma 15.7–22
a
Lung
Renal transplant 53.4–89.1
Liver transplant
Oral 6.3–15.8
a Amenable to radiologic screening
b Oo et al. 2005
al. 2004; Roupret et al. 2004; Siebels et al. 2000). In
order to qualify for nephron sparing resection early
diagnosis is crucial.
By far more common are neoplasms arising from
the native kidneys. Frequently this is heralded by the
development of secondary cysts during the process
of scarring. Since such acquired cystic disease has
been reported in up to 20% of patients and can read-
ily be identified (Fig. 16.2.1), renal ultrasound should
also be performed at least once annually after trans-
plantation (Denton et al. 2002). The benefits of early
detection have been highlighted by a cohort study
comparing the outcome of renal cancer in dialysis
patients with renal cell cancer either detected on
screening or due to symptoms. As expected, tumours
detected on screening were smaller and exhibited
lower histologic grading while tumour stages were
not different. The median survival was 119 months
for 721 cancers detected by screening and thus sig-
nificantly longer compared to 80 months in 76 symp-
tomatic patients (Ishikawa et al. 2004). After adjust-
ment for age and duration of dialysis, screening
conferred a survival benefit of 57 months for surgi-
cally treated patients. As the average life expectancy
of transplant recipients is longer than for dialysis
patients, an even greater benefit of screening has to
be assumed for transplanted patients.
Although not specifically evaluated in this study,
it is of note that 381 cancers were detected using renal
ultrasound and 340 cancers with abdominal CT-scan
First year post transplant Relative increase
477.4 3-fold
343.4 3-fold
91.1–137.2 2-fold
851–2017.1 80-fold
9.4 Up to 6-fold (after fi rst year)
671.0–767 42-fold to
90-fold
667.5–882.0 40-fold
141.8–149.4 Up to3-fold
56–336 Up to 6-fold b
138.4–269.4 20-fold
(Ishikawa et al. 2004). This underlines the prob-
lems frequently encountered in ultrasound imaging
of the native kidneys in renal transplant recipients.
Due to increasing echogenicity of the renal paren-
chyma the kidneys eventually may appear indistin-
guishable from the surrounding structures. A more
subtle diagnosis of cyst morphology, e.g. detection
of complicated cysts, appears exceedingly diffi-
cult. Imaging technologies, such as CT-scan or MRI
result in superior visualisation of such scarred kid-
neys and the acquired cysts contained therein. This
is nicely illustrated in one patient who was found to
have acquired cystic disease on ultrasound and was
then evaluated by MRI (Figs. 16.2.1 and 16.2.2).
Subsequent nephrectomy confirmed a pT1/G1
tumour of the right kidney.
The utility of prospective renal ultrasound and
the additional benefit of MRI scanning was also
shown by Heinz-Peer et al. (1998). In 840 transplant
recipients, prospective renal ultrasound examina-
tions were performed. A total of 169 patients were
diagnosed with ACKD, seven of those were found to
have renal cell cancer. Among 46 patients who were
additionally examined with MRI complex renal
cysts were identified in 17 more patients.
In summary, annual renal ultrasound should be
performed in all patients with advanced renal fail-
ure and additional imaging with CT or MRI should
be instituted in case of technical problems or com-
plex cysts.
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 343

a
Fig. 16.2.1. a Ultrasound of a native kidney with acquired cystic kidney disease. Note the increased echogenicity of the
renal cortex which is almost identical to the surrounding tissues. Various intrarenal cysts can be visualized but further
classification is not possible. b Descriptive sketch for a. The renal border is depicted with a dotted line, cysts are depicted
with solid circles

a b
Fig. 16.2.2. a MRI of native kidneys with acquired cystic kidney disease (T2 weighted image, fat saturated). The patient
with ACKD detected on renal ultrasound underwent MRI. The cysts in both kidneys are well visualized due to the bright
signal. Note the difference of the lesion in the right kidney. b MRI of native kidneys with acquired cystic kidney disease (T1
weighted, fat saturated, after Gadolinium). Note the contrast enhancement of the renal cancer. (Courtesy Dr. M. Treitl)

By far the highest risk of developing late cancers 16.2.4.3.2

is present in patients with analgesic nephropathy.
Among a cohort of 78 such patients receiving a renal
transplant, a urothelial carcinoma of the native kid-
neys or bladder occurred in 11 patients 5–77 months
after transplantation. Eight of these 11 patients died
from this tumour. The authors conclude that beyond
regular radiologic imaging, these patients should
also undergo routine cytologic examinations of the
urine (Kliem et al. 1996). The utility of MRI-scan-
ning has yet to be determined in this specific group
of patients.
Heart Transplantation
Beside the general considerations mentioned above,
recipients of cardiac transplants frequently have a
history of tobacco use and thus may carry a much
higher risk of bronchogenic carcinoma. This question
was addressed in a study with 573 cardiac transplant
recipients. Of those, 324 had a greater than 20 pack
year history of smoking. Overall, bronchogenic car-
cinoma was detected in 10 patients, in two patients
less than 1 year and in 8 patients more than 1 year
344 J. R. Bogner and M. Fischereder
post transplantation. Survival after this diagnosis
was dismal. Of note 5 patients with early stages Ia
and IIa who were detected on annual chest X-ray were
found to have a better prognosis (Potaris et al. 2005).
An even higher incidence of 6.8% bronchogenic car-
cinoma was reported by Rosenbaum et al. (2005).
Again, the progosis of patients with resectable cancer
was superior to patients ineligible for surgery.
Based on these observations, it appears advisable
to perform screening chest radiographs annually in
cardiac transplant recipients with a greater than 10
pack year history of smoking. The additional value
of low-dose chest CT in individuals with a high risk
of lung cancer has previously been shown for oth-
erwise healthy volunteers (Henschke et al. 1999).
If this strategy is applied to heart transplant recipi-
ents, all tumours detected on CT were resectable
compared to only 38% of tumours found on chest
X-ray, arguing for a screening strategy with CT in
high risk heart transplant recipients (Rosenbaum
et al. 2005).
16.2.4.3.3
Liver Transplantation
As already discussed for heart transplant recipients,
tobacco use prior to transplantation is associated
with a substantial increase in lung cancer. Liver
transplantation (OLT) is also increasingly offered
to patients with cirrhosis due to alcohol abuse, pro-
vided patients are abstinent prior to placement on
the waiting list. Alcohol abuse is frequently coin-
cident with tobacco use. Possibly due to this cir-
cumstance, a significant increase in lung cancer
after transplantation has recently been reported
(Jimenez et al. 2003; Oo et al. 2005). Without effec-
tive screening strategies, such neoplasms are usually
detected at advanced stages and little therapeutic
options are available. Median survival in a cohort
of 15 OLT recipients is 5.3 months, clearly underlin-
ing the necessity of adequate screening protocols
(Jimenez et al. 2003). Although not prospectively
evaluated with respect to survival benefit or cost-
effectiveness, routine screening with chest CT as for
heart transplant recipients should be considered.
16.2.4.3.4
Stem Cell Transplantation
Worthy of specific consideration in stem cell trans-
plantation are patients in whom this treatment
is performed for malignant disease (e.g. breast
cancer). They should undergo routine follow-up for
the underlying cancer as recommended elsewhere.
16.2.4.4
Complications at the Site of Anastomosis
Early dysfunction of solid organ transplants is fre-
quently due to acute rejection, disturbed perfusion
or primary non-function. In renal transplantation,
obstruction of the transplant ureter and in hepatic
transplantation bile duct complications are addi-
tional differential diagnoses. Since ultrasound with
colour Doppler technology is readily available and
detects most problems arising from the arterial,
venous, ureteral or biliary anastomosis, routine
postoperative ultrasound of the renal, hepatic or
cardiac graft in the early postoperative period is rec-
ommended (Friedewald et al. 2005; Uzochukwu
et al. 2005). Supplementary use of microbubble con-
trast media enhanced US or CT- or MRI-angiogra-
phy constitute other valuable methods for selected
patients with e.g. those at a high risk of anastomotic
thrombosis (Karani et al. 2005). In a series of 110
adult liver transplant recipients, ultrasonographic
screening 24 and 48 h post surgery detected seven
patients (6.4%) with vascular complications, includ-
ing two (1.8%) hepatic artery and two (1.8%) hepatic
vein stenoses, one (0.9%) hepatic vein thrombosis,
two (1.8%) portal vein thromboses, and one (0.9%)
thrombosis and two (1.8%) stenoses of the infe-
rior vena cava (IVC). In 19 patients (17.3%), bili-
ary complications included anastomotic strictures
and leaks 1 week to 18 months after transplanta-
tion. In 11 patients (10%), large hematomas detected
by US required surgical evacuation (Uzochukwu
et al. 2005). Patients with vascular complications
had significantly lower mean main, right, and left
hepatic artery resistive index values of 0.52 ± 0.18
(SD), 0.49 ± 0.17, and 0.47 ± 0.19, respectively com-
pared to patients without vascular complications
0.72 ± 0.17, 0.72 ± 0.19, and 0.72 ± 0.17, respectively.
Of 27 patients with hepatic artery resistive indices
less than 0.6, six had vascular complications and
only one patient with multiple vascular complica-
tions had a RI of greater 0.6 (Uzochukwu et al.
2005). Although anastomotic complications at the
site of anastomosis are overall infrequent, screening
is warranted due to the therapeutic consequences.
MRI angiography may be of additional value once
venous or arterial complications are suspected, is
however often compromised due to suboptimal
 Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 345

