Professional Documents
Culture Documents
WHO OMS
Edited by
Stanley R. Hamilton
Lauri A. Aaltonen
IARCPress
Lyon, 2000
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Publisher IARCPress
International Agency for
Research on Cancer (IARC)
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and
with support from the
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or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers' products does not imply
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of a similar nature that are not mentioned. Errors and omissions excepted,
the names of proprietary products are distinguished by initial capital letters.
The authors alone are responsible for the views expressed in this publication.
Contents
Intraepithelial neoplasia2. A lesion cha- Tubulovillous adenoma. An adenoma Mucinous adenocarcinoma. An ade-
racterized by morphological changes composed of both tubular and villous nocarcinoma containing extracellular
that include altered architecture and structures, each comprising more than mucin comprising more than 50% of the
abnormalities in cytology and differentia- tumour. Note that ‘mucin producing’ is
20% of the tumour.
tion. It results from clonal alterations in not synonymous with mucinous in this
context.
genes and carries a predisposition for Serrated adenoma. An adenoma com-
progression to invasion and metastasis. posed of saw-toothed glands. Signet-ring cell carcinoma. An adeno-
carcinoma in which the predominant
High-grade intraepithelial neoplasia. Intraepithelial neoplasia (dysplasia) component (more than 50%) is com-
A mucosal change with cytologic and posed of isolated malignant cells con-
associated with chronic inflammatory
architectural features of malignancy but taining intracytoplasmic mucin.
diseases. A neoplastic glandular
without evidence of invasion into the stro-
epithelial proliferation occurring in a Squamous cell (epidermoid) carcino-
ma. It includes lesions termed severe
patient with a chronic inflammatory ma. A malignant epithelial tumour with
dysplasia and carcinoma in situ.
bowel disease, but with macroscopic squamous cell differentiation.
Polyp. A generic term for any excres- and microscopic features that distin-
Adenosquamous carcinoma. A malig-
cence or growth protruding above a guish it from an adenoma, e.g. patchy
nant epithelial tumour with significant
mucous membrane. Polyps can be distribution of dysplasia and poor cir- components of both glandular and squa-
pedunculated or sessile, and are readily cumscription. mous differentiation.
seen by macroscopic examination or
conventional endoscopy. Peutz-Jeghers polyp. A hamartoma- Small cell carcinoma. A malignant
epithelial tumour similar in morphology,
tous polyp composed of branching
Adenoma. A circumscribed benign immunophenotype and behaviour to
bands of smooth muscle covered by nor-
small cell carcinoma of the lung.
lesion composed of tubular and/or villous mal-appearing or hyperplastic glandular
structures showing intraepithelial neopla- mucosa indigenous to the site. Medullary carcinoma. A malignant
sia. The neoplastic epithelial cells are epithelial tumour in which the cells form
immature and typically have enlarged, Juvenile polyp. A hamartomatous solid sheets and have abundant
hyperbasophilic and stratified nuclei. eosinophilic cytoplasm and large, vesic-
polyp with a spherical head composed
ular nuclei with prominent nucleoli. An
of tubules and cysts, lined by normal
Tubular adenoma. An adenoma in intraepithelial infiltrate of lymphocytes is
epithelium, embedded in an excess of characteristic.
which branching tubules surrounded by
lamina propria comprise at least 80% of lamina propria. In juvenile polyposis, the
polyps are often multilobated with a pap- Undifferentiated carcinoma. A malig-
the tumour.
illary configuration and a higher ratio of nant epithelial tumour with no glandular
structures or other features to indicate
Villous adenoma. An adenoma in which glands to lamina propria.
definite differentiation.
leaf-like or finger-like processes of lami-
na propria covered by dysplastic epithe- Adenocarcinoma. A malignant epithe- Carcinoid. A well differentiated neo-
lium comprise at least 80% of the tumour. lial tumour with glandular differentiation. plasm of the diffuse endocrine system.
______________
1
This list of terms is proposed to be used for the entire digestive system and reflects the view of the Working Group convened in Lyon, 6 – 9 November,
1999. Terminology evolves with scientific progress; the terms listed here reflect current understanding of the process of malignant transformation in the
digestive tract. The Working Group anticipates a further convergence of diagnostic terms throughout the digestive system.
2
In an attempt to resolve confusion surrounding the terms ‘dysplasia’, ‘carcinoma in situ,’ and ‘atypia’, the Working Group adopted the term ‘intraepithe-
lial neoplasia’ to indicate preinvasive neoplastic change of the epithelium. The diagnosis does not exclude the possibility of coexisting carcinoma.
Intraepithelial neoplasia should not be used as a generic description of epithelial abnormalities due to reactive or regenerative changes.
01 19.7.2006 7:22 Page 9
CHAPTER 1
Adenocarcinoma
Oesophageal carcinomas with glandular differentiation are
typically located in the distal oesophagus and occur predomi-
nantly in white males of industrialized countries, with a marked
tendency for increasing incidence rates. The most important
aetiological factor is chronic gastro-oesophageal reflux lead-
ing to Barrett type mucosal metaplasia, the most common pre-
cursor lesion of adenocarcinoma.
01 19.7.2006 7:22 Page 10
_____________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for in situ carcinomas and grade III intraepithelial neoplasia, and /3 for
malignant tumours.
2
Intraepithelial neoplasia does not have a generic code in ICD-O. ICD-O codes are available only for lesions categorized as glandular intraepithelial neoplasia grade III
(8148/2), squamous intraepithelial neoplasia, grade III (8077/2), and squamous cell carcinoma in situ (8070/2).
T – Primary Tumour
TX Primary tumour cannot be assessed For tumours of upper thoracic oesophagus
T0 No evidence of primary tumour M1a Metastasis in cervical lymph nodes
Tis Carcinoma in situ M1b Other distant metastasis
T1 Tumour invades lamina propria or submucosa For tumours of mid-thoracic oesophagus
T2 Tumour invades muscularis propria M1a Not applicable
T3 Tumour invades adventitia M1b Non-regional lymph node
T4 Tumour invades adjacent structures or other distant metastasis
_____________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
Definition In both high-risk and low-risk regions, polymorphism in ALDH2, the gene
Squamous cell carcinoma (SCC) of the this cancer is exceedingly rare before encoding aldehyde dehydrogenase 2,
oesophagus is a malignant epithelial the age of 30 and the median age is has been shown to be significantly asso-
tumour with squamous cell differentia- around 65 in both males and females. ciated with several cancers of the upper
tion, microscopically characterised by Recent changes in the distribution pat- digestive tract, including squamous cell
keratinocyte-like cells with intercellular tern in France indicate that the rate of cancer. This observation suggests a role
bridges and/or keratinization. SCC has increased steadily in low-risk for acetaldehyde, one of the main car-
areas, particularly among females, cinogenic metabolites of alcohol in the
ICD-O Code 8070/3 whereas there may be a slight decrease development of oesophageal carcinoma
in high-risk areas. In the United States, a {2177}.
Epidemiology search in hospitalisation records of mili- Nutrition. Risk factors other than tobac-
Squamous cell carcinoma of the oeso- tary veterans indicates that SCC is 2-3 co and alcohol play significant roles in
phagus shows great geographical diver- times more frequent among blacks than other regions of the world. In high-risk
sity in incidence, mortality and sex ratio. among Asians, Whites or Native areas of China, a deficiency in certain
In Western countries, the age-standar- Americans {453}. trace elements and the consumption of
dized annual incidence in most areas pickled or mouldy foods (which are
does not exceed 5 per 100,000 popula- Aetiology potential sources of nitrosamines) have
tion in males and 1 in females. There are, Tobacco and alcohol. In Western coun- been suggested.
however, several well-defined high-risk tries, nearly 90% of the risk of SCC can Hot beverages. Worldwide, one of the
areas, e.g. Normandy and Calvados in be attributed to tobacco and alcohol. most common risk factors appears to be
North-West France, and Northern Italy, Each of these factors influences the risk the consumption of burning-hot bevera-
where incidence may be as high as 30 of oesophageal cancer in a different way. ges (such as Mate tea in South America)
per 100,000 population in males and 2 in With regard to the consumption of tobac- which cause thermal injury leading to
females {1020, 1331}. This type of can- co, a moderate intake during a long peri- chronic oesophagitis and then to precan-
cer is much more frequent in Eastern od carries a higher risk than a high intake cerous lesions {1116, 2191, 387}.
countries and in many developing coun- during a shorter period, whereas the HPV. Conflicting reports have proposed
tries. Regions with very high incidence reverse is true for alcohol. Both factors a role for infectious agents, including
rates have been identified in Iran, Central combined show a multiplicative effect, human papillomavirus (HPV) infection.
China, South Africa and Southern Brazil. even at low alcohol intake. In high-risk Although HPV DNA is consistently
In the city of Zhengzhou, capital of areas of North-West France and Northern detected in 20 to 40% of SCC in high-risk
Henan province in China, the mortality Italy, local drinking customs may partially areas of China, it is generally absent in
rate exceeds 100 per 100,000 population explain the excess incidence of SCC the cancers arising in Western countries
in males and 50 in females {1116, 2191}. {523, 1020}. In Japanese alcoholics, a {954, 679}.
China, Henan 1%
7.8
Iran, North East 20%
5.2
South Africa 50%
19.3
51.6 India, Bombay 50%
Urugay 70%
Fig. 1.01 Worldwide annual incidence (per 100,000) of oesophageal cancer in Fig. 1.02 Squamous cell carcinoma of the oesophagus. Age-standardized incidence
males. Numbers on the map indicate regional average values. rates per 100,000 and proportions (%) due to alcohol and tobacco (dark-blue).
Localization
Oesophageal SCC is located predomi-
nantly in the middle and the lower third of
the oesophagus, only 10-15% being situ-
ated in the upper third {1055}.
Clinical features
Symptoms and signs
The most common symptoms of ad-
vanced oesophageal cancer are dys-
A B phagia, weight loss, retrosternal or epi-
gastric pain, and regurgitation caused
by narrowing of the oesophageal lumen
by tumour growth {606}. Superficial SCC
usually has no specific symptoms but
sometimes causes a tingling sensation,
and is, therefore, often detected inciden-
tally during upper gastrointestinal
endoscopy {464, 1874}.
Endoscopic ultrasonography
Endoscopic ultrasonography is used to
evaluate both depth of tumour infiltration
and para-oesophageal lymph node
involvement in early and advanced
E F stages of the disease {1509, 1935}. For
Fig. 1.03 Macroscopic images of squamous cell carcinoma (SCC) of the oesophagus. A Flat superficial type. the evaluation of the depth of infiltration,
B Lugol iodine staining of the specimen illustrated in A. C Polypoid SCC. D Longitudinal sections of carcino- high frequency endoscopic ultrasono-
ma illustrated in C. E Deeply invasive polypoid SCC. F Longitudinal sections of carcinoma illustrated in E. graphy may be used {1302}. In general,
Tumour spread
The most common sites of metastasis of
oesophageal SCC are the regional lymph
nodes. The risk of lymph node metasta- Fig. 1.07 Squamous cell carcinoma with transmural Fig. 1.08 Squamous cell carcinoma invading thin-
sis is about 5% in carcinomas confined invasion. M, remaining intact mucosa. walled lymphatic vessels.
to the mucosa but over 30% in carcino-
mas invading the submucosa and over
80% in carcinomas invading adjacent tumour. The carcinoma invades the mus- sarcomatoid spindle cell component. It is
organs or tissues {772}. Lesions of the cular layers, enters the loose fibrous also known by a variety of other terms,
upper third of the oesophagus most fre- adventitia and may extend beyond the including carcinosarcoma, pseudosarco-
quently involve cervical and mediastinal adventitia, with invasion of adjacent matous squamous cell carcinoma, poly-
lymph nodes, whereas those of the mid- organs or tissues, especially the trachea poid carcinoma, and squamous cell car-
dle third metastasise to the mediastinal, and bronchi, eventually with the formation cinoma with a spindle cell component
cervical and upper gastric lymph nodes. of oesophagotracheal or oesophago- {1055}. Macroscopically, the tumour is
Carcinomas of the lower third preferen- bronchial fistulae {1789}. characterized by a polypoid growth pat-
tially spread to the lower mediastinal and Oesophageal SCC displays different tern. The spindle cells may be capable of
the abdominal lymph nodes {28}. The microscopic patterns of invasion, which maturation, forming bone, cartilage and
most common sites of haematogenous are categorised as ‘expansive growth’ or skeletal muscle cells {662}. Alternatively,
metastases are the lung and the liver ‘infiltrative growth’. The former pattern is they may be more pleomorphic, resem-
{1153, 1789}. Less frequently affected characterized by a broad and smooth bling malignant fibrous histiocytoma. In
sites are the bones, adrenal glands, and invasion front with little or no tumour cell the majority of cases a gradual transition
brain {1551}. Recently, disseminated dissociation, whereas the infiltrative pat- between carcinomatous and sarcomatous
tumour cells were identified by means of tern shows an irregular invasion front and components has been observed on the
immunostaining in the bone marrow of a marked tumour cell dissociation. light microscopic level. Immunohisto-
about 40% of patients with oesophageal The degree of desmoplastic or inflamma- chemical and electron microscopic stu-
SCC {1933}. Recurrence of cancer fol- tory stromal reaction, nuclear polymor- dies indicate that the sarcomatous spin-
lowing oesophageal resection can be phism and keratinization is extremely dle cells show various degrees of epithe-
locoregional or distant, both with approx- variable. Additionally, otherwise typical lial differentiation. Therefore, the sarcoma-
imately equal frequency {1185, 1027}. oesophageal SCC may contain small foci
of glandular differentiation, indicated by
Histopathology the formation of tubular glands or mucin-
Oesophageal SCC is defined as the pen- producing tumour cells {987}.
etration of neoplastic squamous epitheli-
um through the epithelial basement mem- Verrucous carcinoma (ICD-O 8051/3)
brane and extension into the lamina pro- This rare variant of squamous cell carci-
pria or deeper tissue layers. Invasion noma {19} is histologically comparable to
commonly starts from a carcinoma in situ verrucous carcinomas arising at other
with the proliferation of rete-like projec- sites {969}. On gross examination, its
tions of neoplastic epithelium that push appearance is exophytic, warty, cauli-
into the lamina propria with subsequent flower-like or papillary. It can be found in A
dissociation into small carcinomatous cell any part of the oesophagus. Histologi-
clusters. Along with vertical tumour cell cally, it is defined as a malignant papil-
infiltration, usually a horizontal growth lary tumour composed of well differentia-
undermines the adjacent normal mucosa ted and keratinized squamous epitheli-
at the tumour periphery. The carcinoma um with minimal cytological atypia, and
may already invade intramural lymphatic pushing rather than infiltrating margins
vessels and veins at an early stage of dis- {2066}. Oesophageal verrucous carcino-
ease. The frequency of lymphatic and ma grows slowly and invades locally, with
blood vessel invasion increases with a very low metastasising potential.
increasing depth of invasion {1662}. B
Tumour cells in lymphatic vessels and in Spindle cell carcinoma (ICD-O 8094/3) Fig. 1.09 Verrucous carcinoma. A Typical exo-
blood vessels may be found progressive- This unusual malignancy is defined as a phytic papillary growth. B High degree of differen-
ly several centimetres beyond the gross squamous cell carcinoma with a variable tiation.
A B C
Fig. 1.10 Spindle cell carcinoma. A Typical polypoid appearance. B Transition between conventional and spindle cells areas. C Malignant fibrous histiocytoma-like
area in a spindle cell carcinoma.
tous component may be metaplastic. with intraepithelial neoplasia, invasive the upper half and exhibit a greater
However, a recent molecular analysis of a SCC, or islands of squamous differentia- degree of atypia. In carcinoma in situ, the
single case of a spindle cell carcinoma tion among the basaloid cells {2036}. The atypical cells are present throughout the
showed divergent genetic alterations in proliferative activity is higher than in typi- epithelium without evidence of maturation
the carcinomatous and in the sarcoma- cal SCC. However, basaloid squamous at the surface of the epithelium {1154}. In
tous tumour component suggesting two cell carcinoma is also characterized by a a two-tier system, severe dysplasia and
independent malignant cell clones {823}. high rate of apoptosis and its prognosis carcinoma-in-situ are included under the
does not differ significantly from that of rubric of high-grade intraepithelial neo-
Basaloid squamous cell carcinoma the ordinary oesophageal SCC {1663}. plasia, and may have the same clinical
(ICD-O 8083/3) implications {1055}.
This rare but distinct variant of oeso- Precursor lesions Epidemiological follow-up studies sug-
phageal SCC {1961} appears to be iden- Most studies on precursor lesions of gest an increased risk for the subse-
tical to the basaloid squamous cell carci- oesophageal SCC have been carried out quent development of invasive SCC for
nomas of the upper aerodigestive tract in high-risk populations, especially in Iran patients with basal cell hyperplasia (rela-
{109}. Histologically, it is composed of and Northern China, but there is no evi- tive risk: 2.1), low-grade dysplasia (RR:
closely packed cells with hyperchromat- dence that precursor lesions in low-risk 2.2), moderate-grade dysplasia (RR:
ic nuclei and scant basophilic cyto- regions are substantially different. The 15.8), high-grade dysplasia (RR: 72.6)
plasm, which show a solid growth pat- development of oesophageal SCC is and carcinoma in situ (RR: 62.5) {377}.
tern, small gland-like spaces and foci of thought to be a multistage process which
comedo-type necrosis. Basaloid squa- progresses from the conversion of nor-
mous cell carcinomas are associated mal squamous epithelium to that with
basal cell hyperplasia, intraepithelial
neoplasia (dysplasia and carcinoma in
situ), and, finally, invasive SCC {354,
1547, 377}.
Grading
Grading of oesophageal SCC is tradition-
ally based on the parameters of mitotic
activity, anisonucleosis and degree of
differentiation.
Well differentiated tumours have cytolo-
gical and histological features similar to
those of the normal oesophageal squa-
mous epithelium. In well differentiated
C D oesophageal SCC there is a high propor-
Fig. 1.13 High grade intraepithelial neoplasia of oesophageal squamous epithelium. Architectural disarray, tion of large, differentiated, keratinocyte-
loss of polarity and cellular atypia are much greater than shown in Fig. 1.12. Changes in D extend to the like squamous cells and a low proportion
parakeratotic layer of the luminal surface.
of small basal-type cells, which are loca-
ted in the periphery of the cancer cell
Basal cell hyperplasia nests {1055}. The occurrence of kera-
This lesion is histologically defined as an tinization has been interpreted as a sign
otherwise normal squamous epithelium of differentiation, although the normal
with a basal zone thickness greater than oesophageal squamous epithelium does
15% of total epithelial thickness, without not keratinize.
elongation of lamina propria papillae Poorly differentiated tumours predomi-
{377}. In most cases, basal cell hyper- nantly consist of basal-type cells, which
plasia is an epithelial proliferative lesion usually exhibit a high mitotic rate.
in response to oesophagitis, which is fre- Moderately differentiated carcinomas,
quently observed in high-risk populations between the well and poorly differentia-
for oesophageal cancer {1547}. ted types, are the most common type,
accounting for about two-thirds of all
Squamous cell papilloma (ICD-O 8052/0) oesophageal SCC. However, since no
Squamous cell papilloma is rare and generally accepted criteria have been
usually causes no specific symptoms. It identified to score the relative contribu-
is a benign tumour composed of hyper- tion of the different grading parameters,
plastic squamous epithelium covering grading of SCC suffers from a great inter-
finger-like processes with cores derived observer variation.
from the lamina propria. The polypoid Undifferentiated carcinomas are defined
lesions are smooth, sharply demarcated, by a lack of definite light microscopic
and usually 5 mm or less in maximum features of differentiation. However, ultra-
diameter {249, 1428}. Rarely, giant papil- structural or immunohistochemical inves-
lomas have been reported, with sizes up tigations may disclose features of squa-
Fig. 1.14 Squamous cell papilloma of distal oeso- to 5 cm {2037}. Most squamous cell mous differentiation in a subset of light-
phagus. This lesion was negative for human papilloma- papillomas represent single isolated microscopically undifferentiated carcino-
virus by in situ hybridisation. lesions, typically located in the distal to mas {1881}.
A B C
Fig. 1.15 Squamous cell carcinoma. A Moderately differentiated. B Well differentiated with prominent lymphoid infiltrate. C Well differentiated areas (left) contrast
with immature basal-type cells of a poorly differentiated carcinoma (right).
Prognosis and prognostic factors TP53 17p13 Point mutation, LOH G1 arrest, apoptosis,
Overall, the prognosis of oesophageal genetic stability
SCC is poor and the 5-year survival rates
in registries are around 10%. Cure is p16, p15, 9p22 Homozygous loss CDK inhibitor
foreseen only for superficial cancer. The ARF/CDKN2 Promoter methylation (cell cycle control)
survival varies, depending upon tumour
stage at diagnosis, treatment received, Cyclin D1 11q13 Amplification Cell cycle control
patient’s general health status, morpho-
EGFR 17p13 Amplification, overexpression Signal transduction
logical features and molecular features of
(membrane Tyr kinase)
the tumour. In the past, studies on prog-
nostic factors were largely focused on c-myc 8q24.1 Amplification Transcription factor
patients who were treated by surgery,
whereas factors influencing survival of Rb 13q14 LOH Cell cycle control
patients treated by radiotherapy or by Absence of expression
multimodal therapy have been investi-
gated only rarely. TOC 17q25 LOH Tumour suppressor
Fig. 1.18 TP53 immunoreactivity in squamous cell Fig. 1.19 Immunoreactivity for epidermal growth Fig. 1.20 Fluorescence in situ hybridisation demon-
carcinoma of the oesophagus. factor receptor (EGFR) in oesophageal squamous strating cyclin D1 in squamous carcinoma cells.
cell carcinoma.
finding {935}. Therefore, the determination of oesophageal SCC {1266}. Whereas defence system components, e.g., metal-
of DNA ploidy is currently not considered some studies indicated a negative prog- lothionein and heat shock proteins {897},
to improve the prognostic information pro- nostic influence of p53 protein accumula- and matrix proteinases {1303, 1947,
vided by the TNM system {1055}. tion in cancer cell nuclei {1743, 277}, oth- 2155}. Alterations of these factors in
Extent of resection. The frequency of ers did not observe any prognostic value oesophageal SCC may enhance tumour
locoregional recurrence is negatively of either immunoexpression or TP53 cell proliferation, invasiveness, and
correlated with the distance of the pri- mutation {2014, 1661, 1008, 779, 319}. metastatic potential, and thus may be
mary tumour to the proximal resection Other potential prognostic factors include associated with survival. However, none
margin and possibly to preoperative growth factors and their receptors {927}, of the factors tested so far has entered
chemotherapy {1890, 1027}. oncogenes, including c-erbB-2 and int-2 clinical practice.
Molecular factors {778}, cell cycle regulators {1748, 1297},
The TP53 gene is mutated in 35% to 80% tumour suppressor genes {1886}, redox
Multiple LOH
Amplification of CMYC, EGFR, CYCLIND1, HST1...
Overexpression of CYCLIN D1
LOH at 3p21; LOH at 9p31
M. Werner R. Lambert
Adenocarcinoma of the oesophagus J.F. Flejou G. Keller
P. Hainaut H.J. Stein
H. Höfler
Definition higher incidence among whites and an sia at or immediately below the gastric
A malignant epithelial tumour of the average age at the time of diagnosis of cardia {715, 1797, 1722} is discussed in
oesophagus with glandular differentia- around 65 years {1756}. the chapter on adenocarcinoma of the
tion arising predominantly from Barrett oesophagogstric junction. Despite the
mucosa in the lower third of the oeso- Aetiology broad advocation of endoscopic surveil-
phagus. Infrequently, adenocarcinoma Barrett oesophagus lance in patients with known Barrett
originates from heterotopic gastric The epidemiological features of adeno- oesophagus, more than 50% of patients
mucosa in the upper oesophagus, or carcinoma of the distal oesophagus and with oesophageal adenocarcinoma still
from mucosal and submucosal glands. oesophagogastric junction match those have locally advanced or metastatic dis-
of patients with known intestinal metapla- ease at the time of presentation {1826}.
ICD-O Code 8140/3 sia in the distal oesophagus, i.e. Barrett Chronic gastro-oesophageal reflux is the
oesophagus {1605, 1827}, which has usual underlying cause of the repetitive
Epidemiology been identified as the single most impor- mucosal injury and also provides an
In industrialized countries, the incidence tant precursor lesion and risk factor for abnormal environment during the healing
and prevalence of adenocarcinoma of adenocarcinoma of the distal oesopha- process that predisposes to intestinal
the oesophagus has risen dramatically gus, irrespective of the length of the seg- metaplasia {1799}. Data from Sweden
{1827}. Population based studies in the ment with intestinal metaplasia. have shown an odds ratio of 7.7 for oeso-
U.S.A. and several European countries Intestinal metaplasia of the oesophagus phageal adenocarcinoma in persons
indicate that the incidence of oeso- develops when the normal squamous with recurrent reflux symptoms, as com-
phageal adenocarcinoma has doubled oesophageal epithelium is replaced by pared with persons without such symp-
between the early 1970s to the late columnar epithelium during the process toms {1002, 1001}.
1980s and continues to increase at a rate of healing after repetitive injury to the The more frequent, more severe, and
of about 5% to 10% per year {152, 153, oesophageal mucosa, typically associat- longer-lasting the symptoms of reflux, the
370, 405, 1496}. This is paralleled by ris- ed with gastro-oesophageal reflux dis- greater the risk. Among persons with
ing rates of adenocarcinoma of the ease {1798, 1799}. long-standing and severe symptoms of
gastric cardia and of subcardial gastric Intestinal metaplasia can be detected in reflux, the odds ratio for oesophageal
carcinoma. It has been estimated that more than 80% of patients with adenocar- adenocarcinoma was 43.5. Based on
the rate of increase of oesophageal and cinoma of the distal oesophagus. {1756, these data a strong and probably causal
oesophagogastric junction adenocarci- 1824}. A series of prospective endoscop- relation between gastro-oesophageal
noma in the U.S.A. during the past ic surveillance studies in patients with reflux, one of the most common benign
decade surpassed that of any other type known intestinal metaplasia of the distal disorders of the digestive tract, and
of cancer {152}. In the mid 1990s the oesophagus has shown an incidence of oesophageal adenocarcinoma has been
incidence of oesophageal adenocarcino- oesophageal adenocarcinoma in the postulated.
ma has been estimated between 1 and 4 order of 1/100 years of follow up {1799}. Factors predisposing for the development
per 100,000 per year in the U.S.A. and This translates into a life-time risk for of Barrett oesophagus and subsequent
several European countries and thus oesophageal adenocarcinoma of about adenocarcinoma in patients with gastro-
approaches or exceeds that of squa- 10% in these patients. The length of the oesophageal reflux disease include a
mous cell oesophageal cancer in these oesophageal segment with intestinal markedly increased oesophageal expo-
regions. In Asia and Africa, adenocarci- metaplasia, and the presence of ulcera- sure time to refluxed gastric and duode-
noma of the oesophagus is an uncom- tions and strictures have been implicated nal contents due to a defective barrier
mon finding, but increasing rates are as further risk factors for the development function of the lower oesophageal sphinc-
also reported from these areas. of oesophageal adenocarcinoma by ter and ineffective clearance function of
In addition to the rise in incidence, ade- some authors, but this has not been con- the tubular oesophagus {1823, 1827}.
nocarcinoma of the oesophagus and of firmed by others {1799, 1797, 1827}. Experimental and clinical data indicate
the oesophagogastric junction share The biological significance of so-called that combined oesophageal exposure to
some epidemiological characteristics ultrashort Barrett oesophagus or intestin- gastric acid and duodenal contents (bile
that clearly distinguish them from squa- al metaplasia just beneath a normal Z acids and pancreatic enzymes) appears
mous cell oesophageal carcinoma and line has yet to be fully clarified {1325}. to be more detrimental than isolated
adenocarcinoma of the distal stomach. Whether adenocarcinoma of the gastric exposure to gastric juice or duodenal
These include a high preponderance for cardia or subcardial gastric cancer is contents alone {1241, 1825}. Combined
the male sex (male:female ratio 7:1), a also related to foci of intestinal metapla- reflux is thought to increase cancer risk
Adenocarcinoma 21
01 19.7.2006 7:22 Page 22
A B
Fig. 1.23 Barrett oesophagus. A Haphazardly arranged glands (right) adjacent to hyperplastic squamous epithelium (left). B Goblet cells and columnar cells form vil-
lus-like structures over chronically inflamed stroma. There is no intraepithelial neoplasia.
devised for atypia in ulcerative colitis, changes with enlarged, hyperchromatic erosions or ulcerations are present
namely: negative, positive or indefinite nuclei, prominence of nucleoli, and {1055}. In areas adjacent to erosions and
for intraepithelial neoplasia. If intra- occasional mild stratification in the lower ulcerations, the metaplastic epithelium
epithelial neoplasia is present, it should portion of the glands. However, towards may display villiform hyperplasia of the
be classified as low-grade (synonymous the surface there is maturation of the surface foveolae with cytological atypia
with mild or moderate dysplasia) or high- epithelium with few or no abnormalities. and architectural disturbances. These
grade (synonymous with severe dyspla- These changes meet the criteria of atypia abnormalities are usually milder than
sia and carcinoma in situ) {1582, 1685}. negative for intraepithelial neoplasia, and those observed in intraepithelial neopla-
The criteria used to grade intraepithelial can usually be separated from low-grade sia. There is a normal expansion of the
neoplasia comprise cytological and archi- intraepithelial neoplasia. basal replication zone in regenerative
tectural features {75}. Atypia indefinite for intraepithelial neo- epithelium versus intraepithelial neopla-
plasia. One of the major challenges for sia, where the proliferation shifts to more
Negative for intraepithelial neoplasia the pathologist in Barrett oesophagus is superficial portions of the gland {738}. If
Usually, the lamina propria of Barrett the differentiation of intraepithelial neo- there is doubt as to whether reactive and
mucosa contains a mild accompanying plasia from reactive or regenerative regenerative changes or intraepithelial
inflammatory infiltrate of mononuclear epithelial changes. This is particularly neoplasia is present in a biopsy, the cat-
cells. There may be mild reactive difficult, sometimes even impossible, if egory atypia indefinite for intraepithelial
neoplasia is appropriate and a repeat
biopsy after reflux control by medical
acid suppression or anti-reflux therapy is
indicated.
Low-grade and high-grade intraepithelial
neoplasia. Intraepithelial neoplasia in
Barrett metaplastic mucosa is defined as
a neoplastic process limited to the
epithelium {1582}. Its prevalence in
Barrett mucosa is approximately 10%,
and it develops only in the intestinal type
metaplastic epithelium.
Cytological abnormalities typically extend
to the surface of the mucosa. In low-
grade intraepithelial neoplasia, there is
decreased mucus secretion, nuclear
pseudostratification confined to the lower
half of the glandular epithelium, occa-
sional mitosis, mild pleomorphism, and
minimal architectural changes.
High-grade intraepithelial neoplasia
shows marked pleomorphism and
Fig. 1.24 Barrett oesophagus with low-grade intraepithelial neoplasia on the left and high-grade on the right. decrease of mucus secretion, frequent
Note the numerous goblet cells showing a clear cytoplasmic mucous vacuole indenting the adjacent nucleus. mitosis, nuclear stratification extending
A B
Fig. 1.25 High-grade intraepithelial neoplasia in Barrett oesophagus. A Marked degree of stratification with nuclei being present throughout the thickness of the epithe-
lium. Foci of cribriform, back-to-back glands. B Highly atypical cells lining tubular structures.
to the upper part of the cells and glands, grade intraepithelial neoplasia are often of Barrett oesophagus may be evident,
and marked architectural aberrations. multicentric and occult. Therefore a especially in early carcinomas. In the
The most severe architectural changes systematic tissue sampling has been early stages, the gross findings of Barrett
consist of a cribriform pattern that is a recommended when no abnormality is adenocarcinoma may be subtle with
feature of high-grade intraepithelial neo- evident macroscopically {483}. The usual irregular mucosal bumps or small
plasia as long as the basement mem- pattern of advanced adenocarcinoma at plaques. At the time of diagnosis, most
brane of the neoplastic glands has not endoscopy is that of an axial, and often tumours are advanced with deep infiltra-
been disrupted. The diagnostic repro- tight, stenosis in the distal third of the tion of the oesophageal wall. The
ducibility of intraepithelial neoplasia is far oesophagus; with a polypoid tumour, advanced carcinomas are predominantly
from perfect; significant interobserver bleeding occurs at contact. flat and ulcerated with only one third
variation exists {1572}. having a polypoid or fungating appear-
Radiology ance. Occasionally, multifocal tumours
Adenocarcinoma This approach is still proposed in the pri-
Symptoms and signs mary diagnosis of oesophageal cancer
Dysphagia is often the first symptom of when endoscopic access is not easily
advanced adenocarcinoma in the available {1058}. Today, barium studies
oesophagus. This may be associated are helpful mostly for the analysis of
with retrosternal or epigastric pain or stenotic segments; they are less efficient
cachexia. than endoscopy for the detection of flat
abnormalities. Computerised tomogra-
Endoscopy phy will detect distant thoracic and
The endoscopic pattern of the early abdominal metastases.
tumour stages may be that of a small
polypoid adenomatous-like lesion, but Endoscopic ultrasonography
more often it is flat, depressed, elevated At high frequency, some specificities in
or occult {1011, 1009}. Areas with high the echoic pattern of the mucosa and
submucosa of the columnar lined oeso-
phagus are displayed. However, the pro-
cedure is only suitable for the staging of
tumours previously detected at endo-
scopy; the tumour is hypoechoic. Lymph
nodes adjacent to the oesophageal wall
can also be visualised by this technique
{1614}.
Macroscopy
The majority of primary adenocarcino-
mas of the oesophagus arise in the lower
Fig. 1.26 Mucinous adenocarcinoma arising in third of the oesophagus within a segment Fig. 1.27 Highly infiltrative adenocarcinoma in
Barrett oesophagus. Large mucinous lakes extend of Barrett mucosa {1055}. Adjacent to the Barrett oesophagus (pT3), with extension into the
throughout the oesophageal wall. tumour, the typical salmon-pink mucosa cardia.
Adenocarcinoma 23
01 19.7.2006 7:22 Page 24
Other carcinomas
Adenosquamous carcinoma
(ICD-O code: 8560/3)
This carcinoma has a significant squa-
mous carcinomatous component that is
intermingled with a tubular adenocarci-
noma.
C Mucoepidermoid carcinoma
Fig. 1.28 Adenocarcinoma, tubular type. A Well differentiated, B moderately differentiated and C poorly dif-
(ICD-O code: 8430/3)
ferentiated. This rare carcinoma shows an intimate
mixture of squamous cells, mucus secret-
may be present {1055, 1770}. The rare the diffuse type and show rare glandular ing cells and cells of an intermediate
adenocarcinomas arising independently formations, and sometimes signet ring type.
of Barrett oesophagus from ectopic gas- cells {1458, 1770}. Differentiation may Adenoid cystic carcinoma
tric glands and oesophageal glands dis- produce endocrine cells, Paneth cells (ICD-O code: 8200/3)
play predominantly ulceration and poly- and squamous epithelium. Mucinous This neoplasm is also infrequent and
poid gross features, respectively. These adenocarcinomas, i.e. tumours with more believed to arise, like the mucoepider-
tumours are also found in the upper and than 50% of the lesion consisting of moid variant, from oesophageal glands
middle third of the oesophagus {265, mucin, also occur. {265, 2066}. Both lesions tend to be of
1204}, but are rare. salivary gland type, and small tumours
Grading may be confined to the submucosa.
Histopathology Most adenocarcinomas arising from However, the ordinary oesophageal ade-
Adenocarcinomas arising in the setting Barrett mucosa are well or moderately nocarcinoma can also arise from ectopic
of Barrett oesophagus are typically papil- differentiated {1458}, and display well gastric glands, or oesophageal glands
lary and/or tubular. A few tumours are of formed tubular or papillary structures. {1204, 1055}.
Genetic susceptibility
Several lines of evidence suggest that
there is a genetic susceptibility to oeso-
phageal adenocarcinoma arising from
Barrett oesophagus. The almost exclu-
sive occurrence of Barrett oesophagus in
whites and its strong male predominance
hint at the involvement of genetic factors
{1605}. Several reports describe familial
clustering of Barrett oesophagus, adeno-
carcinoma and reflux symptoms in up to
three generations, with some families
showing an autosomal dominant pattern
of inheritance with nearly complete pene-
trance {470, 480, 482, 569, 861, 1537,
1610, 1959}. Although shared dietary or
environmental factors in these families
could play a role, the earlier age of onset
of Barrett in some families suggests the
influence of genetic factors {861}. The
molecular factors that determine this
genetic susceptibility are largely un- Fig. 1.29 Adenoid cystic carcinoma showing typical cribriform pattern resembling its salivary gland coun-
known and linkage analysis in families terpart.
has not been reported. Recently, an asso-
ciation between a variant of the GSTP1 include hypermethylation of the p16 pro- LOH and gene amplification. A number of
(glutathione S-transferase P1) gene and motor and, more rarely, mutations and other loci are altered relatively late during
Barrett oesophagus and adenocarcino- LOH {948}. the development of adenocarcinoma,
ma has been demonstrated {1994}. GSTs FHIT. Among other early changes in the with no obligate sequence of events.
are responsible for the detoxification of premalignant stages of metaplasia are Prevalent changes (> 50%) include LOH
various carcinogens, and inherited dif- alterations of the transcripts of FHIT, a on chromosomes 4 (long arm) and 5
ferences in carcinogen detoxification presumptive tumour suppressor gene (several loci including APC) and amplifi-
capacity may contribute to the develop- spanning the common fragile site FRA3B cation of ERBB2 {1266, 1264}.
ment of Barrett epithelium and adenocar- {1222}. Phenotypic changes in Barrett oesopha-
cinoma.
Table 1.03
Genetics Genes and proteins involved in carcinogenesis in Barrett oesophagus.
In Barrett oesophagus a variety of mole- Factor Comment
cular genetic changes has been correlat-
ed with the metaplasia-dysplasia-carci- Tumour suppressor genes
noma sequence (Fig. 1.21) {2091}. TP53 60% Mutation – high-grade intraepithelial neoplasia and carcinoma
Prospective follow-up of lesions biopsied APC Late in intraepithelial neoplasia-carcinoma sequence
at endoscopy show that alterations in FHIT Common, early abnormalities
TP53 and CDKN2A occur at early stages CDKN2A (p16) Hypermethylation common in intraepithelial neoplasia
{112, 1337}.
Growth factor receptors
TP53. In high-grade intraepithelial neo-
CD95/APO/Fas Shift to cytoplasm in carcinoma
plasia a prevalence of TP53 mutations of
EGFR Expressed in 60% carcinomas, gene amplification
approximately 60% is found, similar to c-erbB2 Late in dysplasia-carcinoma sequence, gene amplification
adenocarcinoma {789}. Mutation in one
allele is often accompanied by loss of the Cell adhesion
other (17p13.1). Mutations occur in E-cadherin Loss of expression in intraepithelial and invasive carcinoma
diploid cells and precede aneuploidy. Catenins Similar loss of expression to E-cadherin
The pattern of mutations differs signifi-
cantly from that in squamous cell carcino- Proteases
mas. This is particularly evident for the UPA Prognostic factor in carcinoma
high frequency of G:C>A:T transition
Proliferation
mutations, which prevail in adenocarcino-
Ki-67 Abnormal distribution in high-grade intraepithelial neoplasia
mas but are infrequent in SCC (Fig. 1.17).
CDKN2A. Alterations of CDKN2A, a Membrane trafficking
locus on 9p21 encoding two distinct rab11 High expression in low-grade intraepithelial neoplasia
tumour suppressors, p16 and p19arf
Adenocarcinoma 25
01 19.7.2006 7:22 Page 26
gus include expansion of the Ki-67 prolif- oesophagus {298}. Invasive lesions survival rates are better in superficial
eration compartment correlating with the exhibit variable expression of MUC1 and (pT1) adenocarcinoma, ranging from
degree of intraepithelial neoplasia {738}. MUC2. 65% to 80% in different series {735,
Molecules involved in membrane traffick- 1219}.
ing such as rab11 have been reported to Prognostic factors Since the stage at the time of diagnosis
be specific for the loss of polarity seen in The major prognostic factors in adeno- is the most important factor affecting out-
low-grade intraepithelial neoplasia carcinoma of the oesophagus are the come, endoscopic surveillance of Barrett
{1566}. In invasive carcinoma, reduced depth of mural invasion and the pres- patients with early detection of their ade-
expression of cadherin/catenin complex ence or absence of lymph node or dis- nocarcinomas, results in better progno-
and increased expression of various pro- tant metastasis {734, 1049, 1458, 1945}. sis in most cases {1995}.
teases are detectable. Non-neoplastic Gross features and histological differenti-
Barrett oesophagus expresses the ation do not influence prognosis. The
MUC2 but not the MUC1 mucin gene overall 5-year survival rate after surgery
product, whereas neither is expressed in is less than 20% in most series including
intraepithelial neoplasia in Barrett a majority of advanced carcinomas. The
Epidemiology Localization
In an analysis of 8305 carcinoid tumours Carcinoid tumours are typically located
of different sites, only 3 (0.04%) carci- in the lower third of the oesophagus
noids of the oesophagus were reported {1329, 1567, 1754}. Almost all small cell
{1251}. They represented 0.05% of all carcinomas occur in the distal half of the
gastrointestinal carcinoids reported in this oesophagus {190, 421}.
analysis and 0.02% of all oesophageal
cancers. All cases were in males and pre- Clinical features
sented at a mean age of 56 years {1251}. Dysphagia, severe weight loss and
Small cell carcinoma occurs mainly in the sometimes chest pain are the main symp-
sixth to seventh decade and is twice as toms of endocrine tumours of the oesoph-
common in males as females {190, 421, agus. Patients with small cell carcinomas
765, 1026}. The reported frequencies often present at an advanced stage {765,
among all oesophageal cancers were 1026}. Inappropriate antidiuretic hor-
between 0.05% to 7.6 % {190, 421, 765, mone syndrome and hypercalcemia have
1026}. been reported {421}. In addition, a case Fig. 1.30 Small cell carcinoma of the oesophagus.
A. Wotherspoon
Lymphoma of the oesophagus A. Chott
R.D. Gascoyne
H.K. Müller-Hermelink
Definition ary either from the mediastinum, from able degree of plasma cell differentia-
Primary lymphoma of the oesophagus is nodal disease or from a primary gastric tion. Infiltration of these cells into the
defined as an extranodal lymphoma aris- location. Patients are frequently male and overlying epithelium is usually seen.
ing in the oesophagus with the bulk of usually over 50 years old. Tumours Characteristically the CCL cells express
the disease localized to this site {796}. involving the distal portion of the oesoph- pan-B-cell markers CD20 and CD79a
Contiguous lymph node involvement and agus may cause dysphagia {644}. and they are negative for CD5 and CD10.
distant spread may be seen but the pri- They express bcl-2 protein and may be
mary clinical presentation is in the Histopathology positive with antibodies to CD43. Due to
oesophagus with therapy directed at this Primary oesophageal lymphomas may the rarity of these lesions, molecular
site. be of the large B-cell type or may be low- genetics data are not available.
grade B-cell MALT lymphomas {1794}. In common with other sites in the diges-
Clinical features MALT lymphomas show morphological tive tract, secondary involvement of the
The oesophagus is the least common and cytological features common to oesophagus may occur in dissemination
site of involvement with lymphoma in the MALT lymphomas found elsewhere in the of any type of lymphoma.
digestive tract, accounting for less than digestive tract. Lymphoid follicles are Primary oesophageal T-cell lymphoma
1% of lymphoma patients {1399}. Oeso- surrounded by a diffuse infiltrate of cen- has been described but is exceedingly
phageal involvement is usually second- trocyte-like (CCL) cells showing a vari- rare {547}.
Lymphoma 27
01 19.7.2006 7:22 Page 28
Definition as females and has a median age distri- sion or dumb-bell shaped masses with
A variety of rare benign and malignant bution between 30 and 35 years {1712, circular involvement {1712, 1228}. Large
mesenchymal tumours that arise in the 1228}. Sarcomas of the oesophagus leiomyomas (over 0.5 kg) have been
oesophagus. Among these, tumours of accounted for 0.2% of malignant oeso- described {968}. Sarcomas, most of
smooth muscle or ‘stromal’ type are most phageal tumours in SEER data from the them representing malignant gastroin-
common. United States from 1973 to 1987. Males testinal stromal tumours (GISTs), are typi-
were more frequently affected than cally multinodular or less commonly
ICD-O codes females by nearly 2:1 {1928}. Adults plaque-like masses resembling sarco-
Leiomyoma 8890/0 between the 6th and 8th decades are mas of the soft tissues. Many oeso-
Leiomyosarcoma 8890/3 primarily affected. Oesophageal stromal phageal sarcomas protrude into the
Gastrointestinal tumours show demographics similar to mediastinum.
stromal tumour (GIST) 8936/3 those of sarcomas {1228}.
Granular cell tumour 9580/0 Histopathology
Rhabdomyosarcoma 8900/3 Localization Leiomyoma is composed of bland spin-
Kaposi sarcoma 9190/3 Leiomyomas and stromal tumours are dle cells and shows low or moderate cel-
most frequent in the lower oesophagus lularity and slight if any mitotic activity.
Classification and begin as intramural lesions. The There may be focal nuclear atypia. The
The morphological definitions of these larger tumours can extend to medi- cells have eosinophilic, fibrillary, often
lesions follow the WHO histological clas- astinum and form a predominantly medi- clumped cytoplasm. Eosinophilic granu-
sification of soft tissue tumours {2086}. astinal mass. Leiomyomatosis forms locytes and spherical calcifications are
Stromal tumours are described in detail worm-like intramural structures that may sometimes present. Leiomyomas are
in the chapter on gastric mesenchymal extend into the upper portion of the typically globally positive for desmin and
tumours. stomach. smooth muscle actin, and are negative
for CD34 and CD117 (KIT) {1228}.
Epidemiology Clinical features
Leiomyoma is the most common mes- Dysphagia is the usual complaint, but
enchymal tumour of the oesophagus. It many leiomyomas and a small proportion
occurs in males at twice the frequency of stromal tumours are asymptomatic
and are incidentally detected by X-ray as
mediastinal masses. Since most sarco-
mas project into the lumen, they are rela-
tively easy to diagnose by endoscopy or
imaging studies. The endoscopic pattern
is that of a submucosal tumour with a
swelling of a normal mucosa. Endo-
scopic ultrasound helps in determining
the actual size of the tumour, its position
in the oesophageal wall and its eventual
A position in the mediastinum. A CT scan
of the mediastinum is then a useful com-
pliment. Most tumours less than 3 cm in
diameter are benign. Endoscopic tissue
sampling (large biopsy or fine needle
aspiration) is difficult and not very reli-
able for the assessment of malignancy.
Macroscopy
Leiomyomas vary in size from a few mil-
B limeters up to 10 cm in diameter (aver-
Fig. 1.31 Leiomyoma of oesophagus. A Haema- age 2-3 cm). They may be spherical, or Fig. 1.32 Stromal tumour of the oesophagus, involv-
toxylin and eosin stain. B Immunoreactivity for when larger they can form sausage-like ing the oesophageal muscle layer beneath a normal
desmin. masses with a large longitudinal dimen- mucosa.
1 cm
extensive accumulation of lysosomes
filled with lamellar material. Granular cell
tumours are typically PAS- and S100-pro-
tein positive and negative for desmin,
actin, CD34 and KIT. Tumours that
encroach upon the mucosa may elicit a
pseudocarcinomatous squamous hyper-
plasia {862, 1710}.
Rhabdomyosarcoma has been reported
in older adult patients in distal oesopha-
Fig. 1.33 Granular cell tumour of oesophagus. gus. A few well-documented cases have Fig. 1.34 Kaposi sarcoma in a patient with acquired
shown features similar to embryonal immunodeficiency syndrome.
rhabdomyosarcoma {2002}. Demonstra-
Leiomyosarcoma, a malignant tumour tion of skeletal muscle differentiation by leiomyoma {683}, whereas these tumours
featuring differentiated smooth muscle the presence of cross-striations, electron do not have c-kit gene mutations com-
cells, is rare in the oesophagus. In a microscopy, or immunohistochemistry is monly found in GISTs {1018}. Compar-
recent series, such tumours comprised required for the diagnosis. ative genomic hybridization studies have
4% of all combined smooth muscle and Synovial sarcoma has been reported in shown that oesophageal leiomyomas do
stromal tumours. They were large children and in older adults. These not have losses of chromosome 14, as
tumours that presented in older adults, tumours usually present as polypoid often seen in GIST, but instead have
and all patients died of disease. masses in the proximal oesophagus gains in chromosome 5 {450, 1664}.
Diagnosis is based on demonstration of {168, 149}. Oesophageal stromal tumours show simi-
smooth muscle differentiation by α- Kaposi sarcoma may appear as a lar c-kit mutations as observed in gastric
smooth muscle actin, desmin or both, mucosal or less commonly more exten- and intestinal GISTs (see stomach mes-
and lack of KIT expression {1228}. sive mural lesion, usually in HIV-positive enchymal tumours) {1228}.
Stromal tumours (GISTs) are rare in the patients. Histologically typical are spin- Kaposi sarcoma is positive for human
oesophagus, and comprise 20-30% of dle cells with vascular slit formations and herpesvirus 8 by PCR.
the combined cases of smooth muscle scattered PAS-positive globules. The
and stromal tumours. Like elsewhere in tumour cells are positive for CD31 and Prognosis
the digestive system, they predominantly CD34. The prognosis of oesophageal sarcomas,
occur in older adults between the 6th like carcinomas, is largely dependent on
and 8th decades; oesophageal stromal Grading the size, depth of invasion, and presence
tumours may have a male predomi- Histological grading follows the systems or absence of metastasis.
nance. Most oesophageal examples are commonly used for soft tissue tumours.
spindle cell tumours, and a minority are Mitotic activity is the main criterion for
epithelioid. Oesophageal GISTs are iden- grading stromal sarcomas and
tical with their gastric counterparts by leiomyosarcomas, namely those tumours
their positivity for KIT and CD34, variable with over 10 mitoses per 10 HPF are con-
reactivity for smooth muscle actin and sidered high-grade.
general negativity for desmin. Most are
clinically malignant, and commonly Genetics
develop liver metastases. The oeso- Somatic deletions and gene rearrange-
phageal tumours analyzed to date have ments involving the genes encoding
shown similar c-kit mutations (exon 11) alpha5 and 6 chains of collagen type IV
as observed in gastric and intestinal have been described in oesophageal
GISTs {1228}. The pathological features leiomyomatosis associated with Alport
are described with gastric GISTs. syndrome {1704, 1982} and in sporadic
Mesenchymal tumours 29
01 19.7.2006 7:22 Page 30
Secondary tumours 1249, 545}, skin {1569, 1203}, kidney ence of metastasis in the oesophagus is
{1956}, prostate {1318} and ovary {1249}. a sign of poor prognosis, but the outcome
Definition is much better when the primary tumour
Tumours of the oesophagus that originate Localization growth rate is slow, and when other
from but are discontinuous with a primary The most common site of involvement is metastases are excluded {1416, 1249}.
tumour elsewhere in the oesophagus or the middle third of the oesophagus.
an extra-oesophageal neoplasm.
Clinical features Melanoma
Incidence The leading symptom is dysphagia,
Metastatic spread to the oesophagus is whereas achalasia and upper gastroin- ICD-O Code 8720/3
uncommon. An unusually high frequency testinal bleeding with anemia are unusu-
(6.1% of autopsy cases) was reported al {545}. Barium swallow examination, Malignant melanoma in the oesophagus
from Japan {1249}. endoscopy, computed tomography and is much more commonly metastatic than
magnetic resonance imaging demon- primary. Primary oesophageal mela-
Origin of metastases strate in most cases a submucosal nomas are usually polypoid and are clini-
The concept of intramural metastasis in tumour, but any aspect resembling a pri- cally aggressive lesions {400, 353}. They
oesophageal squamous cell carcinoma mary oesophageal carcinoma may be are believed to arise from a zone of atyp-
is discussed in the chapter on squamous observed {545, 1318, 714}. ical junctional proliferation of melano-
cell carcinoma of the oesophagus. cytes and such a proliferation is often
Neoplasms of neighbouring organs such Histopathology and predictive factors present adjacent to the invasive tumour,
as pharynx or gastric cardia {714} can Submucosal localization without invasion although it may not be observed in
spread to the oesophagus via lymphat- of the mucosa is characteristic for a advanced disease. The histology of the
ics. Haematogenous metastases from metastasis. Early metastases of gastric invasive component is indistinguishable
any primary localization may occur. and oesophageal tumours into the from cutaneous melanoma {409}. Growth
Reported primary sites include thyroid oesophagus may be local indicators of is typically expansile rather than infiltra-
{335}, lung {1416, 1249}, breast {2143, systemic spread {896, 714}. The pres- tive.