image quality (Ishigami et al. 2005) if no sophisti-
cated examination technique is employed.
16.2.4.5
Immunological Rejection
For quite a while it has been an intriguing idea
to detect rejection of kidney or heart transplants
non-invasively through colour Doppler ultrasound.
Although some prediction can be made from such
studies, one has to keep in mind that the diagnosis
of acute transplant rejection usually results in modi-
fication of the immunosuppressive therapy which
carries the risk of over-immunosuppression. Any
diagnosis of solid organ rejection should therefore
be based on a definitive diagnosis. Results of state-
of-the-art ultrasound examinations have been com-
pared with biopsy results in various studies.
A total of 48 transplant recipients were evaluated
with Doppler and Doppler tissue imaging assess-
ment along with catheter-measured pulmonary cap-
illary wedge pressure (PCWP) at the time of endo-
myocardial biopsy. Although propagation velocity
(Vp), mitral E-wave velocity (E)/Vp, and E/annular
mitral E-wave velocity were significantly associated
with rejection and an elevated PCWP was associated
with rejection, the sensitivity of these tests for the
prediction of acute rejection was poor (Eun et al.
2005).
For renal transplant recipients, this question was
addressed by Sharma et al. (2004) who performed
6017 serial ultrasound examinations in 614 patients.
Pulsatile index and Resistive index had a sensitiv-
ity of 78% and 60% respectively, and a specificity of
78% and 90% for the discrimination of acute rejec-
tion from acute tubular necrosis. Due to the sub-
stantial overlap between acute rejection and acute
tubular necrosis, the authors concluded that the use
of duplex scanning is greatly limited.
In conclusion, transplant biopsy still has to be
considered the gold standard for the diagnosis of
acute rejection.
16.2.4.6
Osteoporosis
Exposure to corticoid therapy and, in renal trans-
plant recipients preexisting hyperparathyroidism,
predispose transplant recipients to a loss of bone
mineral density, BMD, resulting in osteoporosis and
osteonecrosis. One-third of the patients’ bone loss
occurs during the first year after renal transplanta-
tion but accelerated resorption more than one year
post renal transplantation has also been reported
(Cayco et al. 2000; Marcen et al. 2005). Following
bone marrow transplantation, BMT, a significant
decline of previously normal BMD of lumbar spine
and hip was reported after 12 and 24 months of treat-
ment with cyclosporine A, prednisolone and metho-
trexate (Kashyap et al. 2000). Likewise, within 10
years after cardiac transplant osteoporosis occurred
in 13 of 32 patients, and vertebral fractures were
present in seven of these patients (Glendenning et
al. 1999). After renal transplantation, 193 patients
with > 6 months post transplantation exhibited a
significantly increased number of fractures which
occurred in 17% of patients. Interestingly, trans-
plant recipients with diabetes experienced 40% frac-
tures, compared to a fracture rate of 11% without
diabetes mellitus (Nisbeth et al. 1999). Other fac-

Table 16.2.5. Radiological screening of transplanted patients

System Study Candidates

Transplanted organ Ultrasound with colour Renal, hepatic, cardiac transplants

Doppler (within 24–48 h)
Gastrointestinal Abdominal ultrasound All patients (annually)
abdominal CT/MRI inconclusive ultrasound in
xHepatic transplantation
xPolycystic kidney disease
Renal Abdominal ultrasound All patients (annually)
Pulmonary Chest X-ray liver and heart transplant recipients
(annually)
Chest CT > 10 pack year tobacco use
Breast Mammogram Women > 50 years (per local practice)
346 J. R. Bogner and M. Fischereder
tors affecting bone loss include total steroid dose,
age, PTH level and duration since transplantation
but exhibit a high degree of variability and make a
precise prediction of osteoporosis for the individual
patient problematic (Caglar and Adeera 1999).
The protective effects of bisphosphonate therapy
on bone mineral density are established, although
not for fracture rate (Palmer et al. 2005). Neverthe-
less, screening of transplant recipients within the
first 6 months after transplantation for osteoporo-
sis appears prudent and less costly compared to
bisphosphonate prophylaxis of all patients.
As in the general population, the DEXA method
is the recommended method of osteoporosis
screening.
For transplanted patients the screening recom-
mendations are summarized in Table 16.2.5.
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 Subject Index 349

Subject Index

A B

abdominal Barrett’s esophagus 18

– disease 338 baseline 277
– ultrasound 19 Bavarian Mammography Screening 72
absolute lifetime risk 30, 131 BEIR 128
acoustical impedance 97 believe the negative (BTN) rule 8
ACR 186 believe the positive (BTP) rule 8
AD, see Alzheimer’s disease beneficence 141
adenomatosis coli 18 benign pulmonary nodule 287
adenomyosis 295, 296, 299, 301 bevacizumab 121
adenosine 135 BGO, see bismuth germanate
AFP, see serum D-fetoprotein bias 14
AIDS 336 biconcave deformity 253
ALARA 89, 183 biliary cirrhosis, primary 332
ALCAP-trial 72 biomarker-based test 9
alcoholic biopsy 190, 320
– fatty liver 333 BIRADS, see Breast Imaging Reporting and Data System
– liver cirrhosis/disease 333 bismuth germanate (BGO) 116
allergic reaction 43 bisphosphonate 258
Alzheimer disease (AD) 233, 240, 243 black-blood MR imaging 48
amygdala 236 blood pressure 24, 25
amyloid cascade 235 blurring 82
aneurysm 30 BMD, see bone mineral density
angiogenesis 41 B-mode 98, 165
angioSURF 80, 152 body coil 80
animal experiment 42 bodySURF 80
ankle-brachial pressure index 48 bone
annihilation 114 – densitometry 250, 339
antitrypsin – density 255
– D1-antitrypsin deficiency 331 – disease 338
aortic – fracture 20
– aneurysm 177 – mass 249
– – abdominal 30 – metastasis 67
– arch 33 – mineral density (BMD) 251, 254–256, 345
APC gene 18 bowel
apo B-100 28 – cleansing 93, 205
architectural distortion 187, 189 – preparation 16, 204
arterial spin labeling (ASL) 243 BRCA1/2-gene 16, 311, 313–315
asbestos 263, 264, 267, 271 breast 187, 188
– asbestos-related disease 270 – biopsy 318
asbestosis 268, 270 – Breast Imaging Reporting and Data System (BI-RADS)
asthma 135 73, 186, 187, 189, 190
asymptomatic patient 13, 177 – cancer/carcinoma 101, 183, 189, 191, 293, 311, 313
atelectasis 266, 268 – – inherited 312
atherosclerosis 149, 160, 161, 168 – dose 102
auto-calibration 82 – screening 188
autoimmune – tissue density 186
– disease 336 bronchiectasis 268
– hepatitis 332 brown fat 118
350 Subject Index

Bucky 102 – micro-CT 257

Burkitt’s lymphoma 42 – screening 276, 281
buscopan 94 computed tomography (QCT), quantitative 254, 256
computer-assisted
– detection (CAD) 106, 209
C
– GSM analysis 176
CA-125 18, 19 continuous table movement 78
CAD, see computer-assisted detection controlled operating mode 133
caesium 104 conversion 41
calcification 187 coronary
calcification, eccentric 286 – artery
calcitonin 324 – – bypass surgery 178
calcium 64 – – disease 159
– volume equivalent 90 – calcium 90, 134, 161, 162
cancer/carcinoma 42, 197 – – score 31
– of unknown primary (CUP-syndrome) 118 – – screening 162
carbon dioxide (CO2) 93, 206 – heart disease (CHD) 23, 150
cardiovascular disease (CVD) 23 cost-effectiveness 32, 198
carotid – analysis 178, 282
– artery 98, 165, 167–169 – of screening 176, 177
– – bifurcation 33 critical limb ischemia 59
– – disease 176 Crohn’s colitis 15
– – stenosis 170–172, 177 cross-sectional 69
– – ultrasound 166 crush deformity 253
– bruit 178 CT, see computed tomography
– disease 165 CTC, see computed tomography (CT) colonography
– endarterectomy 171, 178 CUP-syndrome, see cancer of unknown primary
– IMT 170 curative approach 13
– plaque 173 CVD, see cardiovascular/cerebrovascular disease
– stenosis 174 cyst 189
catheter X-ray coronary angiography 64 cystic kidney disease 217
CCT 338 cytology 17
CDD, see charge coupled device
central nervous system 67
D
cerebrovascular
– disease (CVD) 30, 149 dark blood 152
– system 149 DCIS, see ductal in situ cancer
charge coupled device (CCD) 104 DDH, see developmental dislocation/dysplasia of the hip
CHD, see coronary heart disease de novo malignancy 341
chemoprophylaxis 306 delayed contrast-enhanced scan 56
chest X-ray 17, 337 dementia 233, 235, 236, 240
cholangiocarcinoma 337 detrimental radiation effect 128
cholangiocellular carcinoma 332 developmental dislocation/dysplasia of the hip (DDH)
cholesterol level 24 221, 222, 224, 228–230
cirrhosis 344 diabetes mellitus 24, 155, 333
CO2, see carbon dioxide diagnostic work-up 236
coil sensitivity profile 82 Digital Mammography Imaging Screening Trial (DMIST)
colonic distension 206 106
colonoscopy, conventional 14, 16, 202, 203, 212 dislocation/dysplasia of the hip 221, 222, 228–230
color doppler 98, 99 distension 93
colorectal cancer 15, 201, 202 DMIST, see Digital Mammography Imaging Screening Trial
– screening 6, 203 doppler 167, 301, 345
comorbidity 43 – shift 166
complication 14 – sonography 171
compression fracture 252 DQE, see effective quantum efficiency
computed tomography (CT) 159, 236, 240, 266, 268, 275, drugs 333
326, 344 ductal in situ cancer (DCIS) 185, 190
– colonography (CTG) 92, 201–209, 211 duplex ultrasound 165, 176
– dynamic contrast-enhanced 286, 287, 289 Dutch Nationwide Breast Cancer Screening Program 72
– electron beam (EBCT) 89 DXA 254, 255
 Subject Index 351

E fine needle aspiration cytology 190

FLAIR 239, 245
EAC, see Europe Against Cancer FLASH 210
Early Lung Cancer Action Project (ELCAP) 66, 275, 276 flat panel 104
EBCT, see electron beam CT fluorine-18 FDG PET 290
ECG pulsing 90 fluorodeoxyglucose (FDG)
ECG tube current modulation, prospective 90 – [18F]-2-fluoro-2-deoxy-D-glucose 113
echo-planar imaging 84 – 18fluorodeoxyglucose 66, 289
effective – PET/CT 49
– dose E 129 fMRI, see functional MRI
– quantum efficiency (DQE) 103 FNAC 190
ELCAP, see Early Lung Cancer Action Project FOBT, see faecal occult blood test
electric field 133 Fourier
electrolyte lavage 93 – encoding 79
electromagnetic coil 78 – transformation 82
electron beam computed tomography (EBCT) 89 fracture 249
employer 144 Framingham study 45, 160, 161
endometrial full-body screening 9, 10
– abnormality 302 functional MRI (fMRI) 56, 241
– carcinoma 295, 299
– cystic glandular atrophy 295
– hyperplasia 294, 295 G
– polyp 294
– thickening 298, 299 gadolinium 135
endometrium 300 – chelate 43
endorectal coil 134 – oxyorthosilicate (GSO) 116
endovaginal ultrasound 298 gallium
epidemiology 5 – gallium-68 114
epitheloid 268 – scanning 339
EPOQ, see European Protocol for Quality Control gastroesophageal reflux disease (GERD), chronic 18
Epstein-Barr virus 42 genetic
erosion 48 – predisposition 311
ethic code 137 – risk 313
ethnic background 28 geometric distortion 79, 84
euratom 138 geometry factor (g-factor) 83
Europe Against Cancer (EAC) 101 GERD, see chronic gastroesophageal reflux disease
European Protocol for Quality Control of the physical and g-factor, see geometry factor
technical aspects of mammography screening (EPOQ) 103 gradient field 78
EUSOMA 67 GRAPPA 82
Ewing sarcoma 42 Gray (Gy) 128
greyscale 92
– median 175
F gross tumor volume (GTV) 119
ground-glass opacity 268
faecal/fecal growth rate 42
– occult blood test (FOBT) 4, 6 GSM 176
– tagging 204, 212 GSO, see gadolinium oxyorthosilicate
family/familial GTV, see gross tumor volume
– history 24, 311
– risk 15
FAP 18 H
fast gradient-echo 81
fatty streak 46 HAART, see highly active antiretroviral therapy
FDG, see fluorodeoxyglucose HASTE 210
fever of unknown origin 339 HCC, see hepatocellular carcinoma
fibroadenoma 189, 190 HD, see Hodgkin disease
fibrous health care provider 70
– cap 159, 173 heart
– tissue 121 – disease 177
field of view 77 – transplantation 343
352 Subject Index