ME
Fig. 1.35 Primary melanoma of the oesophagus (ME). The gastro-oesophageal Fig. 1.36 Primary malignant melanoma of the distal oesophagus. Zone of atypi-
junction is on the left (arrows). cal junctional proliferation of melanocytes located adjacent to the invasive
tumour. This supports the diagnosis of a primary melanoma.
Definition stomach begins anatomically. The OG lium. Conversely, a tumour that clearly is
Adenocarcinomas that straddle the junc- junction is defined endoscopically as the located in the distal oesophagus could
tion of the oesophagus and stomach are level of the most proximal extent of the have arisen from oesophageal cardiac
called tumours of the oesophagogastric gastric folds {1200}. In normal individuals, epithelium.
(OG) junction. This definition includes the proximal extent of the gastric folds Some investigators actually contend that
many tumours formerly called cancers of generally corresponds to the point at cardiac mucosa is not a normal mucosa
the gastric cardia. which the tubular oesophagus flares to at all, but one that is acquired as a conse-
Squamous cell carcinomas that occur at become the sack-shaped stomach at the quence of chronic inflammation in the dis-
the OG junction are considered carcino- distal border of the lower oesophageal tal oesophagus {272, 1388}.
mas of the distal oesophagus, even if they sphincter. In patients with hiatus hernias,
cross the OG junction. in whom there may be no clear-cut flare at Diagnostic criteria
the OG junction, the proximal margin of Various criteria have been used to cate-
ICD-O code 8140/3 the gastric folds is determined when the gorize tumours in the region of the OG
distal oesophagus is minimally inflated junction as cancers of the gastric cardia
Definition of the with air because over-inflation obscures {1240, 314, 877, 1271, 638, 767, 684}. In
oesophagogastric junction this landmark {1271}. Whenever the most of these classification systems, the
The OG junction is the anatomical region squamocolumnar junction is located anatomic location of the epicenter or pre-
where the tubular oesophagus joins the above the OG junction, there is a colum- dominant mass of the tumour is used to
stomach. The squamo-columnar (SC) nar-lined segment of oesophagus. When determine whether the neoplasm is
epithelial junction may occur at or above the squamocolumnar junction and the OG oesophageal or gastric in origin. Due to
the OG junction. The gastric cardia has junction coincide, the entire oesophagus the use of divergent classification sys-
been defined conceptually as the region is lined by squamous epithelium (i.e. there tems, the patient populations in studies
of the stomach that adjoins the oesopha- is no columnar-lined oesophagus). By on cancers of the gastric cardia are het-
gus {1568}. The gastric cardia begins at definition, the gastric cardia starts at the erogeneous, and often include patients
the OG junction, but its distal extent is OG junction, but there are no endoscopic with gastric tumours and others with
poorly defined. landmarks that define the distal extent of tumours of oesophageal origin. The fol-
Figure 2.01 shows endoscopically recog- the gastric cardia. lowing guidelines are based on the defi-
nizable landmarks that can be used to A potential source of confusion is the his- nition of the OG junction described
identify structures at the OG junction. The tological terminology used to describe above:
squamocolumnar junction (SCJ or Z-line) the most proximal part of the stomach. (1) Adenocarcinomas that cross the
is the visible line formed by the juxtaposi- Cardiac mucosa is characterized by tor- oesophagogastric junction are called
tion of squamous and columnar epithelia. tuous, tubular glands that are comprised adenocarcinomas of the OG junction,
The OG junction is the imaginary line at almost exclusively of mucus-secreting regardless of where the bulk of the tumour
which the oesophagus ends and the cells with few or no parietal (oxyntic) lies.
cells. The histological finding of cardiac (2) Adenocarcinomas located entirely
mucosa does not establish that the spec- above the oesophagogastric junction as
imen has been obtained from the cardia defined above are considered oeso-
of the stomach, for the following reasons: phageal carcinomas.
(1) Cardiac mucosa can be found in the (3) Adenocarcinomas located entirely
distal oesophagus {1479, 678}. below the oesophagogastric junction are
(2) Cardiac mucosa rarely extends more considered gastric in origin. The use of
than 2 to 3 mm below the SC epithelial the ambiguous and often misleading term
junction in the distal oesophagus {1430, ‘carcinoma of the gastric cardia’ is dis-
911}. Therefore it will not line the larger couraged; depending on their size , these
anatomical area often called cardia. should be called carcinoma of the proxi-
(3) Recent studies have shown that the mal stomach or carcinoma of the body of
proximal stomach is lined predominantly, the stomach.
if not exclusively, by oxyntic epithelium
{272, 1388}. Therefore, even a tumour that Epidemiology
Fig. 2.01 Topography of the oesophagogastric junc- is unquestionably located at the cardia Reliable data on the incidence of
tion and cardia {1797}. may not have arisen from cardiac epithe- tumours of the OG junction are not avali-
Aetiology
The most consistent association des-
Reflux Oesophagitis Gastritis
cribed for carcinoma at the OG junction is
with gastro-oesophageal reflux. In con-
trast with the aetiological factors involved Intestinal Metaplasia
in ‘non cardia’ gastric cancer, there is no
consistent association with diet (salty food
in excess and lack of fruits and vitamins)
nor Helicobacter pylori infection, while in Dysplasia
the body and antrum of the stomach,
intestinal metaplasia occurs in relation to
chronic gastritis due to H. pylori infection
{1829, 88, 343}. Adenocarcinoma
Intestinal metaplasia is judged to be the Fig. 2.03 Pathogenetic pathways operative in the evolution of oesophageal and gastric carcinoma. Intesti-
precursor of adenocarcinoma both in the nal metaplasia is a common precursor lesion that may result from gastro-oesophageal reflux disease (GERD)
oesophagus and in the stomach {1797}. or chronic H. pylori infection.
Fig. 2.05 Adenocarcinoma of the proximal stomach (‘pylorocardiac type’). A Macroscopic appearance resembles other adenocarcinmomas. B Glands with tall cells,
pale cytoplasm, and basal or central nuclei.
type is much less common in the proxi- nomas {1476}, the latter are distinguished Small cell carcinoma can occur at this site.
mal than in the distal stomach, and usu- by increased nuclear pleomorphism,
ally not accompanied by atrophic gastri- occasional keratin pearls, and the separa- Grading
tis {2045}. Well differentiated tubular tion of the two components with some Adenocarcinomas in the oesophago-
adenocarcinomas can present consider- areas of purely glandular epithelium and gastric junction region can be graded as
able diagnostic difficulty as the neoplas- mucin. While in the past there were claims well, moderately, or poorly differentiated.
tic tubules may have a deceptively regu- that adenosquamous carcinoma repre- However, agreement on tumour grading
lar appearance and can be readily sented a ‘collision tumour’, it is now gen- is notoriously poor. Blomjous et al. {151}
mistaken for low-grade dysplasia or even erally accepted that this malignancy reported that 3.6% of gastric cardiac
hyperplastic glands. results from dual differentiation and that it cancers were well differentiated, 31%
is analogous to other cancers arising at moderately differentiated, and 43% poor-
Pylorocardiac carcinoma. Mulligan and junctional sites in the body (e.g. uterine ly differentiated, but others consider a
Rember {1847} termed lesions resem- cervix and anal canal). greater proportion well differentiated,
bling normal pyloric glands as ‘pyloro- particularly when early carcinomas are
cardiac carcinomas’. They predominate included {1271, 1903, 1363}.
in the cardiac region and typically have
tall epithelial cells with clear or pale cyto- Precursor lesions
plasm and nuclei in a basal or central Intraepithelial neoplasia
position. However, this pattern is difficult Interobserver agreement on the grading
to distinguish reliably from other gland- of intraepithelial neoplasia in the
forming adenocarcinomas {1847}. absence of invasion of the lamina propria
is poor, particularly in the identification of
Adenosquamous carcinoma low-grade changes, and different terms
Of the less common forms of cancers in have been applied to identical appear-
the oesophagogastric junction region, ances {1683}. Such differences in
adenosquamous carcinoma is the one nomenclature have been reduced by the
most likely to be encountered. The diag- widespread acceptance of a new classi-
nosis rests on the finding of a mixture of fication that embraces the previously dis-
glandular and squamous elements and cordant terminology in a unified scheme
not merely on the presence of small {1637}.
squamoid foci in an otherwise typical ade- Intramucosal non-invasive neoplasia can
nocarcinoma. The latter is a frequent find- be classified as flat (synonymous with
ing in tumours at this site. Such compos- dysplasia) or elevated (synonymous with
ite tumours should also be distinguished adenoma); lesions can be low grade or
from the rare mucoepidermoid carcinoma high grade, the latter including lesions
of the oesophagus, which arises from previously designated as intraglandular
mucous glands and is similar to the sali- carcinoma.
vary gland tumour of that name. Although Intestinal metaplasia
the term mucoepidermoid has been used Fig. 2.06 Adenocarcinoma of the oesophagogastric Putative precancerous lesions other than
synonymously for adenosquamous carci- junction. pT2 lesion. intraepithelial neoplasia are controversial.
Intestinal metaplasia is widely regarded predominance of transition mutations at (IGF1R), 17q12-21 (ERBB2/HER2-neu),
as carrying an increased risk of malig- CpG sites, similar to the pattern seen in 19q13.1 (TGFB1, BCL3, AKT2), 20p12
nant change, but the frequency at which adenocarcinomas in Barrett oesophagus (PCNA), and 20q12-13 (MYBL2, PTPN1).
it is found in the OG junction region (5.3% {585}. Transitions at CpG dinucleotides in The distribution of these imbalances was
to 23% of dyspeptic patients) limits its TP53 are generally assumed to result similar in both groups. However, loss of
value as a criterion for surveillance {716, from endogenous mutational mechanism 14q31-32.1 (TSHR) was significantly
1960, 1800, 2028, 1269}. Some of the (deamination of 5-methylcytosine) which more frequent in Barrett-related adeno-
variability in the reported prevalence of may be enhanced by oxidative or carcinomas than in cardiac cancers.
intestinal metaplasia can be attributed to nitrosative stress. In colon cancers that Overall, the available genetic data sug-
differences in diagnostic criteria. Some frequently exhibit CpG mutations, excess gests that within cancers of the oesoph-
authors accept the finding of columnar nitric oxide production resulting from nitric agogastric junction, a subset of tumours
cells containing acidic glycoproteins oxide synthase-2 expression may con- is genetically similar to adenocarcinomas
(‘columnar blues’ in Alcian blue / PAS tribute to the transition from adenoma to in Barrett oesophagus, whereas another
stained sections) as evidence for intes- carcinoma {51}. subset is genetically distinct from adeno-
tinal metaplasia {1398}. This staining pat- In a study of cancers at the oesopha- carcinomas of both the oesophagus and
tern reflects immature, regenerative cells gogastric junction that did not show evi- distal stomach {314, 1133}.
and is a common finding in biopsy spec- dence of associated Barrett oesopha-
imens of the cardia in children with gus, the prevalence of TP53 mutations Prognosis and predictive factors
GERD. This finding alone is not sufficient was only 30% {1641}. Overexpression of There is a significant relationship between
to identify intestinal metaplasia; intestinal the MDM2 gene was found frequently in grade and prognosis by univariate analy-
metaplasia should only be diagnosed if these tumours, suggesting that TP53 sis. For example, Blomjous et al. found
goblet cells are present. may be inactivated either by mutation or that 31% of patients with well or moder-
by overexpression of the MDM2 gene. ately differentiated cardia tumours sur-
Genetic changes Comparative genomic hybridization has vived 5 years, whereas the survival for
The best characterized somatic alteration been used to compare tumours of the patients with poorly or undifferentiated
found in tumours of this region are muta- ‘gastric cardia’ and tumours in Barrett tumours was only 17% {151}. When T, N,
tions of TP53 which are present in up to oesophagus. Gains and losses of genet- and M status were included in the analy-
60% of carcinomas of the oesophagogas- ic material were identified at a number of sis, however, grade was significantly relat-
tric junction. In 5 patients who had ade- common regions in cancers from both ed to survival only in those patients with
nocarcinomas at the junction associated sites {1718}. Common altered regions negative lymph nodes (53% 5-year sur-
with Barrett oesophagus, the same muta- included chromosome 4q (loci not yet vival for well and moderate compared to
tion was detected in the tumour and in the identified), 3p14 (FHIT, RCA1), 5q 14-21 21% for poor and undifferentiated
surrounding oesophageal intestinal meta- (APC, MCC), 9p21 (MTS1/CDKN2), tumours).
plasia, indicating an oesophageal origin. 14q31-32.1 (TSHR), 16q23, 18q21
No association has been found between (DCC, p15), and 21q21. Minimal overlap-
p53 status and tumour stage or subtype. ping amplified sites were seen at 5p14
The TP53 alterations noted in tumours at (MLV12), 6p12-21.1 (NRASL3), 7p12
the oesophagogastric junction show a (EGFR), 8123-24.1 (MYC), 15q25
CHAPTER 3
Secondary tumours
_____________
1
The classification is modified from the previous WHO histological classification of tumours {2066} taking into account changes in our understanding of these lesions. In the case of
endocrine neoplasms, the classification is based on the recent WHO clinicopathological classification {1784}, but has been simplified to be of more practical utility in morphological
classification.
2
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded
/0 for benign tumours, /3 for malignant tumours, and /1 for unspecified, borderline or uncertain behaviour. Intraepithelial neoplasia does not have a generic code in ICD-O. ICD-O codes
are available only for lesions categorized as glandular intraepithelial neoplaia grade III (8148/2), and adenocarcinoma in situ (8140/2).
____________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
A tumour may penetrate muscularis propria with extension into the gastrocolic or gastrohepatic ligaments or the greater and lesser omentum without perforation of the visceral peri-
toneum covering these structures. In this case, the tumour is classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or omenta, the tumour
is classified as T3.
4
The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
5
Intramural extension to the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites including stomach.
Definition Asia {1471}. There is about a 20-fold dif- frequently has hereditary characteristics,
A malignant epithelial tumour of the ference in the incidence rates when com- perhaps modulated by environmental
stomach mucosa with glandular differen- paring the rates in Japan with those of influences {1738, 1633}.
tiation. Its aetiology is multifactorial; most some white populations from the US and
commonly it develops after a long period those of some African countries. A pre- Aetiology
of atrophic gastritis. dominance of the intestinal type of ade- Diet
Tumours of the oesophagogastric junc- nocarcinoma occurs in high-risk areas, Epidemiological studies in different pop-
tion are dealt with in the preceding while the diffuse type is relatively more ulations show that the most consistent
chapter. common in low-risk areas {1296}. association is diet. This is especially true
of intestinal type carcinomas. An ade-
ICD-O codes Time trends quate intake of fresh fruits and vegeta-
Adenocarcinoma 8140/3 A steady decline in the incidence and bles lowers the risk {1450}, due to their
Intestinal type 8144/3 mortality rates of gastric carcinoma has antioxidant effects. Ascorbic acid,
Diffuse type 8145/3 been observed worldwide over the past carotenoids, folates and tocopherols are
Papillary adenocarcinoma 8260/3 several decades, but the absolute num- considered active ingredients. Salt intake
Tubular adenocarcinoma 8211/3 ber of new cases per year is increasing strongly associates with the risk of gas-
Mucinous adenocarcinoma 8480/3 mainly because of the aging of the pop- tric carcinoma and its precursor lesions
Signet-ring cell carcinoma 8490/3 ulation {1296}. Analysis of time trends by {869}.
histological types indicates that the inci- Other foods associated with high risk in
Epidemiology dence decline results from a decline in some populations include smoked or
Geographical distribution the intestinal type of carcinoma {1296}. cured meats or fish, pickled vegetables
Gastric cancer was the second common- and chili peppers.
est cancer in the world in 1990, with an Age and sex distribution Alcohol, tobacco and occupational
estimated 800,000 new cases and Gastric carcinoma is extremely rare exposures to nitrosamines and inorganic
650,000 deaths per year; 60% of them below the age of 30; thereafter it increas- dusts have been studied in several pop-
occurred in developing countries {1469}. es rapidly and steadily to reach the high- ulations, but the results have been incon-
The areas with the highest incidence est rates in the oldest age groups, both in sistent.
rates (> 40/100,000 in males) are in males and females. The intestinal type
Eastern Asia, the Andean regions of rises faster with age than the diffuse Bile reflux
South America and Eastern Europe. Low type; it is more frequent in males than in The risk of gastric carcinoma increases
rates (< 15/100,000) are found in North females. 5-10 years after gastric surgery, espe-
America, Northern Europe, and most Diffuse carcinoma tends to affect cially when the Bilroth II operation, which
countries in Africa and in Southeastern younger individuals, mainly females; it increases bile reflux, was performed.
45.5
7.4
18.0 77.9
49.1
7.4
7.4
25.9
10.8
< 6.7 < 11.6 < 17.1 < 25.0 < 77.9
Fig. 3.01 Worldwide annual incidence (per 100,000) of stomach cancer in males. Fig. 3.02 The mortality of stomach cancer is decreasing worldwide, including
Numbers on the map indicate regional average values. countries with a high disease burden.
Gastric carcinoma 39
03 19.7.2006 7:41 Page 40
Localization
The most frequent site of sub-cardial
stomach cancer is the distal stomach,
i.e. the antro-pyloric region. Carcinomas
in the body or the corpus of the stomach
are typically located along the greater or
lesser curvature.
Clinical features
Symptoms and signs
Early gastric cancer often causes no
symptoms, although up to 50% of A B
patients may have nonspecific gastroin- Fig. 3.05 Endoscopic views of early, well differentiated adenocarcinoma. A Polypoid type. B Elevated type.
Gastric carcinoma 41
03 19.7.2006 7:41 Page 42
A B A
C D B
Fig. 3.06 Endoscopic views of gastric cancer (A, C) and corresponding images with dye enhancement (B, D). Fig. 3.08 Gastric adenocarcinoma of (A) polypoid
A, B Depressed early gastric cancer. C, D Deep ulcer scar surrounded by superficial early gastric cancer infil- and (B) diffusely infiltrative type.
trating the mucosa and submucosa.
tric cancers, radiology usually is not nec- Macroscopy through the submucosa or subserosa or
essary, but may complement endoscop- Dysplasia may present as a flat lesion via the submucosal lymphatics.
ic findings in some cases. Tumour stag- (difficult to detect on conventional endo- Duodenal invasion occurs more fre-
ing prior to treatment decision involves scopy, but apparent on dye-staining quently than expected based on gross
percutaneous ultrasound or computer- endoscopy) or polypoid growth. Appear- examination. Therefore, resection mar-
ized tomography to detect liver metas- ances intermediate between them gins should be monitored by intraopera-
tases and distant lymph node metas- include a depressed or reddish or discol- tive consultation.
tases. Laparoscopic staging may be the ored mucosa. The macroscopic type of Intestinal carcinomas preferentially meta-
only way to exclude peritoneal seeding in early gastric carcinoma is classified using stasize haematogenously to the liver,
the absence of ascites. critera similar to those in endoscopy (Fig. whereas diffuse carcinomas preferentially
3.03) {1298, 63}. The gross appearance metastasize to peritoneal surfaces {1273,
of advanced carcinoma forms the basis 245}. An equal incidence of lymph node
of the Borrmann classification (Fig. 3.06) metastases occurs in both types of
{63, 175}. tumours with T2 or higher lesions. Mixed
Ulcerating types II or III are common. tumours exhibit the metastatic patterns of
Diffuse (infiltrative) tumours (type IV) both intestinal and diffuse types. When
spread superficially in the mucosa and carcinoma penetrates the serosa, peri-
submucosa, producing flat, plaque-like toneal implants flourish. Bilateral massive
lesions, with or without shallow ulcera- ovarian involvement (Krukenberg tumour)
tions. With extensive infiltration, a linitis can result from transperitoneal or haema-
plastica or ‘leather bottle’ stomach results. togenous spread.
Type I Type II
Mucinous adenocarcinomas appear gela- The principal value of nodal dissection is
Polypoid Fungating
tinous with a glistening cut surface. the detection and removal of metastatic
disease and appropriate tumour staging.
Tumour spread and staging The accuracy of pathological staging is
Gastric carcinomas spread by direct proportional to the number of regional
extension, metastasis or peritoneal dis- lymph nodes examined and their loca-
semination. Direct tumour extension tion. When only nodes close to the
involves adjacent organs. Tumours inva- tumour are assessed, many cancers are
ding the duodenum are most often of the classified incorrectly.
Type III Type IV diffuse type and the frequency of seros-
Ulcerated Infiltrative al, lymphatic, and vascular invasion and Histopathology
Fig. 3.07 Borrmann classification of advanced gas- lymph node metastases in these lesions Gastric adenocarcinomas are either
tric carcinoma. is high. Duodenal invasion may occur gland-forming malignancies composed
A B C
D E F
Fig. 3.09 A Depressed adenocarcinoma. B Depressed signet ring cell carcinoma. C Gastric cancer, dye sprayed (pale area). D, E, F Advanced gastric carcinoma
with varying degrees of infiltration.
of tubular, acinar or papillary structures, present. Individual tumour cells are (papillotubular). Rarely, a micropapillary
or they consist of a complex mixture of columnar, cuboidal, or flattened by intra- architecture is present. The degree of
discohesive, isolated cells with variable luminal mucin. Clear cells may also be cellular atypia and mitotic index vary;
morphologies, sometimes in combination present. The degree of cytological atypia there may be severe nuclear atypia. The
with glandular, trabecular or alveolar solid varies from low to high-grade {466, invading tumour edge is usually sharply
structures {243}. Several classification 1362}. A poorly differentiated variant is demarcated from surrounding structures;
systems have been proposed, including sometimes called solid carcinoma. the tumour may be infiltrated by acute
Ming, Carniero, and Goseki {1623}, but Tumours with a prominent lymphoid stro- and chronic inflammatory cells.
the most commonly used are those of ma are sometimes called medullary car-
WHO and Laurén {419, 87}. cinomas or carcinomas with lymphoid Mucinous adenocarcinomas
stroma {2063}. The degree of desmopla- By definition, > 50% of the tumour con-
WHO classification sia varies and may be conspicuous. tains extracellular mucinous pools. The
Despite their histological variability, usu- two major growth patterns are (1) glands
ally one of four patterns predominates. Papillary adenocarcinomas lined by a columnar mucous-secreting
The diagnosis is based on the predomi- These are well-differentiated exophytic epithelium together with interstitial mucin
nant histological pattern. carcinomas with elongated finger-like and (2) chains or irregular cell clusters
processes lined by cylindrical or floating freely in mucinous lakes. There
Tubular adenocarcinomas cuboidal cells supported by fibrovascu- may also be mucin in the interglandular
These contain prominent dilated or slit- lar connective tissue cores. The cells stroma. Scattered signet-ring cells, when
like and branching tubules varying in tend to maintain their polarity. Some present, do not dominate the histological
their diameter; acinar structures may be tumours show tubular differentiation picture. Grading mucinous adenocarci-
A B C
Fig. 3.10 Features of tubular adenocarcinoma. A Well differentiated tumour with invasion into the muscularis propria. B Solid variant. C Clear cell variant.
Gastric carcinoma 43
03 19.7.2006 7:41 Page 44
B
Fig. 3.15 Hepatoid variant of gastric carcinoma. Fig. 3.16 Gastric choriocarcinoma composed of syncytiotrophoblastic and cytotrophoblastic cells next to
thin-walled vascular structures. A Papillary carcinoma component is adjacent to the choriocarcinoma.
B High magnification of the choriocarcinoma.
Gastric carcinoma 45
03 19.7.2006 7:41 Page 46
A B C
Fig. 3.18 Tubular adenocarcinoma. A Well differentiated; intramucosal invasion. B Moderately differentiated. C Poorly differentiated.
endoscopic/biopsy approach remains to categories: PenA and PenB) the invasion Precursor lesions
be evaluated {1634, 1638}. Histological- of the submucosa is more extensive than Gastritis and intestinal metaplasia
ly, most subtypes of carcinoma occur in in the two above-mentioned variants. Chronic atrophic gastritis and intestinal
EGC in either pure or mixed forms. PenA is defined by a pushing margin, metaplasia commonly precede and/or
Elevated carcinomas with papillary, gran- and is less frequent than PenB, which accompany intestinal type adenocarci-
ular or nodular patterns and a red colour penetrates muscularis mucosae at multi- noma, particularly in high-incidence
are more often well or moderately differ- ple sites. areas {780}. H. pylori associated gastritis
entiated, tubular or papillary tumours The prognosis is worse in PenA carcino- is the commonest gastric precursor
with intestinal features; sometimes a pre- mas (in contrast to adenocarcinomas of lesion.
existing adenoma is recognizable. Flat, the colon, where a pushing margin is However, autoimmune gastritis also
depressed, poorly differentiated carcino- associated with a better prognosis). The associates with an increased carcinoma
mas may contain residual or regenerative coexistence of more than one of the risk. If gastritis persists, gastric atrophy
mucosal islands. Ulcerated lesions are described patterns results in the mixed occurs followed by intestinal metaplasia,
either intestinal or diffuse cancers. variant {950}. beginning a series of changes that may
Adenocarcinoma limited to the mucosal result in neoplasia, especially of intestin-
thickness has also been divided into Stromal reactions al type cancers. In contrast, diffuse gas-
small mucosal (< 4cm=SM) and superfi- The four common stromal responses to tric cancers often arise in a stomach
cial (> 4cm=SUPER) {950}. Both of them gastric carcinoma are marked desmo- lacking atrophic gastritis with intestinal
may be strictly confined at the mucosal plasia, lymphocytic infiltrates, stromal metaplasia.
level (small mucosal M and superficial M) eosinophilia and a granulomatous res-
or focally infiltrate the sub-mucosa (small ponse. The granulomatous reaction is
mucosal SM and superficial SM). In the characterized by the presence of single
penetrating variant, (including two sub- and confluent small sarcoid-like granulo-
mas, often accompanied by a moderate-
ly intense mononuclear cell infiltrate. The
lymphoid response is associated with an
improved survival.