hemochromatosis 330 inflammatory

hepatic iron index 331 – bowel disease 15
hepatitis – joint disease 156
– B 42, 329, 330 – lung nodule 288
– C 42, 99 informed consent (IC) 139
– chronic 329, 330 insulin resistance 24
– D 330 insurance 144
hepatocellular carcinoma (HCC) 42, 329, 331, 333, 334 interleukin-6 29
hepato-splenomegaly 338 intermediate risk indicate 31
hereditary non-polyposis colorectal cancer (HNPCC) 18 intermittent claudication 32
highly active antiretroviral therapy (HAART) 337 International (I)-ELCAP consortium 277
high-risk population/patient 31, 275, 312, 314, 320 International Commission on Non-Ionizing Radiation
high-sensitive C-reactive protein (hsCRP) 29 Protection (ICNIRP) 133
hip International Electrotechnical Commission (IEC) 133
– dislocation 221 International Labor Organization system (ILO) 266
– dysplasia 221, 223 inter-observer variability 69
– screening 221, 230 interval cancer/carcinoma 7, 42
hippocampus 236 intima-media thickness (IMT) 48, 168, 169
histogram analysis 91 intra-observer variability 69
hMLH1/2 18 intravenous drug abuse 330
HNPCC, see hereditary non-polyposis colorectal cancer invasive lobular carcinoma 190
Hodgkin disease (HD) 121 iodine
homocysteine 24 – iodine-124 123
honeycombing 268 – iodine-containing contrast agent 43, 77
hormone replacement 258 ischemia, chronic 155
HPV, see human papilloma virus ischemic stroke 33
HRCT 266, 269 isocentre 79
HR-MRI, see magnetic resonance imaging, high-resolu-
tion
hsCRP, see high-sensitive C-reactive protein K
human immunodeficiency virus (HIV) 140
– encephalopathy 338 kidney 215
– infection 337 – transplantation 341
human papilloma virus (HPV) 17, 42
hydronephrosis 216, 219
hyoscine-N-butylbromide 94 L
hyperhomocysteinemia 27
hyperlipidemia 24, 333 lag time 267
hypertension 24, 45 late enhancement 153
hysterosonography 299–301 LDBI, see Lorad Digital Breast Imager
LDL-cholesterol (LDL-C) 25
leiomyoma 195, 295, 296
leukemia 41
I Life Span Study (LSS) 128
IC, see informed consent lifestyle 28
ICA stenosis 176 LIPID study group 48
ICNIRP, see International Commission on Non-Ionizing lipoprotein 24, 26
Radiation Protection liver
ICRP 128 – cirrhosis 43, 99, 329, 330, 333, 334
IEC, see Internationl Electrotechnical Commission – transplantation 344
ILO, see International Labor Organization local lymph node metastasis 323
image Lorad Digital Breast Imager (LDBI) 104
– receptor 102 low risk group 31
– reconstruction algorithm 84 LSO, see lutetium oxyorthosilicate
image-modulated radiation therapy (IMRT) 119 LSS, see Life Span Study
immunological rejection 345 luminescence radiography 106
immunosuppressive drug 341 lung
IMRT, see image-modulated radiation therapy – cancer 263, 269, 275–277, 282, 285
IMT, see intima-media thickness – emphysema 43
infection 339 lutetium oxyorthosilicate (LSO) 116
 Subject Index 353

lymphatic spread 39 multi-detector computed tomography (MDCT) 53, 90, 201

lymphoma 337 multi-planar reformation (MPR) 57, 91
musculoskeletal system 67
mutation 40
myeloid leukemia, acute 41
M myocardial
– infarction 154, 159
magnetic field 133 – ischemia 160
magnetic resonance – perfusion 56
– angiography (MRA) 241
– – contrast-enhanced 57, 245
– colonography 209, 210
– – diagnostic performance 212 N
– MR-guided intervention 320
– imaging (MRI) 16, 188, 234, 236, 239, 266, 240, 302, 327, nasopharyngeal carcinoma 42
338, 339, 342 National Cholesterol Education Program (NCEP) 48
– – of the whole body NCB 190
– – screening 245, 312 NCEP, see national cholesterol education program
– – dynamic contrast-enhanced 288, 289 necrosis 345
magnetic resonance imaging (MRI), contrast-enhanced needle core biopsy 190
334 neonatal screening 225, 227
magnetic resonance imaging (MRI), diffusion 241, 243, 245 neovascularisation 47
magnetic resonance imaging (HR-MRI), high-resolution 257 nephrogenic systemic fibrosis (NSF) 135
Mainz Model 216 neuroblastoma screening 6
Mainz/Wuppertal screening study 193 neurodegeneration 233
malignancy 187 neuropathic foot 59
mammography 16, 101, 187, 191, 315 neuropathy 59
– examination 184 NHL, see non-Hodgkin’s lymphoma
– screening 4, 6, 183, 318 nitric oxide 46
manual self-examination 16 nitrogen 93
mastectomy 320 non-alcoholic steatohepatitis 333
MCI, see mild cognitive impairment non-calcified pulmonary nodule 278, 285
MDCT, see multi-detector CT non-Hodgkin’s lymphoma (NHL) 121, 337
medullary thyroid carcinoma 323, 324, 326 non-insulin dependent diabetes 45
megaureter 216, 219 non-maleficence 141
– primary 219 non-threshold hypothesis 128
– secondary 219 normal operating mode 133
MEN 2 325 NSF, see nephrogenic systemic fibrosis
mesothelioma 264, 267 N-staging 113
mesothelioma, malignant 264 Nuremberg code 138
metabolic syndrome 333
metalloproteinase 47
microangiopathy 239
O
microcalcification 103, 189
micro-CT 257 obesity 45, 333
microsphere 90Y 121 obstruction 219
microvessel 47 octreotide 324
– density 287 oncocytoma 195
mild cognitive impairment (MCI) 234, 235 organ
MIP 91 – dose 131
mixed nodule 286 – transplant 340
monitor persistent quality 10 osteodensitometry 254
monocyte 24 osteomyelitis 59
Monte-Carlo calculation 129 osteopenia 254
morbidity/mortality rate 7 osteoporosis 249, 250, 252, 254, 258, 345
motivation 69 ovarian cancer 8, 15, 313
MRA, see magnetic resonance angiography over-diagnosis 5, 6, 69
MRI, see magnetic resonance imaging over-therapy/treatment 5, 69
M-staging 113
multi-channel MR technology 56
354 Subject Index

P Q
PACS 92 QA, see quality assurance
Papanicolaou 3, 17 QCT, see quantitative computed tomography
parahippocampal gyrus 236 quality
parallel – assurance (QA) 6, 10, 101
– acquisition technique (PAT) 53, 82 – control 101
– imaging 82 QUS, see quantitative ultrasound
– MRI 82
parenchymal band 268
part-solid nodule 5.0 278 R
PAT, see parallel acquisition technique
paternalism 141 radiation
perfusion measurement, contrast-enhanced 245 – dose consideration 206
– MRI 242 – exposure 54, 89, 92, 118, 314
peripheral arterial occlusive disease 30, 177 – radiation-induced carcinogenesis 43
PET, see positron emission tomography – therapy 20, 178
phase-encoding direction 78 radiofrequency (RF)
plaque 89, 159, 179 – ablation (RFA) 20, 121
– classification 174 – electromagnetic field 78, 133
– disruption 47 radiography, conventional 251
– morphology 175 radiological vertebral index 252
– texture 173 radiolucency, increased 251
pleura/pleural 264
RAM 81
– effusion 266
RCC, see renal cell carcinoma
– mesothelioma 268
real-time trueFISP 81
– plaque 263, 266, 267
recall rate 105
– thickening 267
pneumonia 337 receiver coils 56
polyethylene glycol 93 RECIST 66
polyp 93, 202, 203, 211 recording 103
polyp, flat 16 rectosigmoidoscopy 16
positive predictive value 7 reimbursement 69
positron emission tomography (PET) 31, 113, 241, 289, 339 rejection 345
post-menopausal 249 relative risk 30
– patient 302 renal
– – breast cancer patient 294 – cell 42
postnatal – cell carcinoma (RCC) 193–198
– hip displacement 222 – transplant recipient 345
– kidney screening 215 – ultrasonography 197, 198
prenatal ultrasound scan 218 repeat screening 277
preventive reproduction 103
– mastectomy 320 RES 134
– salpingo-ovaraectomy 320 respiratory distress 20
primary retrospective ECG gating 90
– prevention 270, 320 RFA, see radiofrequency ablation
PROCAM 160 rheumatoid arthritis 337
processing 103 risk
progression 41 – factor 162, 250
progressive temporal atrophy 237 – ratio 145
propagation 41 risk-benefit analyse 132
prostacyclin 46 rounded atelectasis 266, 268
prostate cancer 14, 17
pseudo-disease 7
pulmonary S
– disease 337
– hypertension 337 salivary gland 118
– lesion 119 salpingo-ovaraectomy 320
– nodule 92, 285, 286, 288, 289, 291 sample size calculation 6
– – malignant 287 sampling perfection with application-optimized contrast
– – characterization 286 using (SPACE) 85
pulse sequence 77 sarcoma 268
 Subject Index 355

SARS 140 statistical dependence 9

screening 178, 201, 202, 212, 275, 277, 306, 312, 337, 342 steady-state free-precession (SSFP) 80
– chest radiograph 344 stem cell transplantation 344
– interval 65 stenosis 219
– mammography 185, 189 stochastic 132
– MRI 315 stool tagged 94
– program 177, 193, 194, 215, 270, 296, 314 stress
– screened population 197 – echocardiography 31
– study 198 – fracture 254
– test 3 stroke 23, 154
– ultrasonography 195 structural design 71
sclerosing cholangitis, primary 332, 337 subpleural line 268
second reader 209 supernumerary kidney 216
secondary SURF 80
– prevention 3, 30, 270 surface coil covering 80
selenium 104 surveillance 333
self referral 70 survival time 5
senility 249 susceptibility 82, 84
senographe 2000 D 104 SUV, see standardized uptake value
SenoScan 104 Sv, see Sievert
SENSE 82 symptomatic patient 176
serial chest X-ray 337 systemic disease 56
serum
– amyloid A 29
– D-fetoprotein (AFP) 334
sexual transmission 330 T
SFM 103
shared decision making 144 tamoxifen 293–299, 301, 302, 306
side effects 4, 10 target
Sievert (Sv) 129 – disease 10
sigmoidoscopy 15 – population 15
signal-to-noise ratio (SNR) 81, 83 TC, see total cholesterol
single photon emission computed tomography (SPECT) teratologic hip displacement 222
241 tertiary prevention 270
single-shot turbo-spin-echo sequence 84 thallium 104
Sjogren syndrome 337 the tube current, modulation 74
skeletal disease 249 thyroid nodule 324
SMASH 82 tissue inflammation 115
smoking 24 T-lymphocyte 24
SNR, see signal-to-noise ratio TNM, see tumor-node-metastasis
solid nodule 278 total cholesterol (TC) 25
sonographic screening 221 toxicity of contrast media 43
– of the hip 222 trabecular quantification 251
SPACE, see sampling perfection with application-opti- transducer 98
mized contrast transplantation 346
specific absorption rate 133 – patient 339
SPECT, see single photon emission computed tomography transvaginal sonography/ultrasound 8, 18
spectral treatment recommendation 64
– analysis 167 trueFISP 210
– doppler 98 T-score 254, 255
spinal T-staging 113
– deformity index 252 T-test-binary 8
– fracture index 252 tubular necrosis, acute 345
spin-labeling 245 tumor
splenomegaly 338 – angiogenesis 287
spread, hematogeneous 39 – necrosis factor D (TNF-D) 29
sputum cytology 17 – staging 113
SSFP, see steady-state free-precession – tumor-node-metastasis (TNM) 118
standardized uptake value (SUV) 114 turbo-spin-echo pulse sequence 81
static magnetic field 78 two component test 9
356 Subject Index

U VEGF expression 287

venous contamination 57
UISS 67 vertebral fracture 252
ulcerative colitis 15 vesico-renal reflux 216, 218
ultrasound, contrast-enhanced 98 vesico-urethral reflux 217, 219
ultrasound, quantitative (QUS) 254 VIBE 211
ultrasonography/ultrasound 97, 165, 170, 188, 193, 194, virtual colonoscopy 16
196, 215, 266, 315, 318, 337, 342, 334 volumetric
– abdominal 19 – analysis 239, 245
– endovaginal 298 – MRI 236
unconditional independence 10 VRT 91
under-diagnosis 69 VRT, endoluminal 204, 207, 208
under-treatment 69 vulnerable plaque 159
UNSCEAR 128
urinary tract W
– infection 218
– malformation 217 wavelength 97
urine cytology 19 wedge deformity 253
urticaria 135 whole-body MRI 77
uterus 302 Wilson’s disease 331

X
V
X-ray 4
vacuum-assisted needle core biopsy 190
VANCB 190
vascular Z
– dementia 240
– malformation 155 Z-score 255
 List of Contributors 357

List of Contributors

Silvia H. Aguiar, MD Nikolaus Becker, PhD

Mount Sinai School of Medicine Professor, Division of Cancer Epidemiology
One Gustave L. Levy Place German Cancer Research Center (DKFZ)
Imaging Science Laboratories Im Neuenheimer Feld 280
Box 1234 69120 Heidelberg
New York, NY 10029 Germany
USA

Sandra J. Allison, MD Frank Berger, MD

Department of Radiology Department of Clinical Radiology
Georgetown University Hospital University Hospitals – Grosshadern
3800 Reservoir Road, NW Ludwig-Maximilians-University of Munich
Washington DC 20007-2197 Marchioninistrasse 15
USA 81377 Munich
Germany
Gerald Antoch, MD
Department of Diagnostic and Interventional Radiology Ulrich Beuers, MD
and Neuroradiology Professor, Department of Gastroenterology
University Hospital Essen and Hepatology
Hufelandstrasse 55 Academic Medical Center, University of Amsterdam
45122 Essen Meibergdreef 9
Germany P.O. Box 22700
1100 DE Amsterdam
The Netherlands
Susan M. Ascher, MD
Professor, Department of Radiology
Director, Division of Abdominal Imaging Holger Boehm, MD
Georgetown University Hospital Department of Clinical Radiology
3800 Reservoir Road NW University Hospitals – Grosshadern
Washington DC 20007-2197 Ludwig-Maximilians-University of Munich
USA Marchioninistrasse 15
81377 Munich
Germany
Andrea Baur-Melnyk, MD
Associate Professor of Radiology
Department of Clinical Radiology Johannes Bogner, MD
University Hospitals – Grosshadern Professor, Medical Policlinic
Ludwig-Maximilians-University of Munich University Hospitals – Innenstadt
Marchioninistrasse 15 Ludwig-Maximilians-University of Munich
81377 Munich Pettenkoferstrasse 8a
Germany 80336 Munich
Germany

Christoph R. Becker, MD
Department of Clinical Radiology Gunnar Brix, PhD
University Hospitals – Grosshadern Professor, Federal Office for Radiation Protection
Ludwig-Maximilians-University of Munich Department of Medical Radiation
Marchioninistrasse 15 Hygiene and Dosimetry
81377 Munich 85764 Neuherberg
Germany Germany
358 List of Contributors