Grading
Well differentiated: An adenocarcinoma
with well-formed glands, often resem-
bling metaplastic intestinal epithelium.
Moderately differentiated: An adenocar-
cinoma intermediate between well differ-
A entiated and poorly differentiated.
Poorly differentiated: An adenocarcino-
ma composed of highly irregular glands
that are recognized with difficulty, or sin-
gle cells that remain isolated or are
arranged in small or large clusters with
mucin secretions or acinar structures.
They may also be graded as low-grade
(well and moderately differentiated) or
high-grade (poorly differentiated). Note
B that this grading system applies primari- Fig. 3.20 Intestinal metaplasia. The two glands on
Fig. 3.19 A, B Tubular adenocarcinoma, well differ- ly to tubular carcinomas. Other types of the left exhibit complete intestinal metaplasia,
entiated. gastric carcinoma are not graded. others show the incomplete type.
There are two main types of intestinal inflammation, and the distinction between less common than hyperplastic polyps;
metaplasia: ‘complete’ (also designated intraepithelial and invasive carcinoma overall, they account for approximately
as ‘small intestinal type’ or type I), and {1683, 1025}. Several proposals have 10% of gastric polyps {1843}. They tend
‘incomplete’ (types II and III) {843}. been made for the terminology of the to arise in the antrum or mid stomach in
Different mucin expression patterns char- morphological spectrum of lesions that lie areas of intestinal metaplasia.
acterize the metaplasias: complete shows between non-neoplastic changes and Morphologically, adenomas can be
decreased expression of ‘gastric’ (MUC1, early invasive cancer, including the described as tubular (the most com-
MUC5AC and MUC6) mucins and recent international Padova classification mon), tubulovillous, or villous; the latter
expression of MUC2, an intestinal mucin. {1636}. two have also been called papillotubular
In incomplete intestinal metaplasia, ‘gas- and papillary. Most have epithelium of
tric’ mucins are co-expressed with MUC2 Indefinite for intraepithelial neoplasia intestinal type, but some have gastric
mucin. These findings show that incom- Sometimes, doubts arise as to whether a foveolar features.
plete intestinal metaplasia has a mixed lesion is neoplastic or non-neoplastic (i.e.
gastric and intestinal phenotype reflect- reactive or regenerative), particularly in Low-grade intraepithelial neoplasia
ing an aberrant differentiation program small biopsies. In such cases, the dilem- This lesion shows a slightly modified
not reproducing any normal adult gas- ma is usually solved by cutting deeper mucosal architecture, including the pres-
trointestinal epithelial phenotype {1574}. levels of the block, by obtaining addition- ence of tubular structures with budding
al biopsies, or after removing possible and branching, papillary enfolding, crypt
Intraepithelial neoplasia sources of cellular hyperproliferation. One lengthening with serration, and cystic
Intraepithelial neoplasia (dysplasia) arises important source of a potentially alarming changes. Glands are lined by enlarged
in either the native gastric or of intestinal- lesion is the regeneration associated with columnar cells with minimal or no mucin.
ized gastric epithelia. Pyloric gland ade- NSAID-induced injury or superficial ero- Homogeneously blue vesicular, rounded
noma is a form of intraepithelial neoplasia sion/ulceration caused by gastric acid. or ovoid nuclei are usually pseudostrati-
arising in the native mucosa {2066, 1885}. Cases lacking all the attributes required fied in the proliferation zone located at
In the multi-stage theory of gastric onco- for a definitive diagnosis of intraepithelial the superficial portion of the dysplastic
genesis, intraepithelial neoplasia lies neoplasia may be placed into the catego- tubules.
between atrophic metaplastic lesions ry ‘indefinite for intraepithelial neoplasia’.
and invasive cancer (Table 3.01). In native gastric mucosa, foveolar hyper- High-grade intraepithelial neoplasia
Problems associated with diagnosing proliferation may be indefinite for dyspla- There is increasing architectural distortion
gastric intraepithelial neoplasia include sia, showing irregular and tortuous tubular with glandular crowding and prominent
the distinction from reactive or regenera- structures with epithelial mucus depletion, cellular atypia. Tubules can be irregular in
tive changes associated with active a high nuclear-cytoplasmic ratio and loss shape, with frequent branching and fold-
of cellular polarity. Large, oval/round,
hyperchromatic nuclei associate with
prominent mitoses, usually located near
the proliferative zone in the mucous neck
region.
In intestinal metaplasia, areas indefinite
for intraepithelial neoplasia exhibit a
hyperproliferative metaplastic epithelium.
The glands may appear closely packed,
lined by cells with large, hyperchromatic,
rounded or elongated, basally located
nuclei. Nucleoli are an inconsistent find-
ing. The cyto-architectural alterations tend
to decrease from the base of the glands to
their superficial portion.
Intraepithelial neoplasia
It has flat, polypoid, or slightly depressed
growth patterns; the flat pattern may lack
any endoscopic changes on convention-
al endoscopy, but shows an irregular
appearance on dye endoscopy. In
Western countries, the term adenoma is
applied when the proliferation produces
a macroscopic, usually discrete, protrud-
ing lesion. However, in Japan, adenomas Fig. 3.22 Tubular adenoma of gastric antrum.
Fig. 3.21 Reactive gastritis with marked foveolar include all gross types (i.e. flat, elevated Uninvolved pyloric glands below the lesion show
hyperplasia. and depressed). Gastric adenomas are cystic dilatation.
Gastric carinoma 47
03 19.7.2006 7:41 Page 48
Polyps
Hyperplastic polyps
Hyperplastic polyps are one of the com-
monest gastric polyps. They are sessile
or pedunculated lesions, usually < 2.0
cm in diameter, typically arising in the
antrum on a background of H. pylori gas-
tritis. They contain a proliferation of sur-
face foveolar cells lining elongated, dis-
torted pits extending deep into the
stroma. They may contain pyloric glands,
chief cells and parietal cells. The surface
often erodes. In a minority of cases, car-
cinoma develops within the polyps in
areas of intestinal metaplasia and dys-
plasia.
A B C
Fig. 3.24 High-grade intraepithelial neoplasia in flat gastric mucosa (flat adenoma). A Architectal distortion of the gastric glands. B High degree of cellular atypia.
C Papillary pattern.
Molecular genetics
Loss of heterozygosity studies and com-
parative genomic hybridization (CGH)
A B
analyses have identified several loci with
significant allelic loss, indicating possi-
ble tumour suppressor genes important
in gastric carcinoma. Common target(s)
of loss or gain include chromosomal
regions 3p, 4, 5q, (30 to 40% at or near
APC’s locus) {1656, 1577}, 6q {255}, 9p,
17p (over 60 percent at TP53’s locus)
{1656}, 18q (over 60 percent at DCC’s
locus) {1981}, and 20q {1287, 449,
C D 2192}. Similar LOH losses at 11p15
Fig. 3.25 A Large hyperplastic polyp of the stomach. B, C Typical histology of gastric hyperplastic polyp. D occur in proximal and distal carcinomas,
Hyperplastic polyp with florid epithelial hyperplasia. suggesting common paths of develop-
Gastric carcinoma 49
03 19.7.2006 7:41 Page 50
A B
Fig. 3.26 A, B Fundic gland polyp. Cystic glands are typical.
ment {1288}. Loss of a locus on 7q inactivation of both alleles by mecha- E-cadherin splice site alterations pro-
(D7S95) associates with peritoneal nisms such as hypermethylation {1050, duce exon deletion and skipping. Large
metastasis. 510}. deletions including allelic loss and mis-
The frequency of MSI in sporadic gastric Genes with simple tandem repeat sense point mutations also occur; some
carcinoma ranges from 13% to 44% sequences within their coding regions tumours exhibit alterations in both alleles
{1713}. MSI+ tumours tend to be that are altered in MSI+ tumours include {135}. Somatic E-cadherin gene alter-
advanced intestinal-type cancers. The the TGF-β II receptor, BAX, IGFRII, ations also affect the diffuse component
degree of genome-wide instability varies hMSH3, hMSH6, and E2F-4. A study of of mixed tumours {1136}. Alpha-catenin,
with more significant instability (e.g., gastric cancers displaying the MSI-H which binds to the intracellular domain of
MSI-H: > 33% abnormal loci) occurring phenotype reveal that a majority contain E-cadherin and links it to actin-based
in only 16% of gastric carcinoma, usually mutated TGF-β type II receptors in a cytoskeletal elements, shows reduced
of the subcardial intestinal or mixed type, polyadenine tract {1420, 1462}. Altered immunohistochemical expression in
with less frequent lymph node or vessel TGF-β II receptor genes can also be many tumours and correlates with infiltra-
invasion, prominent lymphoid infiltration, found in MSI-lesions. tive growth and poor differentiation
and better prognosis {430}. Loss of either Allelic loss of TP53 occurs in > 60% of {1189}. Beta catenin may also be abnor-
hMLH1 or hMSH2 protein expression cases and mutations are identified in mal in gastric carcinoma.
affects all MSI-H cases {654} suggesting approximately 30-50% of cases depend- There is evidence of a tumour suppres-
ing on the mutational screening method sor locus on chromosome 3p in gastric
and sample sizes {729, 1937}. TP53 carcinomas {893, 1688}. This area
mutations are identifiable in some intes- encodes the FHIT gene. Gastric carcino-
tinal metaplasias; {497} most alterations mas develop abnormal transcripts, delet-
affect advanced tumours. TP53 muta- ed exons {1411}, a somatic missense
tions in gastric lesions resemble those mutation in exon 6 and loss of FHIT pro-
seen in other cancers with a predomi- tein expression {102}.
nance of base transitions, especially at Somatic APC mutations, mostly mis-
CpG dinucleotides. Immunohistochemi- sense in nature and low in frequency,
cal analyses to detect TP53 overexpres- affect Japanese patients with in situ and
sion can indirectly identify TP53 muta- invasive neoplasia {1309}. Significant
tions but do not have consistent allelic loss (30%) at the APC loci suggest
prognostic value in gastric carcinoma that there is a tumour suppressor gene
patients {557, 766}. Finally, with respect important in gastric tumourigenesis near-
to TP53, there is a polymorphism in by. Indeed, alternative loci have been
codon 72 encoding a proline rather than mapped to commonly deleted regions in
an arginine that strongly associates with gastric carcinomas {1891}.
antral cancers {1735}. Amplification and overexpression of the
Sporadic gastric carcinomas, especially c-met gene encoding a tyrosine kinase
diffuse carcinomas, exhibit reduced or receptor for the hepatocyte growth factor
abnormal E-cadherin expression {1196, occurs in gastric carcinoma {976}. Other
1135}, and genetic abnormalities of the growth factor and receptor signal systems
E-cadherin gene and its transcripts. that may be involved include epidermal
Fig. 3.27 Peutz-Jeghers polyp with hyperplastic Reduced E-cadherin expression is asso- growth factor, TGF-alpha, interleukin-1-a,
glands. ciated with reduced survival {848}. cripto, amphiregulin, platelet-derived
A B C
Fig. 3.28 E-cadherin expression in gastric adenocarcinoma. A Intestinal type of adenocarcinoma showing a normal pattern of membranous staining. B Diffuse type
of adenocarcinoma with reduced E-cadherin expression. Normal expression can be seen in the non-neoplastic gastric epithelium overlying the tumour. C Undiffer-
entiated gastric carcinoma with highly reduced membranous expression and dot-like cytoplasmic expression.
growth factor, and K-sam {1879}. Ampli- advanced cases. Lymph node status, classification scheme for reporting nodal
fication of c-erbB-2, a transmembrane which is part of the TNM system, is also involvement in gastric cancer.
tyrosine kinase receptor oncogene, an important prognostic indicator. The 5th Roder et al recently published data sup-
occurs in approximately 10% of lesions edition of the UICC TNM Classification of porting the value of this reporting sys-
and overexpression associates with a Malignant Tumours {66} and the AJCC tem. These authors found that for
poor prognosis {375}. Telomerase activity Manual for the Staging of Cancer {1} pub- patients who had nodal involvement in
has been detected by a PCR-based lished in 1997, have a number-based 1-6 lymph nodes (pN1), the 5-year sur-
assay frequently in the late stages of gas-
tric tumours and observed to be associat-
ed with a poor prognosis {719}.
Gastric carcinoma 51
03 19.7.2006 7:41 Page 52
C. Capella
Endocrine tumours of the stomach E. Solcia
L.H. Sobin
R. Arnold
Endocrine tumours 53
03 19.7.2006 7:41 Page 54
tiple and multicentric. Of 152 cases stud- which, though larger than those of type I,
ied by endoscopy, 57% had more than are generally smaller than 1.5 cm in size
two growths {1561}. in 75% of cases {1590}.
Type III ECL-cell tumours are usually sin-
Type II ECL-cell carcinoids gle and in 33% of the cases larger than 2
Hypertrophic, hypersecretory gastropa- cm in diameter. Infiltration of the muscu-
thy and high levels of circulating gastrin laris propria is found in 76%, and of the
are critical diagnostic findings. In all serosa in 53% of cases {1590}.
cases, ECL-cell hyperplasia and/or dys-
plasia were noted in the fundic peritu- Histopathology
moural mucosa {1590}. These gastric The histopathological categorization of Fig. 3.32 Sporadic (type III) ECL-cell carcinoid of the
carcinoids are usually multiple and small- endocrine tumours of the stomach gastric body. The surrounding mucosa is normal.
er than 1.5 cm in size in the majority of described here, is a modification of the
cases {1590}. WHO classification of endocrine tumours
{1784}. specimens {1865}. The ECL-cell nature of
Type III (sporadic) ECL-cell carcinoids argyrophil tumours is ultimately assessed
These lesions are not associated with Carcinoid tumour by demonstrating ECL-type granules by
hypergastinaemia or A-CAG. They are A carcinoid is defined morphologically electron microscopy {232, 1591}.
generally solitary growths, and arise in the as a well differentiated neoplasm of the Sporadic ECL-cell carcinoids are usually
setting of gastric mucosa devoid of diffuse endocrine system. more aggressive than those associated
ECL-cell hyperplasia/dysplasia and of with A-CAG or MEN-1. Histopathologi-
significant pathologic lesions except for ECL-cell carcinoid cally, these tumours show a prevalence
gastritis (other than A-CAG). Rare multi- The majority of type I and type II of solid cellular aggregates and large tra-
ple tumours have been observed {1590}. ECL-cell carcinoids are characterized beculae, crowding, and irregular distri-
Clinically, type III tumours present (1) as a by small, microlobular-trabecular aggre- bution of round to spindle and polyhedral
mass lesion with no evidence of endo- gates formed by regularly distributed, tumour cells, fairly large vesicular nuclei
crine symptoms (nonfunctioning carci- often aligned cells (mosaic-like pattern), with prominent eosinophilic nucleoli, or
noid) and with clinical findings similar to with regular, monomorphic nuclei, usual- smaller, hyperchromatic nuclei with irreg-
those of adenocarcinoma, including gas- ly inapparent nucleoli, rather abundant, ular chromatin clumps and small nucle-
tric haemorrhage, obstruction and metas- fairly eosinophilic cytoplasm, almost oli, considerable mitotic activity, some-
tasis, or (2) with endocrine symptoms of absent mitoses, and infrequent angioin- times with atypical mitotic figures and
an ‘atypical carcinoid syndrome’ with red vasion. scarce necrosis.
cutaneous flushing and absence of diar- Tumours with these features (grade 1 Tumours with these histological features
rhoea, usually coupled with liver metas- according to Rindi et al {1589}) are gen- or grade 2 features {1589} show a higher
tases and production of histamine and erally limited to mucosa or submucosa mitotic rate (mean of 9 per 10 HPF), a fre-
5-hydroxytryptophan {1386, 1598}. {1589} and can be considered as quent expression of p53 (60%), a higher
tumours with benign behaviour. The ECL
Non ECL-cell gastric carcinoids. nature of the tumours is confirmed by Table 3.02.
These uncommon tumours may present strong argyrophilia by Grimelius or Histological classification of endocrine neoplasms
with ZES due to their gastrin production Sevier Munger techniques and positive of the stomach1
(which is more frequently found in duo- immunoreactivity for chromogranin A, in 1. Carcinoid –
denal gastrinomas) or with Cushing syn- the absence of reactivity for the well differentiated endocrine neoplasm
drome due to secretion of adrenocorti- argentaffin or diazonium tests for sero- 1.1 ECL-cell carcinoid
cotrophic hormone (ACTH) {711, 1791}. tonin, and no or only occasional 1.2 EC-cell, serotonin-producing
immunoreactivity for hormonal products carcinoid
Macroscopy {1591}. Minor cell sub-populations ex- 1.3 G-cell, gastrin-producing tumour
Type I ECL-cell carcinoids are multiple in pressing serotonin, gastrin, somato- 1.4 Others
57% of cases {1590}, usually appearing statin, pancreatic polypeptide (PP), or
as small tan nodules or polyps that are α-hCG have been detected in a minority 2. Small cell carcinoma –
poorly differentiated endocrine neoplasm
circumscribed in the mucosa or, more of tumours {1591}. A few ECL-cell
often, to the submucosa. Most tumours tumours produce histamine and 3. Tumour-like lesions
(77%) are < 1 cm in maximum diameter 5-hydroxy-tryptophan; these lesions, Hyperplasia
and 97% of tumours are < 1.5 cm. The when they metastasize, can produce Dysplasia
muscularis propria is involved in only a ‘atypical’ carcinoid syndrome {1591}
minority of cases (7%) {1590}. Vesicular monoamine transporter type 2 1
Benign behaviour of ECL-cell carcinoid is associated
with the following: tumour confined to mucosa-sub-
The stomachs with type II tumours are (VMAT-2) is a suitable and specific marker mucosa, nonangioinvasive, < 1cm in size, nonfunc-
enlarged and show a thickened gastric for ECL-cell tumours {1592} while hista- tioning; occurring in CAG or MEN-1/ ZES. Aggressive
behaviour of ECL-cell carcinoid is associated with the
wall (0.6-4.5 cm) due to severe hyper- mine or histidine decarboxylase immuno- following: tumour invades muscularis propria or
beyond, > 1cm in size, angioinvasive, functioning, and
trophic-hypersecretory gastropathy and histochemical analysis, although specific, sporadic occurrence.
multiple mucosal-submucosal nodules is less suitable for routinely processed
A B
Fig. 3.33 A Type I ECL-cell carcinoid in a patient with pernicious anaemia. B Type II ECL-cell carcinoid in a patient with MEN1 and ZES.
Ki67 labelling index (above 1000 per 10 Large cell neuroendocrine carcinoma is a Mixed exocrine-endocrine carcinomas
HPF) and more frequent lymphatic and malignant neoplasm composed of large These consist of neoplastic endocrine
vascular invasion than well differentiated cells having organoid, nesting, trabecular, cells composing more than 30% of the
ECL-cell carcinoids {1589}. In addition, rosette-like and palisading patterns that whole tumour cell population. They are
deeply invasive tumours are associated suggest endocrine differentiation, and in relatively rare in the stomach, despite the
with local and/or distant metastases in which the last can be confirmed by frequent occurrence of minor endocrine
most cases. immunohistochemistry and electron components inside the ordinary adeno-
microscopy. In contrast to small cell carci- carcinoma. They should generally be
EC-cell, serotonin-producing carcinoid noma, cytoplasm is more abundant, classified as adenocarcinomas.
This is a very rare tumour in the stomach nuclei are more vesicular and nucleoli are
{1591}. It is formed by rounded nests of prominent {1954}. These tumours have Precursor lesions
closely packed small tumour cells, often not been well described in the gastroin- ECL-cell carcinoids arising in hypergas-
with peripheral palisading, reminiscent of testinal tract because of their apparent trinaemic conditions (types I and II)
the typical type A histologic pattern of low frequency {1188}. develop through a sequence of hyperpla-
the argentaffin EC-cell carcinoid of the sia-dysplasia-neoplasia that has been
midgut. The tumour cells are argentaffin, well documented in histopathological
intensely argyrophilic and reactive with studies {1777}. The successive stages of
chromogranin A and anti-serotonin anti- hyperplasia are termed simple, linear,
bodies. Electron microscopic examina- micronodular, and adenomatoid. Dyspla-
tion confirms the EC-cell nature by sia is characterized by relatively atypical
detecting characteristic pleomorphic, cells with features of enlarging or fusing
intensely osmiophilic granules similar to micronodules, micro-invasion or newly
those of normal gastric EC-cells. formed stroma. When the nodules
increase in size to > 0.5 mm or invade
Gastrin-cell tumours into the submucosa, the lesion is classi-
Most well differentiated gastrin-cell fied as a carcinoid. The entire spectrum
tumours are small mucosal-submucosal of ECL-cell growth, from hyperplasia to
nodules, found incidentally at endoscopy dysplasia and neoplasia has been
or in a gastrectomy specimen. They may observed in MEN-1/ZES and autoimmune
show a characteristic thin trabecular- chronic atrophic gastritis (A-CAG). A sim-
gyriform pattern or a solid nest pattern. ilar sequence of lesions has been shown
The cells are uniform with scanty cyto- in experimental models of the disease,
plasm and show predominant immunore- mostly based on hypergastrinaemia sec-
activity for gastrin. ondary to pharmacological inhibition of
acid secretion in rodents {1896}.
Small cell carcinoma (poorly differentiat-
ed endocrine neoplasm) Genetic susceptibility
These are identical to small cell carcino- ECL-cell carcinoids are integral compo-
mas of the lung. They correspond to nents of the MEN-1 syndrome {1042}. In
grade 3 tumours according to Rindi et al. patients with familial MEN-1/ZES, type II
{1589}, and are particularly aggressive, Fig. 3.34 ECL-cell carcinoid showing immunoex- gastric carcinoids arise in 13-30% of
malignant tumours {1591}. pression of chromogranin A. cases {854, 1042}. However, patients
Endocrine tumours 55
03 19.7.2006 7:41 Page 56
A B
Fig. 3.35 Sporadic (type III) ECL carcinoid. A Tumour extends from mucosa into submucosa with well delineated inferior border. B The carcinoid (left) has round,
regular, isomorphic nuclei.
with sporadic ZES rarely develop gastric These findings support the concept that of causing ECL-cell tumours without
carcinoids despite serum gastrin levels, these gastric tumours are integral com- requiring the promoting effect of hyper-
which persist 10 fold above normal for a ponents of the MEN-1 phenotype, shar- gastrinaemia.
prolonged time. ing with parathyroid and islet cell The role of MEN-1 in non MEN-associat-
tumours the highest frequency of LOH at ed gastric carcinoids is more controver-
Diagnostic criteria of MEN-1 11q13. In multiple carcinoids from the sial. Analysing six type I gastric carci-
This rare dominantly inherited disorder is same stomach, the deletion size in the noids, Debelenko et al. {394} found
characterized by the synchronous or wild-type allele differed from one tumour 11q13 LOH in one tumour while D’Adda
metachronous development of multiple to another, suggesting a multiclonal ori- et al. {363} detected 11q13 LOH in 12
endocrine tumours in different endocrine gin {394}. One of the type II tumours out of 25 cases (48%). Large deletions in
organs by the third decade of life. The showing LOH at 11q13 was in a patient both the 11q13 and 11q14 regions were
parathyroid glands are involved in who had neither ZES nor hypergastri- observed in two poorly differentiated
90-97%, endocrine pancreas in 30-82%, naemia {173}, suggesting that inactiva- endocrine carcinomas {363}.
duodenal gastrinomas in 25%, pituitary tion of the MEN-1 gene alone is capable
adenomas in more than 60%, and foregut Prognosis and predictive factors
carcinoids (stomach, lung, thymus) in The prognosis of carcinoids is highly
5-9% of cases {394}. Other, so-called variable, ranging from slowly growing
non-classical MEN-1 tumours, such as benign lesions to malignant tumours with
cutaneous and visceral lipomas, thyroid extensive metastatic spread.
and adrenal adenomas, and skin angiofi- Benign behaviour of ECL-cell carcinoids
bromas, may occur {394, 1444}. is associated with the following: tumour
confined to mucosa-submucosa, nonan-
MEN-1 gene gioinvasive, < 1 cm in size, nonfunction-
MEN-1 has been mapped to chromo- ing; occurring in CAG or MEN-1/ ZES.
some 11q13 {107, 1015}. It encodes for a Type I, A-CAG associated tumours, have
610 amino acid nuclear protein, termed an excellent prognosis, as do most type
‘menin’, whose suppressor function II MEN-1/ZES tumours.
involves direct binding to JunD and inhi- Aggressive behaviour of ECL-cell carci-
bition of JunD activated transcription noid is associated with the following:
{271, 18}. The tumour suppressor function tumour invades muscularis propria or
of the gene has been proposed based on beyond, is > 1 cm in size, angioinvasive,
the results of combined tumour deletion functioning, with high mitotic activity and
and pedigree analysis {107, 271, 394}. sporadic occurrence {1591, 1590, 1589}.
High rates of loss of heterozygosity (LOH) Metastasis. Lymph node metastases are
at the MEN-1 gene locus have been detected in 5% of type I and 30% of type
reported in classic tumours of the MEN-1, II cases, while distant (liver) metastases
such as endocrine pancreatic, pituitary are found respectively in 2.5% and 10%
and parathyroid neoplasms {1553, 1923}. of cases. No tumour-related or only
LOH at 11q13 of type II gastric carcinoids exceptional death was observed among
was found in 9 of 10 MEN-1 patients Fig. 3.36 Gastrin cell tumour (gastrinoma) of the patients with type I carcinoid, while only
investigated {123, 173, 219, 394}. pylorus with trabecular growth pattern. 1/10 patients died of type II carcinoid. On
death from the tumour occurs in 27% of more than on the behaviour of gastric
patients with a mean survival of 28 tumours, although some aggressive
months {1590}. ECL-cell carcinomas may be fatal {173}.
In such patients, careful search for asso-
Therapy ciated pancreatic, duodenal, parathyroid,
Polypoid type I carcinoids < 1cm, fewer or other tumours and family investigation
than 3-5 in number, associated with for the MEN-1 gene mutation are needed.