Matthew Cham, MD Christian Fink, MD

Department of Radiology Associate Professor
New York Presbyterian Hospital – Section Chief Cardiothoracic Imaging
Weill Cornell Medical Center Department of Clinical Radiology
525 East 68th Street University Hospital Mannheim
New York, NY 10065 Medical Faculty Mannheim – University of Heidelberg
USA Theodor-Kutzer-Ufer 1–3
68167 Mannheim
Stefan Delorme, MD Germany
Professor, Department of Radiology
German Cancer Research Center (DKFZ) Michael Fischereder, MD
Im Neuenheimer Feld 280 Professor, Medical Policlinic
69120 Heidelberg University Hospitals – Innenstadt
Germany Ludwig-Maximilians-University of Munich
Pettenkoferstrasse 8a
Gerald U. Denk, MD 80336 Munich
Department of Medicine II Germany
University Hospitals – Grosshadern Anno Graser, MD
Ludwig-Maximilians-University of Munich Department of Clinical Radiology
Marchioninistrasse 15 University Hospitals – Grosshadern
81377 Munich Ludwig-Maximilians-University of Munich
Germany Marchioninistrasse 15
81377 Munich
Olaf Dietrich, PhD
Germany
Department of Clinical Radiology
University Hospitals – Grosshadern Jürgen Griebel, MD
Ludwig-Maximilians-University of Munich Federal Office for Radiation Protection
Marchioninistrasse 15 Department of Medical Radiation
81377 Munich Hygiene and Dosimetry
Germany 85764 Neuherberg
Germany
Roger Eibel, MD
Chief, Department of Radiology Volker Heinemann, MD
HELIOS Clinics Schwerin Professor, Department of Internal Medicine III
Teaching Hospitals of the University of Rostock University Hospitals – Grosshadern
Wismarsche Strasse 393–397 Ludwig-Maximilians-University of Munich
19049 Schwerin Marchioninistrasse 15
Germany 81377 Munich
Germany
Marco Essig, MD
Karin Hellerhoff, MD
Professor of Radiology
Department of Clinical Radiology
Head of MRI and Neuroimaging
University Hospitals – Grosshadern
German Cancer Research Center (DKFZ)
Ludwig-Maximilians-University of Munich
Im Neuenheimer Feld 280
Marchioninistrasse 15
69120 Heidelberg
81373 Munich
Germany
Germany
Zahi A. Fayad, PhD, FAHA Claudia I. Henschke, PhD, MD, FCCP
Mount Sinai School of Medicine Department of Radiology
One Gustave L. Levy Place New York Presbyterian Hospital –
Imaging Science Laboratories Weill Cornell Medical Center
Box 1234 525 East 68th Street
New York, NY 10029 New York, NY 10065
USA USA
Dragana Filipas, MD Peter Herzog, MD
Department of Urology Department of Clinical Radiology
Johannes-Gutenberg-University of Mainz University Hospitals – Grosshadern
Medical School Ludwig-Maximilians-University of Munich
Langenbeckstrasse 1 Marchioninistrasse 15
55101 Mainz 81377 Munich
Germany Germany
 List of Contributors 359

Ulrich Hoffmann, MD Maximilian F. Reiser, MD

Professor and Division Head Vascular Medicine Professor and Chairman
Department of Internal Medicine Department of Clinical Radiology
University Hospital University Hospitals –
Ludwig-Maximilians-University of Munich Grosshadern and Innenstadt
Pettenkoferstrasse 8a Ludwig-Maximilians-University of Munich
80336 Munich Marchioninistrasse 15
Germany 81377 Munich
Germany
Harald Kramer, MD
Department of Clinical Radiology Stella Reiter-Theil, PhD
University Hospitals – Grosshadern Professor and Director
Ludwig-Maximilians-University of Munich Institute for Applied Ethics and Medical Ethics
Marchioninistrasse 15 University of Basel
81377 Munich Missionsstrasse 21a
Germany 4055 Basel
Switzerland
Susanne Ladd, MD
Department of Diagnostic and
Interventional Radiology and Neuroradiology James H. F. Rudd, MD, PhD
University Hospital Essen Mount Sinai School of Medicine
Hufelandstrasse 55 One Gustave L. Levy Place
45122 Essen Imaging Science Laboratories
Germany Box 1234
New York, NY 10029
Dennis Nowak, MD USA
Professor, Institute and Outpatient Clinic for
Occupational Socical and Environmental Medicine Thomas Schlossbauer, MD
University of Munich Department of Clinical Radiology
Ziemssenstrasse 1 University Hospitals – Grosshadern
80336 Munich Ludwig-Maximilians-University of Munich
Germany Marchioninistrasse 15
81373 Munich
Sascha Pahernik, MD Germany
Department of Urology
Johannes-Gutenberg-University of Mainz Stefan O. Schoenberg, MD
Medical School Professor and Chairman
Langenbeckstrasse 1 Department of Clinical Radiology
55101 Mainz University Hospital Mannheim
Germany Medical Faculty Mannheim
University of Heidelberg
Claudia Perlet, MD Theodor-Kutzer-Ufer 1–3
Department of Clinical Radiology 68167 Mannheim
University Hospitals – Grosshadern Germany
Ludwig-Maximilians-University of Munich
Marchioninistrasse 15
81373 Munich Johannes Schröder, MD
Germany Professor, Section for Geriatric Psychiatry
Center for Psychosocial Medicine
Sandra A. Polin, MD University of Heidelberg
Department of Radiology Voßstrasse 4
Georgetown University Hospital 69115 Heidelberg
3800 Reservoir Road NW Germany
Washington DC 20007-2197
USA Rüdiger Schulz-Wendtland, MD
Professor, Radiologisches Institut
Friedhelm Raue, MD Gynäkologische Radiologie
Professor, Endocrine Practice Universität Erlangen-Nürnberg
Brückenstrasse 21 Universitätsstrasse 21–23
69120 Heidelberg 91054 Erlangen
Germany Germany
360 List of Contributors

Robert Stahl, MD Gerhard van Kaick, MD

Department of Clinical Radiology Professor Emeritus
University Hospitals – Grosshadern German Cancer Research Center (DKFZ)
Ludwig-Maximilians-University of Munich Im Neuenheimer Feld 280
Marchioninistrasse 15 69120 Heidelberg
81377 Munich Germany
Germany
Norbert Weiss, MD
Nicola Stingelin Giles, MA PD, Department of Vascular Medicine
Institute for Applied Ethics and Medical Ethics Medical Policlinic
University of Basel University Hospitals Munich
Missionsstrasse 21a Ludwig-Maximilians-University of Munich
4055 Basel Pettenkoferstrasse 8a
Switzerland 80336 Munich
Germany
Gabriela Stolz, MD
Birth Registry Mainz Modell Dieter Weitzel, MD
Universitätskinderklinik der Professor, Department of Pediatrics
Johannes-Gutenberg-University of Mainz and Adolescent Medicine
Langenbeckstrasse 1 German Diagnostic Clinic
55101 Mainz Aukamm-Allee 33
Germany 65191 Wiesbaden
Germany
Joachim W. Thüroff, MD
Professor and Chairman, Department of Urology David F. Yankelevitz, MD
University Hospital Mainz Department of Radiology
Johannes-Gutenberg-University of Mainz New York Presbyterian Hospital –
Medical School Weill Cornell Medical Center
Langenbeckstrasse 1 525 East 68th Street
55101 Mainz New York, NY 10065
Germany USA