A-CAG can be endoscopically excised Type III (sporadic) ECL-cell carcinoids
and have an excellent prognosis. If larg- > 1 cm generally require surgical resec-
er than 1 cm or more than 3-5 lesions are tion even when they are histologically
Fig. 3.37 Small cell carcinoma of the stomach. present, antrectomy and local excision of well differentiated.
all accessible fundic lesions is recom-
mended.
the other hand, lymph node metastases In type II carcinoids the clinical evolution
are found in 71% and distant metastases depends on the behaviour of associated
in 69% of patients with type III tumours; pancreatic and duodenal gastrinomas
Definition row involvement. Today, stomach lym- the neoplastic nature of lesions previous-
Primary gastric lymphomas are defined phomas are considered primary if the ly termed ‘pseudolymphoma’ {677}.
as lymphomas originating from the stom- main bulk of disease is present in the Gastric lymphoma has a worldwide dis-
ach and contiguous lymph nodes. stomach. Recognition of morphological tribution; somewhat higher incidences
Lymphomas at this site are considered features characteristic of primary extra- have been reported for some Western
primary if the main bulk of disease is nodal lymphomas of mucosa-associated communities with a high prevalence of
located in the stomach. The majority of lymphoid tissue-type helps in defining Helicobacter pylori infection {420}.
gastric lymphomas are high-grade B-cell these lesions as primary to the stomach Primary Hodgkin disease is very rare in
lymphomas, some of which have devel- irrespective of the degree of dissemina- the gastrointestinal tract.
oped through progression from tion.
low-grade lymphomas of mucosa associ- Age and sex distribution
ated lymphoid tissue (MALT). The low- Epidemiology Incidence rates are similar in men and
grade lesions are almost exclusively Approximately 40% of all non-Hodgkin women. The age range is wide but the
B-cell MALT lymphomas. lymphomas arise at extranodal sites majority of patients are over 50 years at
{1438, 527}, with the gastrointestinal tract presentation.
Historical annotation as the commonest extranodal site,
Classically, primary gastric lymphomas accounting for about 4-18% of all Aetiology
have been considered to be lymphomas non-Hodgkin lymphomas in Western Helicobacter pylori infection
that are confined to the stomach and the countries and up to 25% of cases in the Initial studies of low-grade MALT lym-
contiguous lymph nodes {378}. While Middle East. Within the gastrointestinal phoma suggested that the tumour was
this excludes cases of secondary tract, the stomach is the most frequent associated with H. pylori in 92-98% of
involvement of the stomach by nodal- site of involvement in Western countries cases {447, 2135}; subsequent studies
type lymphomas – which may occur in while the small intestine is most frequent- have suggested an association in
up to 25% of nodal lymphomas {508} – ly affected in Middle Eastern countries. 62-77% {1316, 583, 2146, 890, 178}.
this definition is excessively restrictive Lymphoma constitutes up to 10% of all H. pylori infection is seen less frequently
and excludes more disseminated, higher gastric malignancies; its incidence in high-grade lymphomas with a low-
stage lymphomas arising within the appears to be increasing but this may, at grade component (52-71%) and in pure
stomach as well as those with bone mar- least in part, be due to the recognition of high-grade lymphomas (25-38%) {583,
Lymphoma 57
03 19.7.2006 7:41 Page 58
890, 178}. The organism has been shown sea and vomiting. High-grade lesions
to be present in 90% of cases limited to may appear as a palpable mass in the
the mucosa and submucosa, falling to epigastrium and can cause severe
76% when deep submucosa is involved, symptoms, including weight loss.
and is present in only 48% of cases with
extension beyond the submucosa Imaging
{1316}. It has been shown that the infec- Low-grade MALT lymphomas present as
tion by H. pylori precedes the develop- intragastric nodularity with preferential
ment of lymphoma, both by sequential location in the antrum {2180}. A more
serological studies {1474} and by retro- precise assessment is obtained with spi-
spective studies of archival gastric biop- ral CT, particularly if this is used in con- Fig. 3.38 Multifocal malignant lymphoma of the
sy material {2211, 1314}. junction with distension of the stomach stomach. The two larger lesions are centrally ulcer-
There is some controversy surrounding by water. This technique can identify up ated.
the role of the organism’s genetic fea- to 88% of cases, most of which have
tures and the risk of lymphoma develop- nodularity or enlarged rugal folds, and it
ment. Studies of the association between can assess the submucosal extent of the Helicobacter heilmannii {1842} and in
MALT lymphoma and cagA bearing tumour {1493}. High-grade lymphomas association with coeliac disease {227}.
H. pylori strains have produced conflict- are usually larger and more frequently This organised lymphoid tissue shows all
ing results, ranging from a lack of asso- associated with the presence of a mass the features of MALT, including the infil-
ciation between cagA and lymphoma and with ulceration. In some cases, the tration of the epithelium by B-lympho-
{1492, 384} to a strong association {441}. radiological features may mimic diffuse cytes reminiscent of the lymphoepitheli-
One study claimed no association with adenocarcinoma {1059}. Endoscopic um seen in Peyer patches {2135}.
low-grade lymphoma but a high frequen- ultrasound is emerging as the investiga- The cellular basis of the interaction
cy of cagA strains in high-grade lesions tion of choice in the assessment of the between H. pylori and MALT lymphoma
{1492}. Recently, a truncated form of an extent of lymphoma infiltration through cells has been studied in detail. When
H. pylori associated protein, fldA, has the gastric wall. Local lymph node unseparated cells isolated from low-
been shown to be closely associated involvement can also be assessed by grade gastric MALT lymphomas are incu-
with gastric MALT lymphoma. All strains this technique. bated in vitro with heat treated whole cell
of H. pylori associated with MALT lym- preparations from H. pylori, the tumour
phoma showed a nucleotide G insertion Endoscopy cells proliferate while those cultured in
at position 481 of the fldA gene, com- Some cases show enlarged gastric folds, the absence of the organism or stimulat-
pared to 6/17 stains unassociated with gastritis, superficial erosions or ulcera- ing chemical mitogen rapidly die {768}.
lymphoma. This mutation causes a short tion. In these cases the surrounding nor- The proliferative response appeared to
truncation in the protein and antibodies mal appearing gastric mucosa may har- be strain specific for individual tumours
to this truncated protein could be detect- bour lymphoma, and accurate mapping but varied between tumours from differ-
ed in 70% of the patients studied with of the lesion requires multiple biopsies ent patients {768}. When T-cells were
MALT lymphoma, compared to 17% of from all sites including areas appearing removed from the culture system the pro-
control patients {274}. macroscopically normal. In a proportion liferative response was not seen and this
of cases, endoscopic examination shows could not be induced if the T-cells were
Immunosuppression very minor changes such as hyperaemia replaced by supernatant from other cul-
Lymphomas may arise or involve the and in a few cases random biopsies of tures containing unseparated tumour
stomach in patients with both congenital apparently entirely normal mucosa may derived cells {769}. Together these stud-
and acquired immunodeficiencies. In reveal lymphoma. High-grade lymphoma ies show that the proliferation of the
general, the incidence, clinical features is usually associated with more florid MALT lymphoma is driven by the pres-
and the histology of the lesions is indis- lesions, ulcers and masses. It is often ence of the H. pylori but that this, rather
tinguishable from those that develop out- impossible to distinguish lymphoma from than being a direct effect on the tumour
side the stomach. Up to 23% of gastroin- carcinoma endoscopically.
testinal tract non-Hodgkin lymphomas
arising in HIV infected patients occur in MALT lymphomas
the stomach and the vast majority of Pathogenesis
these are large B-cell or Burkitt/Burkitt- The normal gastric mucosa contains
like lymphomas, {122} although occa- scattered lymphocytes and plasma cells
sional low-grade MALT lymphomas are but is devoid of organised lymphoid tis-
described {2132}. sue. The initial step in the development of
primary gastric lymphoma is the acquisi-
Clinical features tion of organised lymphoid tissue from
Symptoms and signs within which the lymphoma can develop.
Patients with low-grade lymphomas often In most cases, this is associated with Fig. 3.39 Low-grade B-cell MALT lymphoma.
present with a long history of non-specif- infection by H. pylori {572}, although it Perifollicular distribution of centrocyte-like cells
ic symptoms, including dyspepsia, nau- has also been seen following infection by with a predominant monocytoid morphology.
some cases, the CCL cell may be more tritis, the infiltrate surrounding the lym-
reminiscent of a mature small B lympho- phoid follicles in the lamina propria is
cyte while in other cases, the cell may plasma cell predominant while in MALT
have a monocytoid appearance with lymphoma the infiltrate contains a domi-
more abundant, pale cytoplasm and a nant population of lymphocytes with CCL
well defined cell border. Plasma cell dif- cell morphology, infiltrating through the
ferentiation is typical and may be very lamina propria and around glands.
prominent. Dutcher bodies may be iden- Prominent lymphoepithelial lesions,
tified. The CCL cells infiltrate and destroy Dutcher bodies and moderate cytologi-
adjacent gastric glands to form lym- cal atypia are associated only with lym-
phoepithelial lesions. Lympho-epithelial phoma. All of these features may not be
lesions typical for MALT lymphoma are present in biopsy material from a single
defined as infiltration of the glandular case. In some cases it is justifiable to
epithelium by clusters of neoplastic lym- make the diagnosis of low-grade MALT
phoid cells with associated destruction lymphoma in the absence of one or more
of gland architecture and morphological of these features if the overall histological
changes within the epithelial cells, appearances are those of lymphoma.
including increased eosinophilia. Rare or questionable lymphoepithelial
lesions, dense lymphoid infiltration, mild
Immunohistochemistry cytological atypia and muscularis muco-
The immunophenotype of the CCL cell is sae invasion are features more often
similar to that of the marginal zone B-cell. associated with, but not limited to, lym-
There is expression of pan-B-cell anti- phoma {2212}.
Fig. 3.40 Low-grade B-cell MALT lymphoma. Small
lymphoid cells form a diffuse infiltrate extending
gens such as CD20 and CD79a and the In some cases it will not be possible to
into the submucosa. more mature B-cell markers CD21 and make a definite distinction between reac-
CD35. The cells do not express CD10. tive infiltrates and lymphoma and in
They are usually positive for bcl-2 protein these cases a diagnosis of ‘atypical lym-
cells, is due to a mechanism mediated and may express CD43 but do not phoid infiltrate of uncertain nature’ is
via T-cells and that this help is contact express CD5 or CD23. They express sur- appropriate.
dependant. Further studies have shown face and, to a lesser extent, cytoplasmic
that the T-cells responsible for the prolif- immunoglobulin (usually IgM or IgA, Effect of H. pylori eradication
erative drive are specifically those found rarely IgG) and show light chain restric- The histological appearances of gastric
within the tumour and their function can- tion. Immunostaining with anti-cytoker- biopsies from patients showing complete
not be replaced by T-cells derived from atin antibodies is useful in demonstrating regression of lymphoma after H. pylori
elsewhere (e.g. the spleen) in the same lymphoepithelial lesions. Immunostaining
patient {769}. with antibodies that highlight follicular
dendritic cells (anti-CD21, anti-CD23 or
Histopathology anti-CD35) help to demonstrate underly-
The organisation of the lymphoma mim- ing follicular dendritic cell networks in
ics that of normal MALT and the cellular those cases in which the lymphoid folli-
morphology and immunophenotype is cles have been completely overrun by
essentially that of the marginal zone the lymphoma.
B-cell. The neoplastic cells infiltrate
between pre-existing lymphoid follicles, Differential diagnosis
initially loca-lised outside the follicular The distinction between florid gastritis
mantle zone in a marginal zone pattern. and low-grade MALT lymphoma may be A
As the lesion progresses, the neoplastic difficult. In such cases it is essential to
cells erode, colonize and eventually have sufficient biopsy material (up to
overrun the lymphoid follicles resulting in eight biopsies from endoscopically sus-
a vague nodularity to an otherwise dif- picious areas) with good preservation of
fuse lymphomatous infiltrate {800}. The morphology and correct orientation of
morphology of the neoplastic cell can be the biopsy specimen. For the distinction
variable even within a single case. between reactive and neoplastic infil-
Characteristically, the cell is of intermedi- trates, histological evaluation remains the
ate size with pale cytoplasm and an gold standard, but accessory studies
irregular nucleus. The resemblance of may be helpful. In both reactive and neo- B
these cells to the centrocyte of the follicle plastic cases, lymphoid follicles are pres- Fig. 3.41 Low-grade B-cell MALT lymphoma. The
centre has led to the term ‘centrocyte-like ent and these may be associated with centrocyte-like cells show prominent plasma cell
(CCL)’ cell being applied to the neoplas- active inflammation, crypt abscesses differentiation with (A) extracellular immunoglobu-
tic component of MALT lymphomas. In and reactive epithelial changes. In gas- lin deposition, and (B) prominent Dutcher bodies.
Lymphoma 59
03 19.7.2006 7:41 Page 60
A B
C D
Fig. 3.42 A, B, C Low-grade B-cell MALT lymphoma. A, B Lymphoepithelial lesions. C Immunostaining for cytokeratin highlights lymphoepithelial lesions. D Diffuse
large B-cell lymphoma; the neoplastic cells focally infiltrate glandular epithelium to form structures reminiscent of lymphoepithelial lesions.
eradication are characteristic. The lami- PCR based diagnosis regression. Some, but no all of these will
na propria appears ‘empty’ with gland The role of genetic analyses in the diag- eventually show molecular regression but
loss. Scattered lymphocytes and plasma nosis and follow up of low-grade MALT there may be a prolonged time lag
cells are seen within the lamina propria lymphoma remains controversial. Up to between histological and molecular
and there are usually focal nodular col- 10% of well characterized cases of MALT regression {1677}. In the absence of his-
lections of small lymphocytes. These col- lymphoma identified as clonal through tological evidence of residual lymphoma,
lections frequently contain a mixture of demonstration of rearrangement of the the clinical significance of a persistent
B- and T-cells and may be based on fol- immunoglobulin heavy chain gene by clonal population remains uncertain.
licular dendritic cell networks. Southern blot fail to show a clonal pattern
In most cases, the appearances are when examined for immunoglobulin Progression to high-grade lymphoma
insufficient for a diagnosis of residual heavy chain gene rearrangement by PCR The emergence of clusters of large trans-
lymphoma. The significance of these using fresh frozen tissue {418}. This false formed ‘blastic’ B-cells reflects transfor-
lymphoid nodules remains uncertain. In negative rate increases if paraffin embed- mation to high-grade lymphoma {383}.
cases showing partial regression or no ded material is studied {417}. Several Eventually, these areas become conflu-
change following H. pylori eradication, studies have revealed by PCR the pres- ent to form sheets of cells indistinguish-
the lamina propria contains an infiltrate ence of clonal B-cell populations in biop- able from the cells of a diffuse large
morphologically indistinguishable from sies from patients with uncomplicated B-cell lymphoma. As long as a low-grade
that seen at diagnosis, but in these treat- chronic gastritis and no morphological component remains, these tumours may
ed cases lymphoepithelial lesions may evidence of lymphoma {1677, 225, 388}. be termed high-grade MALT lymphomas
be very scanty or absent. In some cases In conjunction with histological assess- but during further progression, all traces
of partial regression and in cases with ment, PCR studies may be useful in mon- of the pre-existing low-grade lymphoma
relapsed low-grade MALT lymphoma fol- itoring regression of MALT lymphomas are lost, making it impossible to distin-
lowing H. pylori eradication, the lymph- following conservative therapy {25}. guish the lesion from a diffuse large
oma may be largely confined to the sub- However, PCR detected clonal B-cell B-cell lymphoma of unspecified type. In
mucosa with only minimal involvement of populations may still be detected in cases with both low- and high-grade
the mucosa. cases showing complete histological components, genetic studies have con-
firmed the transformation of low-grade to mutations in diffuse large B-cell lym- areas of endemic HTLV-1 infection and
high-grade lymphoma in the majority of phomas independent of a rearrangement probably represent gastric manifesta-
cases {1263} while in other cases both of the gene {1070}. Epstein-Barr virus is tions of adult T-cell leukemia/lymphoma
components appear clonally unrelated, not associated with low-grade lym- (ATLL). In these regions, T-cell lymphoma
suggesting the development of a second phomas and has only been seen in some may represent up to 7% of gastric lym-
primary lymphoma {1184, 1491}. high-grade lymphomas {1038, 1437}. phomas {1741}. Most of the remainder
are similar to peripheral T-cell lym-
Molecular genetics of MALT lymphomas Mantle cell lymphoma phomas encountered in lymph nodes but
Early studies confirmed the presence of Mantle cell lymphoma of the stomach is occasionally, gastric NK cell lymphomas
immunoglobulin gene rearrangement in typically a component of multiple lym- are also seen {1741}. It has recently
each case {1803} and suggested that phomatous polyposis of the gastrointesti- been demonstrated that some gastric
there was no involvement of the bcl-1 or nal tract and infrequently encountered T-cell lymphomas display features of
bcl-2 oncogenes {2136}. The transloca- outside this clinical context {1380}. intraepithelial T lymphocyte differentia-
tion t(11;18)(q21;q21) has been identified Morphologically and immunophenotypi- tion (e.g. expression of the human
in a significant number of low-grade cally, the lymphoma is indistinguishable mucosal lymphocyte 1 antigen, CD103),
MALT lymphomas and may be the sole from mantle cell lymphomas of lymph similar to those seen in intestinal T-cell
genetic alteration in these cases. How- nodes, with a diffuse and monotonous lymphomas {520}.
ever, this translocation appears to be less infiltrate of cells with scanty cytoplasm
common in high-grade lesions {1435, 95}. and irregular nuclei that express B-cell Hodgkin disease
Trisomy 3 has been detected in up to 60% markers together with CD5 and cyclinD1. Hodgkin disease may involve the gas-
of cases in some studies using both trointestinal tract but this is usually sec-
metaphase and interphase techniques Other low-grade B-cell lymphomas ondary to nodal disease. Primary gastric
{2134, 2137}, but this finding has not Although the lymphoid tissue in the stom- Hodgkin disease is very rare {2210}.
been confirmed by other studies {1434}. ach contains all the B-cell populations
The translocation t(1;14) (p22; q32) has encountered in nodal lymphoid tissue, Prognosis and predictive factors
also been described in a small proportion other low-grade B-cell lymphomas, such Studies on the regression of low-grade
of cases {2138} and this is associated as follicle centre cell lymphomas, are MALT lymphoma through H. pylori eradi-
with increased survival of tumour cells in very rare and usually indistinguishable cation have shown remission in 67-84%
unstimulated cell culture. Cloning of the from their nodal counterparts. of cases {1926, 1520, 2133}, but this
breakpoint involved in this translocation applies only to low-grade lesions and is
has led to the discovery of a novel gene, Diffuse large B-cell lymphoma most effective for lesions showing super-
bcl-10, on chromosome 1 that may be These lymphomas are morphologically ficial involvement of the gastric wall.
significant in determining the behaviour of indistinguishable from diffuse large B-cell Although remission following H. pylori
MALT lymphomas {2116}. lymphomas that arise within lymph eradication has occasionally been seen
Studies of the immunoglobulin gene of nodes. There is complete destruction of in advanced tumours, the highest suc-
MALT lymphoma cells has shown the the gastric glandular architecture by cess rate of 90-100% is seen in tumours
sequential accumulation of somatic large cells with vesicular nuclei and confined to the mucosa and superficial
mutations, consistent with an ongoing, prominent nucleoli. Variants of large B- submucosa. The time taken to achieve
antigen driven selection and proliferation cell lymphoma (e.g. plasmablastic lym- remission in these patients varies from
{279, 434, 1546}. Study of the third com- phoma) may also be encountered {1541}. 4-6 weeks to 18 months. The stability of
plementary determining region of the these remissions remains to be deter-
immunoglobulin heavy chain gene shows Burkitt lymphoma mined; one study has reported a relapse
a pattern of changes associated with the Although rare, classical Burkitt lym- in 10% of patients after a mean follow-up
generation of antibody diversity and phomas may be encountered in the period of 24 months {1338} while others
increased antigen binding affinity {131}. stomach {55}. The morphology is identi- have found sustained remissions for up
Transformation of low-grade MALT lym- cal to that of Burkitt lymphoma encoun- to six years {801}.
phoma to a high-grade lesion has been tered elsewhere, with diffuse sheets of Surgical resection is associated with pro-
associated with several genetic alter- medium sized cells with scanty cyto- longed survival {552} in many cases.
ations. While the t(11;18) chromosomal plasm and round/oval nuclei containing Involvement of the resection margins and
translocation is not seen in high-grade small nucleoli. Within the sheets there are advanced stage are poor prognostic fea-
MALT lymphoma and may be protective numerous macrophages, giving a ‘starry- tures, but not with the addition of
against transformation, alterations in the sky’ appearance. Mitoses are frequent chemotherapy {1262}. Irrespective of
genes coding for p53, p16, c-myc and and apoptotic debris abundant. The treatment modality, the only significant
trisomy 12 have all been identified in cells express CD10 in addition to independent prognostic variables are
high-grade lesions {1489, 1490, 1341, pan-B-cell markers. Close to 100% of stage and tumour-grade {260, 1653,
270, 435, 1992}. Bcl-6 protein has also nuclei are immunoreactive for Ki-67. 1262, 320, 383}.
been described in high-grade lym-
phomas while being absent from low- T-cell lymphoma
grade lesions {1425}. Some studies have Primary gastric T-cell lymphomas are
shown a high level of bcl-6 gene hyper- rare. Most have been reported from
Lymphoma 61
03 19.7.2006 7:41 Page 62
M. Miettinen
Mesenchymal tumours of the stomach J.Y. Blay
L.H. Sobin
Definition may be primary in the omentum and tion occurs in 20-30% of cases. Infiltra-
Most gastrointestinal mesenchymal neo- mesentery. They are most common in the tion by direct extension to the pancreas
plasms are gastrointestinal stromal stomach (60-70%), followed by small or liver occurs. On sectioning GISTs vary
tumours (GIST) or smooth muscle types. intestine (20-30%), colorectum and from slightly firm to soft, tan, often with
They are predominantly located in the oesophagus (together < 10%) {1227}. foci of haemorrhage. Larger tumours
stomach. The definitions of other mes- may undergo massive haemorrhagic
enchymal lesions follow the WHO histo- Clinical features necrosis and cyst formation leaving only
logical classification of soft tissue GISTs present a spectrum from clinically a narrow rim of peripheral viable tissue;
tumours {2086}. benign, small to medium-sized tumours, malignant tumours may form complex
to frank sarcomas. According to our esti- cystic masses. Multinodular peritoneal
Terminology mate, approximately 30% of GISTs are seeding is typical of malignant GISTs.
The designation GIST was originally intro- clinically malignant, and a substantial
duced as a neutral term for tumours that number of patients with apparent radical Histopathology
were neither leiomyomas nor schwanno- surgery will relapse {1344, 462}. Typical Typically GISTs are immunohistochemi-
mas. The term GIST is now used for a of the malignant GISTs at all locations is cally positive for KIT tyrosine kinase
specific group of tumours comprising the intra-abdominal spread as multiple receptor (stem cell factor receptor),
majority of all gastrointestinal mesenchy- tumour nodules, and distant metastases which is perhaps their single best defin-
mal tumours. These tumours encompass most commonly to liver followed by lung ing feature {920, 713, 1665, 1762}.
most gastric and intestinal mesenchymal and bone in decreasing frequency The c-kit positivity of GISTs parallels that
tumours earlier designated as leiomyoma, {478A, 1984, 1855}. Vague abdominal seen in the interstitial cells of Cajal, the
cellular leiomyoma, leiomyoblastoma and discomfort is the usual complaint in pacemaker cells regulating autonomic
leiomyosarcoma {80, 76, 78, 79, 1227}. symptomatic tumours. Both benign and motor activity {1139, 1654}. Based on
Currently, the terms leiomyoma and sarcomatous GISTs that project into the this, and on the expression of an embry-
leiomyosarcoma are reserved for those lumen may ulcerate and be a source of onic form of smooth muscle myosin
tumours that show smooth muscle differ- bleeding {80, 78, 79}. heavy chain in GISTs and Cajal cells
entiation, histologically or by immunohis- {1648} the origin from Cajal cells has
tochemistry, e.g. with strong and diffuse Macroscopy been proposed {920, 1762}. However,
actin and desmin positivity. Most tumours Small gastric GISTs appear as serosal, considering the origin of Cajal cells and
historically called leiomyosarcoma {31, submucosal or intramural nodules that smooth muscle from a common precur-
1559, 1750} are now classified as GISTs; are usually incidental findings during sor cell {1035, 2186}, the hybrid Cajal
hence the old literature on gastric (and abdominal surgery or endoscopy. Some cell and smooth muscle differentiation
intestinal) leiomyosarcomas largely tumours may ulcerate, especially the seen in many GISTs, and the occurrence
reflects GISTs. epithelioid stromal tumours. The larger of GISTs in the omentum and mesentery
tumours protrude intraluminally or to the {1225}, their origin from such a precursor
Epidemiology serosal side, and may have a massive cell pool with differentiation towards a
GIST accounts for 2.2% of malignant gas- extragastric component that masks the Cajal cell phenotype is more likely.
tric tumours in SEER data. There is no gen- gastric origin. Intraluminal tumours are Electron microscopic observations show-
der preference (M:F, 1.1:1), in contrast to often lined by intact mucosa, but ulcera- ing hybrid autonomic nerve and smooth
carcinomas which have a M:F of 2:1 muscle features in many GISTs are also
{1928}. Adults between the 6th and 8th consistent with origin from a multipoten-
decade are primarily affected. The ratio of tial precursor cell {474, 1227}.
the age-adjusted incidence rates for Morphology. GISTs may resemble
Blacks and Whites is greater for sarcomas smooth muscle tumours histologically as
(3 to 1) than for carcinomas (2 to 1). Black well as grossly. The majority of gastric
women are affected six times more fre- GISTs are spindle cell tumours that show
quently than white women (0.6 versus 0.1 a variety of histological patterns {1866}.
per 100,000 per year, analogous to the Some, including many of the smaller
ratio for uterine leiomyosarcomas) {1584}. ones, are collagen-rich and paucicellular.
A perinuclear vacuolization pattern is
Localization common. Tumours with moderate cellu-
GISTs occur at every level of the tubular Fig. 3.43 Cajal cells immunoexpress KIT antigen larity and focal nuclear palisading can
gastrointestinal tract and additionally (CD117) in fetal small intestine. resemble nerve sheath tumours. Peri-
A B
Fig. 3.45 Gastrointestinal stromal tumour. A Ulceration is present at the summit of the lesion. B Cut surface showing transmural extension.
Mesenchymal tumours 63
03 19.7.2006 7:41 Page 64
Fig. 3.47 Examples of mutations of the exon 11 of the c-kit gene in gastrointestinal stromal tumours. A Nucleotide sequence of the c-kit gene. B Predicted amino
acid sequences of the mutant KIT. The top line in each figure represents the germline I and the wild type KIT protein, respectively. Each line below them re-pres-
ents one case. The codons are indicated by numbers. The shaded areas correspond to deletions (black) or point mutations (gray). Courtesy of Dr. J. Lasota,
Washington D.C.
phorylation) of the tyrosine kinase and pulmonary chondroma, gastric epithe- sarcomas varied considerably, e.g. 49%
further the phosphorylation cascade that lioid GIST and paraganglioma in the 5-year survival for males versus 74% for
leads into mitogenic activation {928, 713, Carney triad has probably a common yet females; 37% for Blacks versus 66% for
1310, 1356}. The most common muta- unknown genetic link {246}. Whites {1928}.
tions appear to be in-frame deletions of
3-21 base pairs, followed by point muta- Prognosis and predictive factors Other mesenchymal tumours
tions and occasionally described inser- The prognosis of GISTs is largely Gastrointestinal autonomic nerve tumour
tions {475, 713, 1018, 1289}. Association dependent on the mitotic rate, size, (GANT)
of neurofibromatosis type I has been depth of invasion, and presence or Gastrointestinal autonomic nerve tumour
described in rare cases; these tumours absence of metastasis {462}. Although (GANT), or the previous designation plex-
represent phenotypical GISTs, but race and gender did not play a role in osarcoma, has been applied to mes-
molecular genetic studies are not avail- survival rates in the SEER data for gastric enchymal tumours that have shown ultra-
able {1681A}. The rare combination of carcinomas, the 5-year survival rates for structural features of autonomic neurons:
A B
Fig. 3.48 Malignant gastrointestinal stromal tumours. A Tumour cells form perivascular collars surrounded by necrosis. B Numerous mitotic figures are present.
Fig. 3.49 Glomus tumour. Uniform tumour cells and Fig. 3.50 Gastric schwannoma including part of the Fig. 3.51 Gastric lipoma.
dilated thin-walled blood vessels. lymphoid cuff.
cell processes with neurosecretory type ly in the gastric antrum as small intramu- active. Schwannomas are positive for
dense core granules and arrays of micro- ral masses (1-4 cm in diameter, average S100-protein and negative for desmin,
tubules {702, 701, 1023, 2038}. Histologi- 2 cm). They occur in older adults (mean actin and KIT.
cally, such tumours have shown a variety 6th decade) with equal sex incidence
of spindle cell and epithelioid patterns {77}. One-third manifests as ulcer, Lipoma
similar to those seen in GISTs; at least one-third as bleeding, and one-third is Lipomas composed of mature adipose
some of these tumours are positive for asymptomatic. The lesions are often sur- tissue may be observed in the stomach.
KIT. It therefore appears that GANT and rounded by hyperplastic smooth muscle They typically protrude into the lumen.
GIST groups overlap, and may even and have sheets of rounded or epithe-
merge. Because electron microscopy is lioid cells with sharp cell borders outlined Granular cell tumour
currently applied less widely for tumour by well-defined basement membranes Lesions similar to those in peripheral soft
diagnosis than before, GAN-type differen- demonstrable by PAS-stain or immunos- tissues are occasionally encountered in
tiation in gastrointestinal tumours is prob- taining for basement membrane proteins the stomach, where they principally
ably underestimated. Correlative light such as laminin and collagen type IV. occur as small submucous nodules and
microscopic, ultrastructural, immuno- The tumour cells have small, uniform less commonly as intramural or sub-
histochemical and molecular genetic nuclei and mitotic activity is virtually serous masses. These lesions occur pre-
studies are needed to resolve the ques- absent. The tumour cells are positive for dominantly in middle age, and show a
tion of the relationship of GANT and GIST. smooth muscle actin and negative for strong predilection for Blacks. Associa-
keratins. Multiple glomus tumours with ted gastric ulcer symptoms are common.
Leiomyoma and leiomyosarcoma apparent intravascular spread have See chapter on mesenchymal tumours of
Well-documented true gastric leiomy- been described {666}. the oesophagus for pathological features
omas and leiomyosarcomas are so infre- {862}.
quent that there is no significant data on Schwannomas
demographic, clinical or gross features. These lesions are rare in the gastroin-
Leiomyomas are composed of bland testinal tract, but the stomach is their
spindle cells showing low or moderate most common site within the digestive
cellularity and slight if any mitotic activity. system. They are not associated with
There may be focal nuclear atypia. The neurofibromatosis types I or II and occur
cells have eosinophilic, fibrillary, often predominantly in older adults (average
clumped cytoplasm. Leiomyosarcomas 58 years in the largest series). They
are tumours that show histologically and grossly and clinically resemble GISTs.
immunohistochemically evident smooth Schwannomas are usually covered by
muscle differentiation. They usually pres- intact mucosa and principally involve the
ent in older age and are typically of high- muscularis propria. The tumours vary
grade malignancy. As defined here, from 0.5-7 cm (mean 3 cm) in diameter, Fig. 3.52 Kaposi sarcoma of the stomach.
leiomyomas and leiomyosarcomas are and are spherical or ovoid, occasionally
typically globally positive for desmin and showing a plexiform multinodular pattern.
smooth muscle actin, and are negative Histologically, gastrointestinal schwanno- Kaposi sarcoma
for CD34 and CD117 (KIT). Tumours with mas usually show a spindle cell pattern Kaposi sarcoma may occur in the stom-
mitotic counts exceeding 10 mitoses per like cellular schwannoma with vague ach as a mucosal lesion or, less com-
10 high power fields are classed as high- nuclear palisading. The tumours often monly, as a mural mass, usually in HIV-
grade. have sprinkled lymphocytes and a nodu- positive patients.
lar lymphoid cuff {366, 1666}. The dis-
Glomus tumours tinction between schwannoma and GIST
Lesions similar to glomus tumours of is important because the former is
peripheral soft tissue occur predominant- benign even when large and mitotically
Mesenchymal tumours 65
03 19.7.2006 7:41 Page 66
C. Niederau
Secondary tumours of the stomach L.H. Sobin
Definition
Tumours of the stomach that originate
from an extra-gastric neoplasm or which
are discontinuous with a primary tumour
elsewhere in the stomach.
Incidence
Metastatic disease involving the stomach
is unusual. An autopsy study from the
USA found 17 metastases to the stomach
in 1010 autopsies of cancer patients, giv- Fig. 3.53 Multiple gastric metastases from rhab- Fig. 3.54 Metastatic lobular carcinoma of the
ing a frequency of 1.7% {1220}. In a large domyosarcoma of the spermatic cord in a 15-year breast. Typical single file growth pattern.
series of autopsies from Malmö (Table old boy.
3.02), 92 gastric metastases were found
in 7165 patients (1.28%) who had cancer
at the time of death {130}. metastases are described as volcano- in 10 of 747 (1.3%) of patients with lung
like ulcers {618; 1108}. On endoscopy, cancer (see Table 4.01) {1220}. Several
Clinical features pigmentation may not be evident in some studies have shown lung, breast, other
Gastrointestinal symptoms may occur in melanomas {1069}. In patients with meta- gastrointestinal carcinomas, and mela-
up to 50% of patients with gastric metas- static lobular breast carcinoma the endo- noma to be the most frequent primary
tases. Bleeding and abdominal pain are scopic appearance may be that of linitis lesions {1220, 158, 873, 618}. Less fre-
the most common clinical features, fol- plastica. In such cases, conventional quently, cancers of the ovary, testis, liver,
lowed by vomiting and anorexia. Intesti- biopsies may be too superficial to colon, and parotid metastasize to the
nal and gastric metastases were found include diagnostic tissue in the submu- stomach {1220; 618; 1148; 1872}.
after a median interval of 6 years (range, cosa. Endosonography may help direct Of all the primary cancers that can lead
0.12-12.5 years) following the diagnosis attention to the deeper infiltrate {1097}. to gastric metastasis, breast cancer
of primary breast cancer {1700}. Gastric Gastric melanomas often appear as does so most frequently. Some reports
metastasis from a breast cancer has polypoid or target lesions on barium show that between 50% and 75% of
occurred up to 30 years after diagnosis X-ray studies {1718} and, less commonly, patients with breast cancer develop gas-
of the primary neoplasm {1148}. Occa- as a submucosal mass {1148}. tric metastases {1148; 455}. However, in
sionally, metastatic breast cancer in the a Dutch study covering a 15-year-period,
stomach is detected before the primary Origin there were only 27 patients with gastric
tumour is diagnosed. In a large Swedish autopsy series {130} , metastases from primary breast cancer
most gastric metastases were from pri- {1872}.
Imaging and endoscopy mary breast cancer, followed by mela- There is no preferential localization of
An upper gastrointestinal endoscopy noma and lung cancer (Table 3.02). metastases to subsites in the stomach.
study identified 14 metastatic tumours in There were gastric metastases in 25 of Cancers at any site can produce gastric
the upper gastrointestinal tract, 13 of 695 (3.6%) patients with breast cancer, metastases through haematogeneous
which were in the stomach {873}. Many whereas gastric metastases were found spread. Lesions of the pancreas, oeso-
Table 3.02
Metastases to the stomach, small intestine, colon and appendix. Data are from 16,294 autopsies {130}.
Site of metastasis No. of cases with metastasis % of all autopsies Most frequent primary cancer Next most frequent primary cancer
CHAPTER 4
_____________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
The non-peritonealized perimuscular tissue is, for jejunum and ileum, part of the mesentery and, for duodenum in areas where serosa is lacking, part of the retroperitoneum.
Definition ileal conduits {1965} and in ileal reser- are the commonest presentations {2123}.
A malignant epithelial tumour of the small voirs, both continent abdominal (Kock) Some tumours are largely asymptomatic
intestine. Neoplasms of the periam- {347} and pelvic {2013, 1730}. The and may be discovered by endoscopy
pullary region include those of the duo- occurrence of adenocarcinomas in {1809}.
denal mucosa, ampulla of Vater, common Meckel’s diverticulum {985} and in small
bile duct and pancreatic ducts. bowel duplications {496} has been Imaging
reported. The radiological methods that have the
ICD-O codes highest diagnostic accuracy are spiral
Adenocarcinoma 8140/3 Localization CT scan with contrast medium and ente-
Mucinous adenocarcinoma 8480/3 The duodenum is the main site, contain- roclysis; the two methods can be com-
Signet-ring cell carcinoma 8490/3 ing more adenocarcinomas than the plementary. With enteroclysis, a filling
jejunum and ileum combined {1928}. In defect, an irregular and circumscribed
Epidemiology the duodenum, carcinomas are most thickening of the folds with wall rigidity,
Relative to the length and surface area of common around the ampulla of Vater slowed motility, eccentric passage of the
the small intestine, adenocarcinomas of {1657, 2123}, possibly due to biliary or contrast medium, or a clear stenosis may
the duodenum, jejunum and ileum are pancreatic effluents. be observed {199}. Small bowel adeno-
remarkably rare. Data from the United carcinoma may appear on CT scan as an
States SEER program {1928} for 1973 to Clinical features annular lesion, a discrete nodular mass,
1987 show an age-adjusted incidence Symptoms and signs or an ulcerative lesion. CT scan, with
rate for adenocarcinoma of the small The symptoms of small bowel adenocar- global vision of the abdomen, can con-
intestine of 0.4 per 100,000 per year. cinoma are related to the size and loca- tribute to staging the tumour {1145}.
Although some reports suggest an tion of the tumour. With push enteroscopy, it is possible to
increasing incidence of adenocarcinoma In the jejunum and ileum, early symp- visualize endoscopically the entire
of the small intestine {1339, 1715}, this is toms are often non-specific, with vague jejunum. Expansion or infiltrative growth
not reflected in the SEER data base. The periumbilical abdominal pain and rum- of the tumour causes at a relatively early
median age at manifestation is approxi- bling. Later, cramp-like pain is present in phase, an alteration of the endoluminal
mately 67 years for non-mucinous ade- up to 80% of cases, and this may be surface; via push enteroscopy it is thus
nocarcinoma, mucinous carcinoma and accompanied by nausea, vomiting, possible to identify small lesions and to
carcinoids. weight loss, asthenia, and intermittent take biopsies. Push enteroscopy is also a
obstructive episodes. Massive bleeding good diagnostic method to diagnose
Aetiology is rare (8%), but an important clinical tumours causing occult bleeding {1495,
A major factor in the development of finding is chronic bleeding with second- 1619}.
small bowel adenocarcinoma is chronic ary iron-deficiency anaemia, which may Exploration of the ampulla of Vater
inflammation. In particular, long-standing be found in the early stages of develop- requires a lateral viewing fibroscope,
Crohn’s disease with multiple strictures is ment of the tumour. Other clinical signs adapted to tissue sampling and endo-
associated with small bowel carcinoma are bloating of the loops of the bowel, scopic sphincterotomy. The terminal
{1016, 1223, 582, 1578}. One study meteorism, and the presence of a palpa- ileum may be visualized through retro-
showed that individuals with Crohn’s dis- ble mass {20}. Perforation is a possible grade ileoscopy during colonoscopy.
ease have an 86-fold increased risk of complication of small intestinal carcino- Sonde enteroscopy can identify tumours
adenocarcinoma of the small intestine mas {681}. throughout the small bowel, but it is ham-
{623}. Coeliac disease is another well Duodenal carcinomas present in a differ- pered by the inability to take biopsies
recognized aetiological factor for small ent manner, because of the larger cir- {1064}.
bowel carcinoma {116, 1354, 2141}. cumference of the duodenum compared
There is some epidemiological evidence with the more distal parts of the small Macroscopy
that cigarette use and alcohol consump- intestine, and because of the relative The macroscopic pathology of small
tion are also risk factors {1339}. accessibility of the duodenum to endo- bowel carcinomas is determined by a
Carcinoma can develop in ileostomies in scopy {498, 1657}. Unlike jejunal and number of factors, of which stage and site
patients with ulcerative colitis or familial ileal carcinomas, carcinomas of the duo- are the most significant. Many carcinomas
adenomatous polyposis (FAP) subse- denum, especially those of the proximal of the jejunum and ileum are detected at
quent to colonic metaplasia and intraepi- duodenum, do not present with bowel an advanced stage {498, 189}. A further
thelial neoplasia in the ileostomy mucosa obstruction. Biliary obstruction, frank or determinant of the macroscopic features
{1599, 558}. Carcinoma can also arise in occult blood loss and abdominal pain is the presence or absence of predispos-
A B
Fig. 4.03 Adenocarcinoma. A Well differentiated, invasive. B Poorly differentiated, infiltrating fat.
Histologically, adenomas in the small after colectomy for FAP), Peutz-Jeghers an increased incidence of gastric and
intestine are similar to those in the colon, syndrome and juvenile polyposis. The colonic carcinomas in first-degree rela-
but with a propensity to be more villous highest risk is in FAP. Duodenal adeno- tives {1830}. Primary small bowel carci-
or tubulovillous in architecture {2127A, mas develop in a high proportion of FAP noma can be the presenting neoplasm in
1342}. The adenomatous cells resemble patients {228}, and the relative risk of hereditary non-polyposis colorectal can-
those of colonic adenomas, with varying duodenal carcinoma is over 300 times cer (HNPCC), occurring at an earlier age
degrees of dysplasia, but the columnar that of the normal population {1397}; than sporadic cases and carrying a bet-
cells are unequivocally enterocytic in these carcinomas represent a major ter prognosis {1604, 125}.
nature; goblet cells are frequent and cause of death in FAP patients after total
some lesions have Paneth and endocrine colectomy. Genetics
cells {500, 1237}. In FAP, carcinomas are usually associat- Patients with HNPCC and germline muta-
ed with a macroscopically definable ade- tions of hMSH2 or hMLH1 have an
Other associated conditions nomatous component and are usually approximately 4% lifetime risk of small
Juvenile polyposis and Peutz-Jeghers accompanied by many other adenomas bowel cancer, which exceeds the risk of
syndrome have a recognized association in the second and third parts of the duo- the normal population 100 fold {2005}. In
with small intestinal carcinoma {1830, denum {1808, 204}. Adenomas do occur Peutz-Jeghers syndrome, the most com-
1604, 1506}. elsewhere in the small bowel in FAP, mon site of polyps is in the small intes-
including the ileum and the pelvic ileal tine, and 2-3% of patients are at risk for
Genetic susceptibility reservoir {1376}, but carcinomas are dis- developing intestinal carcinoma {431,
These include: familial adenomatous tinctly unusual. 721}. In juvenile polyposis, small intestin-
polyposis (FAP), hereditary non-polypo- It has been proposed that patients with al polyps occur with less frequency, but
sis colorectal cancer (HNPCC), Crohn’s carcinoma of the small intestine have an duodenal carcinoma has been reported
disease, coeliac disease, ileostomies, increased incidence of multicentric car- {749}. Genes mutated in the germline of
ileal conduits and pouches (especially cinomas of the gastrointestinal tract, with patients with inherited syndromes that
A B
Fig. 4.04 Mucinous adenocarcinoma of the ileum arising in a patient with Crohn’s disease. A Large mucin filled lakes. B More mucin than neoplastic epithelium.
Carcinoma 73
04 19.7.2006 7:45 Page 74
predispose to small bowel neoplasia in some of these tumours {14}. (56%) and lower than for colon (87%)
(APC, hMSH2, hMLH1, LKB1, and In one study of Crohn-associated small and rectum (79%). This relation is reflect-
Smad4) may therefore play a role in the bowel cancers, 43% had KRAS muta- ed in survival figures for all stages.
genesis of these tumours. tions, 57% had p53 overexpression, 33% Another recent population-based study
Studying the genetics of small bowel had 17p loss, 17% had 5q loss, none had from Sweden showed 5- and 10-year sur-
adenocarcinomas has been difficult due 18q loss, 1 had microsatellite instability, vival rates for small intestinal adenocarci-
to the rarity of these tumours {1715}. and none had TGF beta-RII mutations noma of 39% and 37% for duodenal
There is evidence supporting a multistep {1562}. These findings were similar to tumours and 46-41% for jejuno-ileal
pathway of carcinogenesis similar to that those seen in sporadic small bowel carci- tumours {2201}. The survival of patients
described for colorectal carcinomas noma, and indicate that the transforma- undergoing curative resection is 63%
{2018}. The incidence of KRAS mutation tion from intraepithelial neoplasia to carci- when regional lymph nodes are not
is 14-52% {83, 2185, 14}, p53 overex- noma may occur in a similar fashion. involved, and 52% when there are nodal
pression 40-67%, 17p loss 38-67%, and metastases {2011}. Long-term survival is
18q loss 18-30% {14, 1562}. One report Prognosis and predictive factors associated with well differentiated
found no 5q loss {1562} while another In SEER data, the overall 5-year survival tumours and local invasion only {1888,
found the frequency to be 60% {14}. for adenocarcinoma of the small bowel 1336}.
15-45% of small bowel tumours have was 28%, and for mucinous adenocarci- One study found a significant inverse
high levels of microsatellite instability noma 22% {1928}. 5-year survival for association between immunoreactivity for
{14, 1562, 705}, and mutations in the localized adenocarcinomas (63%) was c-neu and survival in duodenal adeno-
TGF beta-RII gene have been identified higher than for gastric adenocarcinoma carcinoma {2208}.
Definition Incidence
Peutz-Jeghers syndrome (PJS) is an As the condition is rare, well documented
inherited cancer syndrome with autoso- data on the incidence are not available.
mal dominant trait, characterized by Based on numbers of families registered
mucocutaneous melanin pigmentation in the Finnish Polyposis Registry, the inci-
and hamartomatous intestinal polyposis, dence of PJS is roughly one tenth of that
preferentially affecting the small intes- of familial adenomatous polyposis.
tine. Associated extra-intestinal neo-
plasms are less common and include Diagnostic criteria
tumours of the ovary, uterine cervix, The following criteria are recommended:
testis, pancreas and breast. (1) three or more histologically confirmed Fig. 4.05 Peutz-Jeghers syndrome. Pigmentation of
Peutz-Jeghers polyps, or (2) any number lips, peri-oral skin, tongue and fingers.
MIM No. 175200 of Peutz-Jeghers polyps with a family his-
tory of PJS, or (3) characteristic, promi-
Synonyms and historical annotation nent, mucocutaneous pigmentation with the emphasis on the prominence of the
The syndrome was first described by a family history of PJS, or (4) any number pigmentation.
Peutz {1512} and Jeghers {850}. Several of Peutz-Jeghers polyps and character-
designations have been used synony- istic, prominent, mucocutaneous pig- Intestinal neoplasms
mously, including Peutz-Jeghers polypo- mentation. Penetrance appears to be high, and both
sis, periorificial lentiginosis, and polyps- Some melanin pigmentation is often sexes are equally affected {691}. Polyps
and-spots syndrome. present in unaffected individuals, hence are most common in the small intestine,
A B
Fig. 4.06 Peutz-Jeghers polyp of the colon. Arbor- Fig. 4.07 A A lobulated pedunculated Peutz-Jeghers polyp of the small intestine. B This small intestinal
izing smooth muscle separating colonic glands into Peutz-Jeghers polyp exhibits haemorraghic infarction due to intussusception.
lobules (Masson trichrome stain).
but may occur anywhere in the gastroin- smooth muscle that shows tree-like cancers {579, 154}, the question of
testinal tract. branching. This is covered by the whether or not the Peutz-Jeghers polyp
mucosa native to the region, heaped into is itself precancerous has proved difficult
Signs and symptoms folds producing a villous pattern. Diag- to resolve. Epithelial misplacement has
These include abdominal pain, intestinal nostic difficulty occurs when there is sec- apparently been overdiagnosed as can-
bleeding, anaemia, and intussusception. ondary ischaemic necrosis. This compli- cer in the past {1728}, but it is likely that
Typical age at clinical manifestation is cation arises when a polyp has caused the increased risk of malignancy in the
from two to twenty years. Characteristic intussusception, a common form of pres- stomach, small bowel and colon {154,
pigmentation allows diagnosis of asymp- entation. Some polyps may lack diagnos- 1807} is due to malignant progression
tomatic patients in familial cases. tic features. from hamartoma to adenocarcinoma.
Epithelial misplacement involving all lay- The evidence is threefold: (1) intraepithe-
Imaging ers of the bowel wall (pseudoinvasion) lial neoplasia (dysplasia), though uncom-
The presence of polyps may be demon- has been described in up to 10% of mon, has been described in Peutz-
strated by upper gastrointestinal and small intestinal Peutz-Jeghers polyps Jeghers polyps {1506, 2017}; (2) carci-
small bowel contrast radiography, and by {1728}. Mechanical forces associated nomas may occur in contiguity with
air contrast barium enema. Periodic with intussusception or raised intralumi- Peutz-Jeghers polyps {317, 1506}; (3)
small bowel X-ray examination at two to nal pressure due to episodic intestinal the responsible gene LKB1 (STK11) is
five-year intervals is advisable in the fol- obstruction are the likely explanation for located on chromosome 19p, and loss of
low-up of the affected patients. this observation. Epithelial misplacement heterozygosity at this locus has been
Endoscopy is superior to radiological may be florid and extend into the serosa, demonstrated in the majority of Peutz-
imaging in that it enables polypectomy thereby mimicking a well differentiated Jeghers polyps and associated intestinal
for diagnostic and therapeutic purposes. adenocarcinoma. Useful diagnostic fea- cancers {633, 691, 2052}.
Upper gastrointestinal tract endoscopy tures are the lack of cytological atypia,
and colonoscopy every two years with presence of all the normal cell types, Extraintestinal manifestations
snare excision of all polyps detected is mucinous cysts and haemosiderin depo- Predisposition to cancer of multiple
presently recommended. Small bowel sition {1728}. organ systems is an important feature of
polyps may be reached by an entero- the syndrome {579, 154}. The most well
scope but rarely for the full bowel length; Dysplasia and cancer in Peutz-Jeghers documented extra-intestinal neoplasms
thus, imaging remains an integral com- polyps include sex cord tumours with annular
ponent of clinical management. While the Peutz-Jeghers syndrome is tubules (SCTAT) of the ovary {2188}, ade-
associated with a 10 to 18-fold excess of noma malignum of the uterine cervix
Macroscopy gastrointestinal and non-gastrointestinal {2188}, Sertoli cell tumours of the testis
Peutz-Jeghers polyps occur within the
stomach, small and large intestines, and
rarely within oesophagus, nasopharynx
and urinary tract. The small intestine is
the site of predilection. The polyps are
lobulated with a darkened head and
closely resemble adenomas. The stalk is
short and broad or absent. Size is typi-
cally 5 to 50 mm.
Histopathology
A typical Peutz-Jeghers polyp has a A B
diagnostically useful central core of Fig. 4.08 Peutz-Jeghers polyps. A Small intestine. B Colon.
Peutz-Jeghers syndrome 75
04 19.7.2006 7:45 Page 76
A B
Fig. 4.09 Peutz-Jeghers polyp of small intestine. Pseudoinvasion characterized by benign mucinous cysts Fig. 4.10 Peutz-Jeghers polyp of small intestine.
extending through bowel wall into mesentery. Patient was well ten years after removal. Pseudoinvasion. Islands of mucosa are separated
by smooth muscle.
{231, 2118}, carcinoma of the pancreas 2072}. Sequence alignments revealed cAMP-dependent protein kinase (PKA)
{579}, and carcinoma of the breast that these proteins are most conserved {325}. Although the function of LKB1
{1587, 1952}. within the kinase domain, with 96% of remains to be determined, it is worth not-
The cutaneous melanin pigmentation identity between human and mouse and ing that PAR-4, the C.elegans orthologue
occurs typically around the mouth as 42% identity between human and the of LKB1, is required for establishing
freckle-like spots. Other sites commonly nematode. Human LKB1 contains a polarity during the first cell cycles of the
affected are digits, palms and feet, buc- nuclear localization signal (NLS) flanking embryo {2072}. PAR-4 expression is also
cal mucosa, and anal region. While dra- the N-terminus part of the catalytic essential for embryonic viability and for
matic pigmentation is a helpful sign, it domain {1343, 1768} and a putative intestinal organogenesis. Since the car-
may fade with time, and some affected prenylation motif within the C-terminus dinal clinical feature of PJS is the pres-
individuals never display pigmentation. {325}. The LKB1 gene product is located ence of intestinal hamartomatous polyps,
both in the nucleus and in the cytoplasm it appears plausible that the function of
Genetics {1343}. LKB1 displays an autocatalytic LKB1 has been conserved across evolu-
Chromosomal location and mode of activity in vitro, and is the substrate of the tion as it exerts a key regulatory role dur-
inheritance ing intestinal development.