Medical Radiology
Diagnostic Imaging
Innovations in Diagnostic Imaging
Edited by J. H. Anderson
Radiology of the Upper Urinary Tract
Edited by E. K. Lang
The Thymus - Diagnostic Imaging,
Functions, and Pathologic Anatomy
Edited by E. Walter, E. Willich,
and W. R. Webb
Interventional Neuroradiology
Edited by A. Valavanis
Radiology of the Pancreas
Edited by A. L. Baert,
co-edited by G. Delorme
Radiology of the Lower Urinary Tract
Edited by E. K. Lang
Magnetic Resonance Angiography
Edited by I. P. Arlart, G. M. Bongartz,
and G. Marchal
Contrast-Enhanced MRI of the Breast
S. Heywang-Köbrunner and R. Beck
Spiral CT of the Chest
Edited by M. Rémy-Jardin and J. Rémy
Radiological Diagnosis of Breast Diseases
Edited by M. Friedrich and E.A. Sickles
Radiology of the Trauma
Edited by M. Heller and A. Fink
Biliary Tract Radiology
Edited by P. Rossi, co-edited by
M. Brezi
Radiological Imaging of Sports Injuries
Edited by C. Masciocchi
Modern Imaging of the Alimentary Tube
Edited by A. R. Margulis
Diagnosis and Therapy of Spinal Tumors
Edited by P. R. Algra, J. Valk,
and J. J. Heimans
Interventional Magnetic
Resonance Imaging
Edited by J. F. Debatin and G. Adam
Abdominal and Pelvic MRI
Edited by A. Heuck and M. Reiser
Orthopedic Imaging
Techniques and Applications
Edited by A. M. Davies
and H. Pettersson
Radiology of the Female Pelvic Organs
Edited by E. K.Lang
Magnetic Resonance of the Heart
and Great Vessels
Clinical Applications
Edited by J. Bogaert, A.J. Duerinckx,
and F. E. Rademakers
Modern Head and Neck Imaging
Edited by S. K. Mukherji and
J. A. Castelijns
Diagnostic Imaging and Radiation Oncology
Titles in the series already published
Radiological Imaging of
Endocrine Diseases
Edited by J. N. Bruneton
in collaboration with B. Padovani
and M.-Y. Mourou
Trends in Contrast Media
Edited by H. S. Thomsen, R. N. Muller,
and R. F. Mattrey
Functional MRI
Edited by C. T. W. Moonen
and P. A. Bandettini
Radiology of the Pancreas
2nd Revised Edition
Edited by A. L. Baert. Co-edited by
G. Delorme and L. Van Hoe
Emergency Pediatric Radiology
Edited by H. Carty
Spiral CT of the Abdomen
Edited by F. Terrier, M. Grossholz,
and C. D. Becker
Liver Malignancies
Diagnostic and
Interventional Radiology
Edited by C. Bartolozzi and R. Lencioni
Medical Imaging of the Spleen
Edited by A. M. De Schepper
and F. Vanhoenacker
Radiology of Peripheral Vascular Diseases
Edited by E. Zeitler
Diagnostic Nuclear Medicine
Edited by C. Schiepers
Radiology of Blunt Trauma of the Chest
P. Schnyder and M. Wintermark
Portal Hypertension
Diagnostic Imaging-Guided Therapy
Edited by P. Rossi
Co-edited by P. Ricci and L. Broglia
Recent Advances in
Diagnostic Neuroradiology
Edited by Ph. Demaerel
Virtual Endoscopy and
Related 3D Techniques
Edited by P. Rogalla, J. Terwisscha
Van Scheltinga, and B. Hamm
Multislice CT
Edited by M. F. Reiser, M. Takahashi,
M. Modic, and R. Bruening
Pediatric Uroradiology
Edited by R. Fotter
Transfontanellar Doppler Imaging
in Neonates
A. Couture and C. Veyrac
Radiology of AIDS
A Practical Approach
Edited by J.W.A.J. Reeders and
P.C. Goodman
Subject Index 361
CT of the Peritoneum
Armando Rossi and Giorgio Rossi
Magnetic Resonance Angiography
2nd Revised Edition
Edited by I. P. Arlart, G. M. Bongratz,
and G. Marchal
Pediatric Chest Imaging
Edited by Javier Lucaya and
Janet L. Strife
Applications of Sonography
in Head and Neck Pathology
Edited by J. N. Bruneton
in collaboration with C. Raffaelli and
O. Dassonville
Imaging of the Larynx
Edited by R. Hermans
3D Image Processing
Techniques and Clinical Applications
Edited by D. Caramella and
C. Bartolozzi
Imaging of Orbital and
Visual Pathway Pathology
Edited by W. S. Müller-Forell
Pediatric ENT Radiology
Edited by S. J. King and
A. E. Boothroyd
Radiological Imaging of the
Small Intestine
Edited by N. C. Gourtsoyiannis
Imaging of the Knee
Techniques and Applications
Edited by A. M. Davies
and V. N. Cassar-Pullicino
Perinatal Imaging
From Ultrasound to MR Imaging
Edited by Fred E. Avni
Radiological Imaging of the
Neonatal Chest
Edited by V. Donoghue
Diagnostic and Interventional
Radiology in Liver Transplantation
Edited by E. Bücheler, V. Nicolas,
C. E. Broelsch, X. Rogiers,
and G. Krupski
Radiology of Osteoporosis
Edited by S. Grampp
Imaging Pelvic Floor Disorders
Edited by C. I. Bartram and
J. O. L. DeLancey
Associate Editors: S. Halligan,
F. M. Kelvin, and J. Stoker
Imaging of the Pancreas
Cystic and Rare Tumors
Edited by C. Procacci and
A. J. Megibow
High Resolution Sonography
of the Peripheral Nervous System
Edited by S. Peer and G. Bodner
362 Subject Index
Imaging of the Foot and Ankle
Techniques and Applications
Edited by A. M. Davies,
R. W. Whitehouse, and J. P. R. Jenkins
Radiology Imaging of the Ureter
Edited by F. Joffre, Ph. Otal,
and M. Soulie
Imaging of the Shoulder
Techniques and Applications
Edited by A. M. Davies and J. Hodler
Radiology of the Petrous Bone
Edited by M. Lemmerling and
S. S. Kollias
Interventional Radiology in Cancer
Edited by A. Adam, R. F. Dondelinger,
and P. R. Mueller
Duplex and Color Doppler Imaging
of the Venous System
Edited by G. H. Mostbeck
Multidetector-Row CT of the Thorax
Edited by U. J. Schoepf
Functional Imaging of the Chest
Edited by H.-U. Kauczor
Radiology of the Pharynx
and the Esophagus
Edited by O. Ekberg
Radiological Imaging
in Hematological Malignancies
Edited by A. Guermazi
Imaging and Intervention in
Abdominal Trauma
Edited by R. F. Dondelinger
Multislice CT
2nd Revised Edition
Edited by M. F. Reiser, M. Takahashi,
M. Modic, and C. R. Becker
Intracranial Vascular Malformations
and Aneurysms
From Diagnostic Work-Up
to Endovascular Therapy
Edited by M. Forsting
Radiology and Imaging of the Colon
Edited by A. H. Chapman
Coronary Radiology
Edited by M. Oudkerk
Dynamic Contrast-Enhanced Magnetic
Resonance Imaging in Oncology
Edited by A. Jackson, D. L. Buckley,
and G. J. M. Parker
Imaging in Treatment Planning
for Sinonasal Diseases
Edited by R. Maroldi and P. Nicolai
Clinical Cardiac MRI
With Interactive CD-ROM
Edited by J. Bogaert, S. Dymarkowski,
and A. M. Taylor
Focal Liver Lesions
Detection, Characterization, Ablation
Edited by R. Lencioni, D. Cioni,
and C. Bartolozzi
Multidetector-Row CT Angiography
Edited by C. Catalano and
R. Passariello
Paediatric Musculoskeletal Diseases
With an Emphasis on Ultrasound
Edited by D. Wilson
Contrast Media in Ultrasonography
Basic Principles and Clinical Applications
Edited by Emilio Quaia
MR Imaging in White Matter Diseases of
the Brain and Spinal Cord
Edited by M. Filippi, N. De Stefano,
V. Dousset, and J. C. McGowan
Diagnostic Nuclear Medicine
2nd Revised Edition
Edited by C. Schiepers
Imaging of the Kidney Cancer
Edited by A. Guermazi
Magnetic Resonance Imaging in
Ischemic Stroke
Edited by R. von Kummer and T. Back
Imaging of the Hip & Bony Pelvis
Techniques and Applications
Edited by A. M. Davies, K. J. Johnson,
and R. W. Whitehouse
Imaging of Occupational and
Environmental Disorders of the Chest
Edited by P. A. Gevenois and
P. De Vuyst
Contrast Media
Safety Issues and ESUR Guidelines
Edited by H. S. Thomsen
Virtual Colonoscopy
A Practical Guide
Edited by P. Lefere and S. Gryspeerdt
Vascular Embolotherapy
A Comprehensive Approach
Volume 1: General Principles, Chest,
Abdomen, and Great Vessels
Edited by J. Golzarian. Co-edited by
S. Sun and M. J. Sharafuddin
Vascular Embolotherapy
A Comprehensive Approach
Volume 2: Oncology, Trauma, Gene
Therapy, Vascular Malformations,
and Neck
Edited by J. Golzarian. Co-edited by
S. Sun and M. J. Sharafuddin
Head and Neck Cancer Imaging
Edited by R. Hermans
Vascular Interventional Radiology
Current Evidence in
Endovascular Surgery
Edited by M. G. Cowling
Ultrasound of the Gastrointestinal Tract
Edited by G. Maconi and
G. Bianchi Porro
Imaging of Orthopedic Sports Injuries
Edited by F. M. Vanhoenacker,
M. Maas, J. L. M. A. Gielen
Parallel Imaging in
Clinical MR Applications
Edited by S. O. Schoenberg, O. Dietrich,
and M. F. Reiser
MRI and CT of the Female Pelvis
Edited by B. Hamm and R. Forstner
Ultrasound of the Musculoskeletal System
S. Bianchi and C. Martinoli
Spinal Imaging
Diagnostic Imaging of the Spine and
Spinal Cord
Edited by J. W. M. Van Goethem,
L. van den Hauwe, and P. M. Parizel
Radiation Dose from Adult and Pediatric
Multidetector Computed Tomography
Edited by D. Tack and P. A. Gevenois
Computed Tomography of the Lung
A Pattern Approach
J. A. Verschakelen and W. De Wever
Clinical Functional MRI
Presurgical Functional Neuroimaging
Edited bei C. Stippich
Imaging in Transplantation
Edited by A. A. Bankier
Radiological Imaging of the Digestive
System in Infants and Children
Edited by A. S. Devos and
J. G. Blickman
Pediatric Chest Imaging
Chest Imaging in Infants and Children
2nd Revised Edition
Edited by J. Lucaya and J. L. Strife
Radiological Imaging
of the Neonatal Chest
2nd Revised Edition
Edited by V. Donoghue
Radiology of the Stomach and Duodenum
Edited by A. H. Freeman and E. Sala
Imaging in Pediatric Skeletal Trauma
Techniques and Applications
Edited by K. J. Johnson and E. Bache
Percutaneous Tumor Ablation in
Medical Radiology
Edited by T. J. Vogl, T. K. Helmberger,
M. G. Mack, and M. F. Reiser
Screening and Preventive Diagnosis with
Radiological Imaging
Edited by M. F. Reiser, G. van Kaick,
C. Fink, and S. O. Schoenberg
Color Doppler US of the Penis
Edited by M. Bertolotto
Image Processing in Radiology
Current Applications
Edited by E. Neri, D. Caramella,
and C. Bartolozzi
123