PJS is an autosomal dominant trait with
nearly complete penetrance. The PJS Gene mutations and their relationship to
gene, LKB1 (STK11), maps to 19p13.3, clinical manifestations
and there is some evidence suggestive Germline mutations are usually truncat-
of locus heterogeneity {1210}. ing, but missense type mutations have
also been described {853, 690}. Wild
Gene structure type LKB1 is capable of autophosphory-
LKB1 consists of 9 coding exons. The lation {1210, 2176}, and the effect of mis-
open reading frame consists of 1302 sense mutations occurring in the kinase
base pairs, corresponding to 433 amino domain can be evaluated observing this
acids. Codons 50 to 337 encode the cat- property in autophosphorylation assays.
alytic kinase domain of the gene. Somatic mutations of LKB1 in tumours
have been reported but are rare.
Gene product
The human LKB1 gene is ubiquitously Prognosis
expressed in adults {853, 690}. It While intussusception has been a major
encodes a protein of 433 amino acids source of mortality in PJS kindreds
which possesses a serine/threonine {2093} surgery constitutes an effective
kinase domain framed by a short N-ter- treatment. Thus, prognosis of the affect-
minus sequence (48 residues) and a ed individuals is mainly related to the risk
more extended C-terminus region of 122 of malignancy in PJS {579, 154}. Due to
amino acids {853, 690}. LKB1 shares a the rarity of the syndrome, there is little
significant sequence similarity with the information on prognosis, but one report
Saccharomyces cerevisiae SNF1 kinase suggests that PJS-associated cancers
which phosphorylates transcriptional are particularly aggressive {1807}.
repressor and regulates glucose-
repressible genes. Homologs of LKB1
have been identified in several species Fig. 4.11 Structure of the LKB1 gene. Germline
including mouse, Xenopus, and mutations in Peutz-Jeghers patients are most fre-
Caenorhabditis elegans {1852, 1768, quent in the kinase domain.
C. Capella
Endocrine tumours of the small intestine E. Solcia
L.H. Sobin
R. Arnold
Definition An extensive review of all cases record- and a long standing chronic inflammato-
Endocrine tumours of the small intestine ed in the Zollinger-Ellison Syndrome ry process {233}.
exhibit site-related differences, depend- (ZES) registry showed 13% of patients to
ing on their location in the duodenum have duodenal wall gastrinomas, while Localization
and proximal jejunum or in the distal the majority of patients had a pancreatic In a series of duodenal endocrine
jejunum and ileum. They include carci- tumour {726}. More recent studies have tumours {208}, 43 lesions were located in
noid tumours (well differentiated neo- shown a higher proportion of duodenal the first part, 41 in the second part, 2 in
plasms of the diffuse endocrine system), tumours (38-50%), possibly related to the third part, and 2 in the fourth part.
small cell carcinomas (poorly differentiat- improved diagnostic tools {429, 2076}. Nonfunctioning G-cell tumours are locat-
ed endocrine neoplasms) identical to ed in the duodenal bulb, while the site of
small cell carcinomas of the lung and Age and sex distribution about 1/3 gastrinomas associated with
malignant large cell neuroendocrine car- In a series of 99 cases of endocrine overt ZES is in the first, second or third
cinomas. The classification used here is tumours of the duodenum, males were part of the duodenum or in the upper
adapted from the WHO histological clas- more frequently affected (M/F ratio: jejunum {1780}. The preferential location
sification of endocrine tumours {1784}. 1.5:1), with a mean age at manifestation of somatostatin-cell tumours, gangliocyt-
of 59 years (range, 33 to 90 years) {208}. ic paragangliomas and small cell carci-
ICD-O Codes G-cell tumours associated with overt ZES nomas is at, or very close to, the ampulla
Carcinoid 8240/3 (gastrinomas) differ from their apparently of Vater {206, 210, 233, 1149, 1780,
Gastrin cell tumour 8153/1 nonfunctioning counterpart in arising ear- 1870, 2196}.
Somatostatin cell tumour 8156/1 lier in life (mean age at diagnosis is 39
EC-cell, serotonin-producing years, as opposed to 66 years) {1780}. Clinical features
neoplasm 8241/3 Somatostatin-cell tumours affect females Endocrine tumours of the duodenum
L-cell, glucagon-like peptide slightly more frequently than males produce symptoms either by virtue of
and PP/PYY producing tumour (1.2:1) and become clinically manifest at local infiltration causing obstructive jaun-
Gangliocytic paraganglioma 8683/0 a mean age of 45 years (range 29 to 83 dice, pancreatitis, haemorrhage, and
Small cell carcinoma 8041/3 years) {1780}. Gangliocytic paragan- intestinal obstruction (nonfunctioning
gliomas are slightly more common in tumours) or, less frequently, by secreted
males than in females and affect patients peptide hormones (functioning tumours).
Endocrine tumours of the duode- ranging in age from 23 to 83 years, with The prevalent position of somatostatin-
num and proximal jejunum an average of 54 years {210}. The few cell tumours, gangliocytic paraganglio-
cases of small cell carcinoma recorded in mas, and small cell carcinomas in the
Epidemiology the literature were in males ranging in ampullary region explains their frequent
Incidence and time trends age from 51 to 76 years. association with obstructive biliary dis-
Endocrine tumours of the duodenum ease. About 20% of the tumours, espe-
were rare in some older series, accoun- Aetiology cially those located in the duodenal bulb,
ting for 1.8-2.9% of gastrointestinal Apart from genetic susceptibility (see are asymptomatic and often incidentally
endocrine tumours {587, 2016}. However, below), there is little knowledge about discovered, e.g. by imaging analysis,
in recent histopathology series, duodenal possible aetiological factors involved in endoscopy or pathological examination
tumours amount to 22% of all gastroin- the pathogenesis of duodenal and proxi- of gastrectomy and duodenopancreate-
testinal endocrine neoplasms {1780}. mal jejunal endocrine tumours. An isolat- ctomy specimens removed for gastric
Jejunal tumours account for about 1% ed report demonstrates that a sporadic and pancreatic cancers.
{587, 1780} of all gut endocrine tumours. gastrin-cell tumour of the duodenum orig- Zollinger-Ellison Syndrome (ZES) with
Gastrin-cell (G-cell) tumours represent inated from hyperplastic and differentiat- hypergastrinaemia, gastrin hypersecre-
the largest group (62%) in reported ed G-cells located in the mucosal crypts tion, and refractory peptic ulcer disease,
series of endocrine tumours arising in {1114}. A case of a small multifocal is the only syndrome of endocrine hyper-
the upper small intestine, followed by somatostatin-cell tumour of the proximal function consistently observed in associ-
somatostatin-cell tumours (21%), gan- duodenum has been reported in a patient ation with endocrine tumours of the duo-
gliocytic paragangliomas (9%), unde- with celiac sprue, showing somatostatin- denum and upper jejunum {208, 429,
fined tumours (5.6%) and PP-cell cell hyperplasia in the mucosa, suggest- 726, 1780, 2076}. The association with
tumours (1.8%) {1780}. ing a relationship between D-cell growth ZES is found in about 15% of duodenal
Endocrine tumours 77
04 19.7.2006 7:46 Page 78
Endocrine tumours 79
04 19.7.2006 7:46 Page 80
A B
Fig. 4.15 Gangliocytic paraganglioma. A Immunoreactivity for cytokeratin (CAM 5.2) in epithelial cells. B Immunoreactivity for S100 in spindle cells.
cases of jejunal gastrinomas {233} and Small cell carcinomas show histological Aetiology
in 25% of 103 cases of duodenal signs of high-grade malignancy (high At present, there is little knowledge about
tumours with ZES, 24% of which also mitotic rate, tumour necrosis, deep mural the aetiology of jejuno-ileal EC-cell carci-
had MEN-1 syndrome {724}. Local invasion, angioinvasion, and neuroinva- noids. Although endocrine tumours of
lymph node metastases seem to have lit- sion). Metastases are present in all cases lower jejunum and ileum are not general-
tle influence on survival of patients with {2196} and patients die usually within ly associated with preneoplastic lesions,
ZES {398, 2076}. In a study focusing on 7-17 months of diagnosis. there have been reports of focal micro-
metastatic rate and survival in patients proliferations of EC-cells in cases of mul-
with ZES, no difference was found in the tiple ileal tumours {1736} and of intraep-
frequency of metastases to lymph nodes ithelial endocrine cell hyperplasia in the
{429}, when comparing primary pancre- Endocrine tumours of the mucosa adjacent to jejuno-ileal carci-
atic (48%) and duodenal (49%) tumours. distal jejunum and ileum noids {1291}.
In contrast, the same study found a sig- Approximately 15% of carcinoid tumours
nificantly higher frequency of metas- Endocrine tumours of this segment of the of the small intestine are associated with
tases to the liver in patients with pancre- small intestine are mainly EC-cell, sero- non-carcinoid neoplasms, most frequent-
atic gastrinomas than in patients with tonin-producing carcinoids, and, less fre- ly adenocarcinomas of the gastrointesti-
duodenal gastrinomas (52% vs. 5%). quently, L-cell, glucagon-like peptide nal tract {1251, 1253}, supporting the
The 10-year survival rate of patients with and PP/PYY-producing tumours. hypothesis that secretion of growth fac-
duodenal gastrinomas (59%) is signifi- tors is involved in their aetiopathogenesis
cantly better than for patients with pan- Epidemiology {1251}.
creatic gastrinomas (9%) {2076}. The Incidence and time trends
more favourable prognosis of duodenal Endocrine tumours of the lower jejunum Localization
tumours is mainly linked to their smaller and ileum have an incidence of 0.28-0.89 In the AFIP series of 167 jejuno-ileal
size and less frequent association with per 100,000 population per year {60, endocrine tumours {211}, 70% were
liver metastases. 587}. Jejuno-ileal lesions account for located in the ileum, 11% in the jejunum,
Somatostatin cell tumours are often 23–28% of all gastrointestinal endocrine 3% in Meckel diverticulum. These data
malignant, despite their rather bland his- tumours, making this site the second suggest that small bowel endocrine
tological appearance {1780, 210, 381}. most frequent location for endocrine tumours occur 6.5 times more frequently
Malignant somatostatin cell tumours are tumours, following the appendix {587, in the ileum than in the jejunum. The
* 2 cm in diameter {381}, invade the duo- 2016}. A recent SEER analysis of 5468 majority of the tumours are located in the
denal muscularis propria, the sphincter cases found an increase in the proportion distal ileum near the ileocaecal valve.
of Oddi, and/or the head of the pancreas, of ileal and jejunal carcinoids and
and can metastasise to paraduodenal decrease in the proportion of appen- Clinical features
lymph nodes and liver. diceal carcinoids {60}. Patients with jejuno-ileal endocrine
Gangliocytic paragangliomas are usually tumours present most commonly with
benign, in contrast to gastrin and Age and sex distribution intermittent crampy abdominal pain, sug-
somatostatin cell tumours that arise in the Endocrine tumours of lower jejunum and gestive of intermittent intestinal obstruc-
same area. However, occasional large ileum are distributed more or less equal- tion {1253}. Patients frequently have
tumours (size > 2 cm) may spread to ly between males and females. Patients vague abdominal symptoms for several
local lymph nodes, mainly attributable to range in age from the third to the tenth years before diagnosis, reflecting the
the endocrine component of the lesion decade, with a peak in the 6th and 7th slow growth rate of these neoplasms
{197, 783}. decades {211, 587, 1253, 1780}. {1253}. Preoperative diagnosis is difficult
Macroscopy
Jejuno-ileal endocrine tumours are multi-
ple (ranging from 2 to 100 tumours) in
about 25-30% of cases {211, 1253,
1845}. The size of the tumours is < 1 cm
in 13% and * 2 cm in 47% of cases {211}.
They usually appear as deep mucosal-
submucosal nodules with apparently
intact or slightly eroded overlying Fig. 4.16 Multiple carcinoids of the ileum with mesenteric lymph node metastases.
mucosa. Deep infiltration of the muscular
wall and peritoneum is frequent.
Extensive involvement of the mesentery type A structure {1780}. In areas of deep tumours {655}, electron microscopic
stimulates considerable fibroblastic or invasion with abundant desmoplastic examination of serotonin-immunoreactive
desmoplastic reaction, with consequent reaction, the cell nests may be oriented tumours (particularly those failing to
angulation, kinking of the bowel and into cords and files. Mesenteric arteries react with histochemical tests) can con-
obstruction of the lumen. Infarction of the and veins located near the tumour, or firm their EC-cell nature by detecting
involved loop of the small intestine may away from it, may be thickened and their characteristic pleomorphic, intensely
occur as a consequence of fibrous adhe- lumen narrowed or even occluded by a osmiophilic granules {1778}.
sions, volvulus, or occlusion of the peculiar elastic sclerosis, which may Substance P and other tachykinins, such
mesenteric blood vessels. lead to ischaemic lesions in the intestine as neurokinin A, are reliable markers of a
{72}. Most tumour cells are intensely fraction of jejuno-ileal EC-cell tumours
Microscopy argyrophilic and reactive with chromo- {144, 1173}; foregut (gastric, pancreatic
EC-cell, serotonin-producing carcinoids granin A and B antibodies. In about 30% and duodenal) EC-cell tumours remain
are formed by characteristic rounded of cases, a variable number of cells is mostly unreactive {1780}. Minor popula-
nests of closely packed tumour cells, also reactive for prostatic acid phos- tions of enkephalin, somatostatin, gastrin,
often with peripheral palisading (Type A) phatase {211}. ACTH, motilin, neurotensin, glucagon/gli-
{1775}. Often, within the solid nests, The identification of tumour cells as EC- centin, and PP/PYY immunoreactive cells,
rosette type, glandular-like structures are cells can be accomplished using histo- unassociated with pertinent hyperfunc-
detected. This variant of the fundamental chemical methods for serotonin, includ- tional signs, have been reported in some
structure designated as mixed insular + ing argentaffin, diazonium, and immuno- ileal and jejunal tumours mostly com-
glandular (A + C) structure seems prog- histochemical tests. Because serotonin posed of EC-cells {1173, 2168}.
nostically more favourable than the pure occurs in some non EC-cell and related Dopamine and norepinephrine have also
A B C
Fig. 4.17 EC-cell carcinoid. A Typical mixed insular-acinar structure. B Positive Grimelius silver reaction. C Immunoexpression of TGFα.
Endocrine tumours 81
04 19.7.2006 7:46 Page 82
been detected in addition to serotonin in this tumour suppressor gene is not impli- Prognosis and predictive factors
a type A (insular) argentaffin carcinoid of cated in the pathogenesis of these A recent report revealed a 21% mortality
the ileum {588}. In many cases of jejuno- tumours {1780, 2044, 2077}. rate for jejuno-ileal carcinoids, compared
ileal EC-cell tumours, however, no other Several growth factors and related with 4% for duodenal, 6% for gastric, and
hormones apart from serotonin and sub- receptors have been localised in tumour 3% for rectal carcinoids {211}. In two stud-
stance P or related tachykinins are cells of EC-cell carcinoids, including ies, the overall 5-year survival rate of
detected {1173}. transforming growth factor-α (TGFα) and patients with jejuno-ileal endocrine
The main criteria for considering a epidermal growth factor (EGF)-receptor, tumours was about 60% and the 10-year
jejuno-ileal carcinoid to have an aggres- insulin-like growth factor-1 (IGF-1), and survival rate was 43% {211, 1845}. In
sive potential are deep invasion of the IGF-1 receptors, platelet-derived growth patients with no liver metastases, the
wall (muscularis propria or beyond) factor (PDGF), transforming growth fac- 5- and 10-year survival rates were 72%
and/or presence of metastases. tor-β (TGFβ), basic fibroblast growth fac- and 60%, respectively, as opposed to
According to these criteria, in the large tor (bFGF), acidic fibroblast growth factor 35% and 15% for patients with liver
AFIP series {211}, 141 of 159 cases (aFGF), and fibroblast growth factor metastases {1845}, demonstrating the rel-
(89%) of jejuno-ileal carcinoids were con- receptor-4 (FGFR4) {22, 284, 993, 995, atively slow rate of growth of some EC-cell
sidered aggressive. 1291}. tumours. Metastases are generally con-
Some of these growth factors, such as fined to regional lymph nodes and liver.
Genetic susceptibility TGFα, exert a proliferative effect reflected Extra-abdominal metastases were found
Unlike gastric ECL-cell tumours and duo- by an increased mitotic index and signifi- in only 0.5% of the cases reported by
denal gastrin cell tumours, jejuno-ileal cantly increased DNA levels in primary Moertel et al. {1253}. In one study, univari-
carcinoids are only occasionally associ- cell cultures of midgut carcinoids. These ate analysis showed that survival was
ated with MEN-1 {1444}. Rare examples findings suggest the involvement of an negatively correlated with distant metas-
of familial occurrence of ileal EC-cell car- autocrine loop {22}. A similar growth pro- tases at the time of surgery, mitotic rate,
cinoids have been reported {1252A}. moting role in midgut carcinoid tumour tumour multiplicity, the presence of carci-
cells is assigned to IGF-1 {22}. PDGF, noid syndrome, depth of intestinal wall
Genetics TGFα, bFGF, and aFGF seem to be main- invasion, and female gender; by multivari-
A recent study {829} reported frequent ly involved in tumour stromal reaction, ate analysis, survival was negatively asso-
(78%) LOH on chromosome 11q13 in including stromal desmoplasia {22, 993, ciated with distant metastases, carcinoid
sporadic carcinoids of both foregut (lung 995}, by acting on receptors expressed syndrome, and female gender {211}.
and thymic) and midgut/hindgut (intes- on fibro-blasts or stimulating the promo- In summary, jejuno-ileal carcinoid
tinal, including EC-cell tumours, and rec- tion of new vasculature and tumour pro- tumours that are clinically nonfunctioning,
tosigmoidal) origin. Other studies, how- gression {22, 993, 995}. 1 cm or less in diameter, confined to the
ever, have shown retention of heterozy- Neural adhesion molecule (NCAM), a mucosa/submucosa and non-angioinva-
gosity on 11q13 in sporadic carcinoids of member of the immunoglobulin super- sive, are generally cured by complete
midgut and hindgut origin {394, 1938}, family of cell adhesion molecules, is local excision. Invasion beyond submu-
suggesting that LOH of the MEN-1 gene, highly expressed in midgut carcinoid cosa or metastatic spread indicates that
unlike gastric and duodenal endocrine tumours {22}. the lesion is aggressive. If the lesion,
tumours, is not involved in the pathogen- Because NCAM has not been shown in although confined to the mucosa/submu-
esis of EC-cell tumours. normal gut endocrine cells, the novel cosa, shows angioinvasion, or is over
Accumulation of p53 has not been expression of this adhesion molecule in 1 cm in size, it is of uncertain malignant
detected in EC-cell tumours examined carcinoids may be of importance for potential.
immunohistochemically, suggesting that growth and metastases.
R.D. Gascoyne
B-cell lymphoma of the small intestine H.K. Müller-Hermelink
A. Chott
A. Wotherspoon
B-cell lymphoma 83
04 19.7.2006 7:46 Page 84
Histopathology
MALT lymphoma
The majority of intestinal lymphomas
involving the small bowel are B-cell lym-
phomas of MALT type, including both
low-grade and aggressive types {792,
793, 796}. These so-called ‘Western’
types are distinct from IPSID and αHCD.
The histological features of Western type
small intestinal lymphoma are similar to Fig. 4.18 High-grade B-cell lymphoma of the small intestine.
gastric MALT lymphoma, except that
lymphoepithelial lesions are less promi-
nent {792}. phoma characterized by the synthesis of characteristic features of MALT lym-
In contrast to gastric MALT lymphomas, α heavy chain. The histology is charac- phoma are now evident, and follicular
diffuse large B-cell lymphomas arising in teristic of MALT lymphoma with marked colonization may be so marked as to
the small bowel are much commoner plasma cell differentiation. mimic follicular lymphoma. Stage C is
than low-grade B-cell lymphomas of Three stages of IPSID are recognized. In characterized by the presence of large
MALT-type {796}. Some of these lym- stage A, the lymphoplasmacytic infiltrate masses and transformation to frank large
phomas may have a low-grade MALT is confined to the mucosa and mesen- cell lymphoma. Numerous centroblasts
component, providing evidence that their teric lymph nodes, and cytological atyp- and immunoblasts are present. Plasma-
histogenesis is related to the mucosal ia is not present. Although the infiltrate cytic differentiation is still evident, but
immune system. Precise criteria for may obliterate the villous architecture, marked cytological atypia is usually
defining a MALT lymphoma of large cell endoscopic examination appears nor- found, including Reed-Sternberg-like
type are lacking, as are the criteria for mal. Resection specimens reveal reac- cells. Mitotic activity is increased.
distinguishing transformation within a tive lymphoid follicles, lymphoepithelial Mesenteric lymph node involvement
low-grade MALT lymphoma {383}. When lesions and small clusters of parafollicu- occurs early in the course of disease,
both histologies are evident, the lesion is lar clear cells. This phase of the disease with both plasma cell infiltration of nodal
best described as composite. When is typically responsive to antibiotic thera- sinuses and marginal-zone areas dis-
small foci of large transformed cells or py. In stage B, nodular mucosal infiltrates tended by small atypical lymphoma cells
early sheeting-out of large cells are develop and there is extension below the with moderate amounts of pale, clear
detected within a background of low- muscularis mucosae. A minimal degree cytoplasm.
grade intestinal MALT lymphoma, their of cytological atypia is apparent. This Immunohistochemical studies demon-
presence should be noted. Currently, the stage appears to represent a transitional strate the production of α heavy chain
prognostic impact of these findings and phase, can be seen macroscopically as without light chain synthesis {798}. The
their effect on treatment are undeter- thickening of mucosal folds, and is typi- IgA is almost always of the IgA1 type,
mined. Diffuse large B-cell lymphomas cally not reversible with antibiotics. The with intact carboxy-terminal regions and
arising in the small bowel that lack a
background of low-grade MALT lym-
phoma are currently best classified as
extranodal diffuse large B-cell lym-
phoma, not otherwise specified {670}.
IPSID / αHCD
Immunoproliferative small intestinal dis-
ease and α heavy chain disease are part
of a spectrum of lymphoproliferative dis-
eases prevailing in the Middle East and
Mediterranean countries {792}. They are A B
subtypes of small intestinal MALT lym- Fig. 4.19 Malignant lymphomatous polyposis. A Typical polypoid mucosa. B Polypoid mantle cell lymphoma.
deletion of most of the V and all of the spleen, bone marrow and peripheral
CH1 domains. The molecular characteri- blood involvement {84}.
zation of individual cases is variable. The
small lymphoma cells express CD19 and Burkitt lymphoma
CD20, but fail to express CD5, CD10 and Burkitt lymphoma occurs in two major
CD23. forms, defined as endemic and spo-
radic. Endemic Burkitt is found primarily
Mantle cell lymphoma in Africa and typically presents in the jaw,
Mantle cell lymphoma (MCL) typically orbit or paraspinal region, and is strong-
involves both spleen and intestines and ly associated with Epstein-Barr virus
may present as an isolated mass or as (EBV). A
multiple polyps throughout the gastroin- In other endemic regions however, it is
testinal tract where it is referred to as relatively common for Burkitt lymphoma
multiple lymphomatous polyposis {424, to present in the small intestine, usually
791, 1292}. Importantly, other histologi- involving the ileum, with preferential
cal subtypes of non-Hodgkin lymphoma localization to the ileocaecal region
can also produce this clinico-pathologi- {792}. In parts of the Middle East, pri-
cal entity. mary gastrointestinal Burkitt lymphoma is
The polyps range in size from 0.5 cm to a common disease of children. Sporadic
2 cm with much larger polyps found in or non-endemic Burkitt lymphoma is a
the ileocaecal region. The histology of rare disease, not associated with EBV
MCL involving the small bowel is identi- infection, that frequently presents as pri- B
cal to MCL at nodal sites {110}. The mary intestinal lymphoma. Burkitt lym- Fig. 4.20 Burkitt lymphoma. A Large ileocecal
architecture is most frequently diffuse, phoma is also seen in the setting of HIV mass. B Starry-sky effect due to phagocytic histio-
but a nodular pattern and a less com- infection when it often involves the gas- cytes.
mon true mantle-zone pattern are also trointestinal tract {236}.
observed. Reactive germinal centers The histology in all cases is identical and
may be found and are usually com- is characterized by a diffuse infiltrate of an unusual finding for lymphomas,
pressed by the surrounding lymphoma medium-sized cells with round to oval whereby the cytoplasmic borders of indi-
cells, thereby appearing as replacing nuclear outlines, 2-5 small but distinct vidual cells ‘square-off’ against each
the normal mantle zones. Intestinal nucleoli and a small amount of intensely other.
glands may be destroyed by the lym- basophilic cytoplasm. Numerous mitotic Burkitt lymphoma may rarely demon-
phoma, but typical lymphoepithelial figures and apoptotic cells are present. strate a true follicular architecture, con-
lesions are not seen. The low power The prominent starry-sky appearance is sistent with the proposed germinal cen-
appearance is monotonous with frequent caused by benign phagocytic histiocytes ter histogenesis of this neoplasm. It is a
epithelioid histiocytes, mitotic figures engulfing the nuclear debris resulting mature B-cell lymphoma and the neo-
and fine sclerosis surrounding small from apoptosis. Thin sections often show plastic cells express pan-B-cell antigens
blood vessels. The lymphoma cells are
small to medium sized with irregular
nuclear outlines, indistinct nucleoli and
scant amounts of cytoplasm. Large
transformed cells are typically not pres-
ent. The lymphoma cells are mature
B-cells and express both CD19 and
CD20. Characteristically the cells co-
express CD5 and CD43. Surface
immunoglobulin is found including both
IgM and IgD. Light chain restriction is
present in most cases, with some studies
demonstrating a predominance of lamb-
da. CD10 and CD11c are virtually always
negative. Bcl-1 (cyclin D1) is found in vir-
tually all cases and can be demonstrat-
ed within the nuclei of the neoplastic
lymphocytes in paraffin sections.
MCL is an aggressive lymphoma, which
typically presents in advanced stage
with involvement of mesenteric lymph
nodes and spread beyond the abdomen,
including peripheral lymph nodes, Fig. 4.21 Follicular lymphoma of terminal ileum.