Medical Radiology
Radiation Oncology
Lung Cancer
Edited by C.W. Scarantino
Innovations in Radiation Oncology
Edited by H. R. Withers
and L. J. Peters
Radiation Therapy
of Head and Neck Cancer
Edited by G. E. Laramore
Gastrointestinal Cancer –
Radiation Therapy
Edited by R.R. Dobelbower, Jr.
Radiation Exposure
and Occupational Risks
Edited by E. Scherer, C. Streffer,
and K.-R. Trott
Radiation Therapy of Benign Diseases
A Clinical Guide
S. E. Order and S. S. Donaldson
Interventional Radiation
Therapy Techniques – Brachytherapy
Edited by R. Sauer
Radiopathology of Organs and Tissues
Edited by E. Scherer, C. Streffer,
and K.-R. Trott
Concomitant Continuous Infusion
Chemotherapy and Radiation
Edited by M. Rotman
and C. J. Rosenthal
Intraoperative Radiotherapy –
Clinical Experiences and Results
Edited by F. A. Calvo, M. Santos,
and L.W. Brady
Radiotherapy of Intraocular
and Orbital Tumors
Edited by W. E. Alberti and
R. H. Sagerman
Interstitial and Intracavitary
Thermoradiotherapy
Edited by M. H. Seegenschmiedt
and R. Sauer
Non-Disseminated Breast Cancer
Controversial Issues in Management
Edited by G. H. Fletcher and S.H. Levitt
Current Topics in
Clinical Radiobiology of Tumors
Edited by H.-P. Beck-Bornholdt
Practical Approaches to
Cancer Invasion and Metastases
A Compendium of Radiation
Oncologists’ Responses to 40 Histories
Edited by A. R. Kagan with the
Assistance of R. J. Steckel
Diagnostic Imaging and Radiation Oncology
Titles in the series already published
Radiation Therapy in Pediatric Oncology
Edited by J. R. Cassady
Radiation Therapy Physics
Edited by A. R. Smith
Late Sequelae in Oncology
Edited by J. Dunst and R. Sauer
Mediastinal Tumors. Update 1995
Edited by D. E. Wood and
C. R. Thomas, Jr.
Thermoradiotherapy
and Thermochemotherapy
Volume 1:
Biology, Physiology, and Physics
Volume 2:
Clinical Applications
Edited by M.H. Seegenschmiedt,
P. Fessenden, and C.C. Vernon
Carcinoma of the Prostate
Innovations in Management
Edited by Z. Petrovich, L. Baert,
and L.W. Brady
Radiation Oncology
of Gynecological Cancers
Edited by H.W. Vahrson
Carcinoma of the Bladder
Innovations in Management
Edited by Z. Petrovich, L. Baert,
and L.W. Brady
Blood Perfusion and
Microenvironment of Human Tumors
Implications for
Clinical Radiooncology
Edited by M. Molls and P. Vaupel
Radiation Therapy of Benign Diseases
A Clinical Guide
2nd Revised Edition
S. E. Order and S. S. Donaldson
Carcinoma of the Kidney and Testis,
and Rare Urologic Malignancies
Innovations in Management
Edited by Z. Petrovich, L. Baert,
and L.W. Brady
Progress and Perspectives in the
Treatment of Lung Cancer
Edited by P. Van Houtte,
J. Klastersky, and P. Rocmans
Combined Modality Therapy of
Central Nervous System Tumors
Edited by Z. Petrovich, L. W. Brady,
M. L. Apuzzo, and M. Bamberg
Age-Related Macular Degeneration
123
Current Treatment Concepts
Edited by W. A. Alberti, G. Richard,
and R. H. Sagerman
Subject Index 363
Radiotherapy of Intraocular
and Orbital Tumors
2nd Revised Edition
Edited by R. H. Sagerman,
and W. E. Alberti
Modification of Radiation Response
Cytokines, Growth Factors,
and Other Biolgical Targets
Edited by C. Nieder, L. Milas,
and K. K. Ang
Radiation Oncology for Cure and Palliation
R. G. Parker, N. A. Janjan,
and M. T. Selch
Clinical Target Volumes in Conformal and
Intensity Modulated Radiation Therapy
A Clinical Guide to Cancer Treatment
Edited by V. Grégoire, P. Scalliet,
and K. K. Ang
Advances in Radiation Oncology
in Lung Cancer
Edited by Branislav Jeremi´
c
New Technologies in Radiation Oncology
Edited by W. Schlegel, T. Bortfeld,
and A.-L. Grosu
Technical Basis of Radiation Therapy
4th Revised Edition
Edited by S. H. Levitt, J. A. Purdy,
C. A. Perez, and S. Vijayakumar
CURED I • LENT
Late Effects of Cancer Treatment
on Normal Tissues
Edited by P. Rubin, L. S. Constine,
L. B. Marks, and P. Okunieff
Clinical Practice of Radiation Therapy for
Benign Diseases
Contemporary Concepts and Clinical
Results
Edited by M. H. Seegenschmiedt,
H.-B. Makoski, K.-R. Trott, and
L. W. Brady