B-cell lymphoma 85
04 19.7.2006 7:46 Page 86
CD19, CD20, CD22, and CD79a. In Genetics Burkitt lymphoma, the chromosome 8
approximately 60-80% of cases, the neo- MALT lymphoma breakpoints are usually far 5’ of the
plastic cells co-express CD10, but fail to Cytogenetic and molecular features of c-myc gene, while their chromosome 14
express CD5 or CD23. Surface immuno- intestinal MALT lymphomas are incom- breakpoints most often occur in the loca-
globulin expression is moderately pletely understood; the presence of either tion of the IgH gene joining segments.
intense and is nearly always IgM with t(1;14)(p22;q32) or t(11;18)(q21;q21) and The variable chromosome 8 breakpoints
either kappa or lambda light chain the corresponding molecular abnormali- and their location far from the c-myc cod-
restriction. The growth fraction, as ties, rearrangement of bcl-10 or AP12- ing sequences make it impossible in
assessed by Ki-67 or the paraffin equiva- MLT, have not been described at this site; most cases to demonstrate c-myc
lent MIB-1, is typically in excess of 90% thus their relationship to gastric MALT rearrangements by Southern blot analy-
of tumour cells. Burkitt lymphoma cells lymphomas is unclear {2116, 412}. sis. In contrast, sporadic cases frequent-
uniformly fail to express bcl-2. Trisomy 3 is common in gastric MALT ly have c-myc breakpoints within non-
lymphomas, but the frequency of this coding introns and exons of the gene
Burkitt-like lymphoma cytogenetic abnormality in primary intes- itself, typically in the first exon or intron,
This group of atypical Burkitt lymphomas tinal lymphomas is unknown {413}. or in the 5’ flanking regions of the gene.
appears to represent a morphological In most of these cases, c-myc rearrange-
overlap between Burkitt lymphoma and IPSID ments can be demonstrated using
diffuse large B-cell lymphoma. The over- Although cytogenetic abnormalities have Southern analysis {670}.
all cell size is similar to Burkitt, but with been detected in IPSID, no consistent
greater pleomorphism {827}. These changes have been described. Southern Burkitt-like lymphoma/
cases lack the typical monomorphic blot analysis reveals clonal immunoglob- Atypical Burkitt lymphoma
appearance of Burkitt lymphoma and ulin heavy-chain (IgH) gene rearrange- This category is cytogenetically hetero-
demonstrate slight variation in both cell ments, but consensus IgH polymerase geneous and may contain three or more
size and shape. The cells may have mul- chain reaction (PCR) strategies may biological groups {1387}. Importantly, the
tiple nucleoli as in Burkitt lymphoma or a yield false negative results. frequency of variant c-myc translocations
single distinct nucleolus. A starry-sky precludes the accurate recognition of
pattern may be evident and the mitotic Mantle cell lymphoma cases using molecular techniques alone.
rate is usually significantly increased. MCL is cytogenetically characterized by
These lymphomas have a predilection a t(11;14)(q13;q32) translocation which Prognostic factors
for the gastrointestinal tract of adults, deregulates expression of the bcl-1 onco- The main determinants of clinical out-
and also occur in the setting of HIV infec- gene on chromosome 11. Rearrange- come in small intestinal lymphomas are
tion. ment can be detected using Southern histological grade, stage, and resectabil-
blot analysis, PCR or fluorescent in situ ity {424}. Advanced age at diagnosis, an
Other B-cell lymphomas hybridization (FISH). acute presentation with perforation, and
Any subtype of B-cell lymphoma can the presence of multifocal tumours have
present as a primary small intestinal lym- Burkitt lymphoma an adverse impact on survival. The
phoma, including those thought to arise Burkitt lymphoma demonstrates a con- behaviour of diffuse large B-cell lym-
from peripheral lymph node equivalents. sistent cytogenetic abnormality in all phoma is not affected by the presence of
De novo diffuse large B-cell lymphomas cases, with rearrangement of the c-myc a low-grade MALT component {424}. The
are the commonest lymphomas in the oncogene on chromosome 8. The char- expression of bcl-2 protein and the pres-
small bowel, and may develop from low- acteristic translocation, t(8;14)(q24;q32), ence of TP53 mutations may adversely
grade MALT lymphomas. is seen in most cases; the remainder affect outcome in this group, but a sys-
Indolent lymphomas such as small lym- shows variant translocations including tematic study of small intestinal lym-
phocytic lymphoma, lymphoplasmacytic the immunoglobulin light chain loci, phomas is lacking {567, 770}.
lymphoma and follicular lymphoma (cen- t(2;8)(p12;q24) or t(8;22)(q24;q11), invol- MCL is an aggressive neoplasm. A blas-
troblastic/centrocytic) can present as pri- ving kappa and lambda light chain toid cytology, increased mitotic index
mary small intestinal disease. The latter genes, respectively. In the classical and peripheral blood involvement are
subtype can occasionally produce the t(8;14), the c-myc oncogene is translo- recognized as adverse factors {84}.
clinico-pathological entity of multiple cated from chromosome 8 to the heavy Mutations in the p53 gene and homozy-
lymphomatous polyposis, but can usual- chain locus on chromosome 14. In the gous deletions of p16 have recently been
ly be distinguished from MCL by immu- variant translocations, a part of the light shown to be associated with poor prog-
nophenotypic and molecular genetic chain constant region is translocated to nosis {1099, 700}. Burkitt-like lymphomas
analysis {1034}. chromosome 8, distal to the c-myc gene. with ‘dual translocation’ of both bcl-2 and
Lymphoblastic lymphoma may underlie Thus, in the variant translocations, c-myc c-myc oncogenes have a markedly
small intestinal lymphoma and frequently remains on chromosome 8 and is dereg- shortened overall survival {1137}.
produces a mass in the ileocaecal ulated by virtue of its juxtaposition to the
region. Characteristic nuclear features immunoglobulin light chain genes. The
and the expression of terminal molecular characteristics of the c-myc
nucleotidyl transferase may aid in estab- translocation also differ between endem-
lishing the diagnosis. ic and sporadic cases. In endemic
R.D. Gascoyne
Intestinal T-cell lymphoma H.K. Müller-Hermelink
A. Chott
A. Wotherspoon
Definition elsewhere in the small intestine and, shows multiple circumferential ulcers,
A peripheral T-cell lymphoma arising in rarely, in the stomach and colon {305}. ulcerated plaques and strictures, without
the intestine, usually as a complication of the formation of large tumour masses
coeliac disease (gluten sensitive entero- Clinical features {424}. The intact mucosa between the
pathy), histologically characterised by The most frequent symptoms are abdom- lesions may contain thickened folds or
differentiation towards the intestinal inal pain and weight loss {303}. About appear completely normal. Loops of
intraepithelial T-cell phenotype. 40% of patients present as acute abdom- bowel may adhere to each other or addi-
inal emergencies due to intestinal perfo- tionally to the left or right colon, causing
ICD-O codes ration and/or obstruction {305, 424}. palpable conglomerate tumours.
T-cell lymphoma 9702/3 Patients may have a short history of mal-
Enteropathy associated 9717/3 absorption, sometimes diagnosed as Tumour spread and staging
adult coeliac disease which is usually About 70% of the patients present with
Epidemiology and aetiology gluten-insensitive or, less frequently, a localized intestinal disease with or with-
Intestinal T-cell lymphoma (ITL) is rare, long history of coeliac disease lasting for out contiguous lymph node involvement
accounting for only about 5% of all gas- years or even decades {796}. {305}. Disseminated disease involves
trointestinal lymphomas, and is normally Signs and symptoms of the disease may liver, spleen, lung, testes, and skin, but
associated with coeliac disease {305}. mimic inflammatory bowel disease (IBD), rarely the bone marrow {303, 794}.
There is marked geographic variation in particularly Crohn disease. Radiographic
the incidence of ITL, with a high inci- studies may be helpful, but they are often Histopathology
dence in Northern Europe, reflecting the interpreted as consistent with a segmen- The histological appearances of ITL are
notion that ITL arises against the same tal or diffuse inflammatory process. variable both between cases and
genetic background as that predispos- Except for leukocytosis, laboratory data between different tumour sites in the
ing to coeliac disease {753}. are usually unremarkable, including nor- same patient. The most frequently
There is no clear sex predominance and mal levels of lactate dehydrogenase encountered type is composed of highly
in Europe, the median age at diagnosis is {303}. pleomorphic, medium to large cells, fol-
around 60 years {305, 424, 374}. In con- Refractory coeliac disease and ulcera- lowed by a lymphoma type that shows a
trast, a small series of Mexican patients tive jejunitis are two conditions that fre- morphology most consistent with ana-
had a median age of 24 years and there quently have a history of coeliac disease plastic large cell lymphoma. The border
was circumstantial evidence for a possi- for years, become resistant to gluten-free between these two histologies is not
ble aetiological role of the Epstein Barr diet and may, but not necessarily, sharp and transition from one to the other
virus, which is absent in European cases progress to ITL {1385, 92}. In ulcerative may occur, even within the same tumour
{1552, 795}. Congenital or acquired jejunitis, patients develop non-specific {307}.
immunodeficiency disorders are not inflammatory ulcers without overt histo- About 20% of ITL are characterized by
known to be associated with ITL. logical evidence of lymphoma. the monotonous appearance of densely
packed small to medium-sized cells
Localization Macroscopy almost without any recognizable stroma
The proximal jejunum is the most frequent The affected bowel segment is often components. Most of the rather
site of disease, although it may occur dilated and oedematous, and usually monomorphic cells contain only slightly
A B C
Fig. 4.22 Intestinal T-cell lymphoma. Histological features of the most common variants. A Pleomorphic medium and large cells. B Anaplastic large cells. C
Monomorphic small to medium cells.
T-cell lymphoma 87
04 19.7.2006 7:46 Page 88
irregular nuclei with small nucleoli and band-like or patchy microscopic lesions CD3+CD4-CD8-CD7+CD5- and co-
moderately wide, pale or sometimes entirely confined to the mucosa {303}. express the cytotoxic granule-associated
clear cytoplasm {307}. Rare variants of Fibrosis and admixed inflammatory cells protein TIA-1, often together with the acti-
ITL are composed predominantly of pleo- are constant features of the pleomorphic vation-dependent cytotoxic molecule
morphic small cells or immunoblasts. medium and large cell and the anaplas- granzyme B {305, 382}. Some correla-
Irrespective of morphology, the lym- tic large cell ITL types; in the former, an tions between ITL morphology and phe-
phoma cells often invade and destroy the abundance of eosinophils may mask the notype exist; pleomorphic medium and
overlying epithelium. Most frequently, the neoplastic infiltrate {1731}. In contrast, large cell lymphomas and lymphomas of
enterocytes of the upper and intermedi- the monomorphic small to medium-sized anaplastic large cell histology are often
ate villous regions, or in cases of severe variant characteristically lacks fibrotic CD4-CD8-, the latter express CD30+ but
villous atrophy, the epithelium of the changes and inflammatory background are always ALK1 negative; the monomor-
upper parts of the elongated crypts are {307}. phic small to medium-sized variant is fre-
the preferential targets of lymphoma cell quently associated with a CD56+CD8+
attack. These features are best appreci- Histopathology phenotype {307}.
ated at the borders of ulcerated tumours. of the enteropathic mucosa Cytologically normal IEL abundantly
However, they may also be present as In the vast majority of cases, the macro- present in the intact enteropathic
scopically normal intestinal mucosa mucosa in ITL, in ulcerative jejunitis, and
shows features of coeliac disease, i.e. in refractory coeliac disease share an
increase in normal appearing intraepithe- identical aberrant phenotype with ITL
lial lymphocytes (IEL), villous atrophy, and and are monoclonal, as demonstrated by
crypt hyperplasia {794}, which has PCR {103}. They therefore are consid-
prompted O’Farrelly and co-workers to ered a neoplastic population which, in
coin the term ‘enteropathy associated the absence of concurrent overt ITL, may
T-cell lymphoma’ {1383}. An increase in represent the first step in ITL lymphoma-
normal appearing IEL (duodenum / genesis (‘intraepithelial lymphoma’) and
jejunum, * 40/100 enterocytes; ileum, may have already persisted for years
* 20/100 enterocytes) represents the sin- {238}.
A gle most important feature suggestive of
coeliac disease {1172}. The severity of ITL diagnosis of endoscopic biopsies
these enteropathic changes is highly vari- Most cases of ITL are diagnosed on sur-
able and similar to coeliac disease; they gical resection specimens. In a minority
are most pronounced proximally and however, endoscopic biopsies, usually
improve distally so that the lower jejunum taken from the stomach, duodenum, or
and ileum may appear normal. Further- colon, are available. These patients fre-
more, enteropathy may be minimal or quently have a longer than 6 months his-
absent if the patient is on a gluten free tory of abdominal pain and weight loss.
diet, or if enteropathic sites are missed Some of them are clinically suspected to
B because of their patchy distribution. have inflammatory bowel disease, and
Occasionally, the non-neoplastic mucosa occasionally patients had already been
in ITL shows a strikingly intense or florid biopsied with the diagnosis of IBD or an
intraepithelial lymphocytosis {2142}. unclear inflammatory process, thus
emphasizing the challenging task of ITL
Immunological phenotyping diagnosis in endoscopic biopsies. The
Similarities of the immunophenotypes in immunohistochemical demonstration of
normal or activated (reactive) intraep- an aberrant phenotype is essential in
ithelial lymphocytes (IEL) and the tumour diagnosing ITL, especially in cases
cells in ITL provide an important part of which lack overt cytological atypia
evidence that ITL cells are the neoplastic and/or invasiveness. Furthermore, the
counterpart of IEL. The expression of the neoplastic infiltrate may be subtle or
HML-1 defined αEβ7 (CD103) on non- superficial and therefore easily over-
neoplastic IEL and in > 50% of ITL, but looked in routinely stained sections.
C not in resting peripheral blood T-cells,
Fig. 4.23 Coeliac disease. The non-neoplastic strongly supports this view {1802}. The Genetics
mucosa distant from an anaplastic large cell intes-
vast majority of normal IEL are resting Very few data on chromosomal abnor-
tinal T-cell lymphoma displays villous atrophy, crypt
hyperplasia (A) and an increase in cytologically
cytotoxic CD3+CD8+CD4-CD2+CD7+ malities in ITL exist. Deletion of the Y
unremarkable intraepithelial lymphocytes (B) with- CD5low TIA-1+ T-cells using the αβ T-cell chromosome and chromosome 9 abnor-
out evidence of lymphoma. Both the lymphoma receptor, but minor subsets such as malities were found among a phenotypi-
(ALCL) and the intraepithelial lymphocytes (IEL) CD4-CD8- or CD56+ are present as well cally aberrant intraepithelial T-cell popu-
share the same dominant T-cell clone (C) and the as predominantly CD4-CD8- γδ T-cells lation {2142}; a t(4;16)(q26;p13) translo-
same aberrant immunological phenotype. {1113, 304}. In ITL, most cases are cation was present in a mesenteric
T-cell lymphoma 89
04 19.7.2006 7:46 Page 90
C. Niederau
Secondary tumours of the L.H. Sobin
small and large intestines
Definition frequent primary sites (see Table 3.02) Primary melanomas of the intestine are
Tumours of the intestines that originate {130, 1022, 1378, 1209, 1457, 458}. very rare. Although most melanomas
from an extra-intestinal neoplasm or which Metastatic spread from primary lung found in the small bowel have no history
are discontinuous with a primary tumour cancer to the small intestine is more fre-
elsewhere in the gastrointestinal tract. quent than to stomach and colon (Table Table 4.01
4.01). Virtually all primary cancers can Frequency of metastasis from breast (695 cases)
Epidemiology occasionally lead to metastases in the and lung (747 cases) to gastrointestinal tract {130}.
Metastatic spread to the small intestine is small intestine and, because of the low
Primary Stomach Small Colon
more frequent than to any other site in the frequency of primary small bowel cancer,
site intestine
gastrointestinal tract (see Table 3.02). a high proportion of small intestinal
Secondary carcinomas of the small malignancies are metastatic.
bowel are as common as primary carci- The pathogenesis of intestinal metastasis Breast 3.6% 1.7% 1.4%
nomas at this site {1234}. usually involves haematogenous spread
of tumour cells. Invasion from neighbour-
Origin ing primary tumours also occurs, e.g. Lung 1.3% 4.4% 1.9%
For small intestine, melanoma, lung, pancreatic carcinoma to duodenum and
breast, colon and kidney are the most prostate carcinoma to rectum.
Metastasis
A B
Fig. 4.27 Metastatic adenocarcinoma, small intestine. A Tumour is beneath swollen mucosa. B Tumour in muscularis propria. Submucosa is oedematous.
A B
Fig. 4.28 A, B Metastatic malignant melanoma, small intestine.
Secondary tumours 91
04 19.7.2006 7:46 Page 92
Fig. 4.29 Metastatic adenocarcinoma, small intes- Fig. 4.30 Metastatic breast carcinoma, colon. Fig. 4.31 Metastatic breast carcinoma, caecum,
tine. Muscularis propria contains tumour. Mucosa Tumour cells expand submucosa. diastase-PAS stain. Many tumour cells are mucin
is free of neoplasia. positive.
of a primary tumour, the general consen- Macroscopy multiple primary small bowel carcinoids
sus is that they are virtually all secondary, Typical features of intestinal metastases and their metastases may not be possi-
usually from misdiagnosed or regressed include intestinal wall thickening, submu- ble. This also applies to leiomyosarco-
primary melanomas {458}. cosal spread, and ulcers. Melanomas mas/stromal tumours of the small intes-
may not be pigmented and may appear tine.
Clinical features as nodules or polyps.
Small intestinal metastases can cause Prognosis
bleeding and obstruction as well as non- Histopathology Intestinal metastases usually represent a
specific symptoms such as abdominal Metastases are typically submucosal or late stage of disease in which other
discomfort, gas distension, and diar- subserosal making the distinction haematogenous metastases are also fre-
rhoea {1378, 580}. between primary and secondary tumours quently found. Therefore, the prognosis
relatively easy. Cytokeratin immunohisto- is poor. Exceptions are melanoma and
Imaging chemistry may help to differentiate renal cancer in which metastases con-
The identification of a small bowel tumour between primary colon cancer (positive fined to the bowel may be associated
always raises the question of whether the for cytokeratin 20), metastases from with prolonged survival after resection.
tumour is primary or secondary. Contrast ovary and breast (usually positive for
radiography shows narrowing and cytokeratin 7) and those from liver, kidney
abnormalities of the small intestinal wall. and prostate (usually negative for both
Advanced cases result in stenosis with cytokeratins 7 and 20) {2047, 129}. On
distension due to obstruction. the other hand, the distinction between
CHAPTER 5
N.J. Carr
Adenocarcinoma of the appendix M.J. Arends
G.T. Deans
L.H. Sobin
Definition with abdominal distension. Rarely, exter- mucocoele, but this is descriptive not a
A malignant epithelial neoplasm of the nal fistulation occurs {251, 393, 707}. pathological diagnosis {250, 251}.
appendix with invasion beyond the mus-
cularis mucosae. Imaging Tumour spread and staging
Ultrasound, computerised tomography Although the TNM classification currently
ICD-O codes (CT) scan or barium enema are of limited uses the same criteria as for colorectal
Adenocarcinoma 8140/3 benefit in the pre-operative diagnosis of tumours, appendiceal cases should be
Mucinous adenocarcinoma 8480/3 cases presenting as acute appendicitis. separately classified. This is particularly
Signet-ring cell carcinoma 8490/3 Ultrasound and CT scan are the pre- important because of the special nature
ferred imaging procedures in cases pre- of pseudomyxoma peritonei, where
Epidemiology senting with abdominal mass or malignant cells may be scarce and acel-
Adenocarcinoma of the appendix occurs pseudomyxoma peritonei {393, 707}. lular mucin may seem to have spread fur-
in 0.1% of appendicectomies, corre- Serial CT scanning and CEA measure- ther than the malignant cells {250}.
sponding to an estimated incidence of ments can assess the extent of peri- Well differentiated mucinous appen-
0.2/100,000 per annum {393, 1928}. toneal involvement and the subsequent diceal adenocarcinomas generally grow
Adenocarcinomas accounted for 58% of course of the disease. Intraepithelial neo- slowly, and typically produce the clinical
malignant appendiceal tumours in the plasia of the appendix may occur con- picture of pseudomyxoma peritonei.
SEER database, the remainder being currently with a carcinoma elsewhere in Lymph node metastases tend to occur
mostly carcinoids. The rates for the car- the large intestine {393}. late. Rarely, tumour growth in the
cinomas stayed constant during the peri- retroperitoneum may produce ‘pseudo-
od 1973-1987 {1928}. The median age of Macroscopy myxoma retroperitonei’ {1194}. The
patients with mucinous and non-muci- In cases of primary adenocarcinoma, the behaviour of non-mucinous carcinomas
nous adenocarcinoma was about 65 appendix may be enlarged, deformed or resembles that of their colonic counter-
years in SEER data; other studies sug- completely destroyed {250, 251, 1612}. parts.
gest a peak age at manifestation in the Well differentiated lesions are often cys-
sixth decade {250, 393}. Males appear to tic and may be called cystadenocarcino- Pseudomyxoma peritonei
be more commonly affected than mas. A grossly appreciated swelling of Pseudomyxoma peritonei is the pres-
females {393}. the appendix due to the accumulation of ence of mucinous material on peritoneal
mucus within the lumen can be termed surfaces. It is not a complete histological
Aetiology
Patients with chronic ulcerative colitis
(UC) have an increased susceptibility to
formation of epithelial dysplasia and
malignancy in affected segments of
bowel; inflammatory involvement of the
appendix is seen in approximately half of
UC cases with pancolitis.
Both adenoma and adenocarcinoma of
the appendix have been described in
patients affected by long-standing ulcer-
ative colitis {1394}.
Clinical features
Signs and symptoms
Many patients with appendiceal adeno-
carcinoma have clinical features indistin-
guishable from acute appendicitis. Most
of the remaining cases present as an
abdominal mass {250, 393}. Spread to
the peritoneal cavity may produce large
volumes of mucus, causing pseudomyx-
oma peritonei. Such cases may present Fig. 5.01 Mucinous adenocarcinoma arising in a villous adenoma. The lumen is lined by a villous adenoma.
Adenocarcinoma 95
05 19.7.2006 7:53 Page 96
A B
Fig. 5.02 Appendiceal mucinous adenocarcinoma. Fig. 5.03 Pseudomyxoma peritonei. A Several loops of bowel are encased in a multilocular mucinous mass.
B Well differentiated mucus producing epithelium embedded in a fibrous matrix; mucus is present within the
lumen and is extravasated into the stroma.
diagnosis in itself; the prognosis will such cases are examples of well differen- mine the extent of invasion, because well
depend on the nature of the causative tiated adenocarcinoma. differentiated carcinomas of the appen-
lesion. Nevertheless, pseudomyxoma Although most cases of pseudomyxoma dix can mimic adenomas by invading on
peritonei is often applied to a distinctive peritonei are due to spread from a pri- a broad front rather than showing infiltra-
clinical picture produced by well differ- mary carcinoma of the appendix, cases tive or single-cell invasion. Conversely, in
entiated mucinous adenocarcinomas in have been reported in association with some adenomas, acellular mucin dis-
which the growth of malignant cells with- mucinous carcinomas of other sites, sects through the wall, mimicking inva-
in the peritoneal cavity causes a slow but including gallbladder, stomach, colorec- sion; this feature may be especially
relentless accumulation of mucin. Cells tum, pancreas, fallopian tube, urachus, prominent if there is inflammation. If there
may be very scanty within this mucinous lung, and breast {346, 612, 707, 981, is acellular mucin in the appendiceal
material. 1199, 2199}. wall, the diagnosis of adenoma should
A distinctive feature of well differentiated Although the ovary has been thought of only be made if the muscularis mucosae
mucinous carcinomatosis is its distribu- as a common primary site {104, 1705}, is intact since this term implies that the
tion in the abdomen. There is a tendency there is an accumulating body of evi- lesion is curable by complete excision.
to spare the peritoneal surfaces of the dence based on immunohistochemistry It is appropriate to use the term muci-
bowel, whereas large-volume disease is and molecular genetics suggesting that nous tumour of uncertain malignant
found in the greater omentum, beneath this is not the case, and that in most potential for neoplasms in which the his-
the right hemidiaphragm, in the right patients with low-grade mucinous tu- tological features do not allow distinction
retrohepatic space, at the ligament of mours of the ovary and appendix with between a lesion that is benign (an ade-
Treitz, in the left abdominal gutter and in pseudomyxoma peritonei the lesions are noma) from one that has the potential to
the pelvis {1854}. In these cases, tumour probably metastatic from an appendiceal cause metastases (an adenocarcinoma).
growth tends to remain confined to the primary {1536, 1611, 1612, 1871, 2187}. The term low-grade mucinous cystic
abdomen for many years. Mucinous tumour has also been used for lesions
cysts within the spleen occur occasional- Histopathology that are histologically not frankly malig-
ly {433}. The majority of appendiceal adenocarci- nant {2187A}.
It has been suggested that appendiceal nomas are well differentiated and muci-
adenomas can cause widespread pseu- nous {250, 706}. If signet-ring cells Grading
domyxoma peritonei with an ultimately account for more than 50% of the neo- Grading is the same as in the large intes-
fatal outcome, and some authors use the plasm, the term signet-ring cell carcino- tine. Some adenocarcinomas of the
term ‘adenomucinosis’ for the spread of ma is appropriate. appendix are so well differentiated that
such lesions through the abdomen {1611, The term mucinous cystadenocarcinoma their neoplastic features may be very
1612}. It is considered more likely that may be used for well differentiated muci- subtle {250}.
nous tumours with cystic structures. How-
ever, this designation is descriptive and
does not constitute a separate disease
entity {251, 2115}.
Diagnostic criteria
The fundamental criterion for making the
diagnosis of adenocarcinoma is the
presence of invasive neoplasm beyond
the muscularis mucosae; this is the same
criterion that is applied throughout the
large intestine (see Table 5.01). However,
Fig. 5.04 Pseudomyxoma peritonei. in practice it is not always easy to deter- Fig. 5.05 Mucocoele of appendix.
Fig. 5.06 Serrated adenoma of appendix. Fig. 5.07 Serrated adenoma (left) and tubulovillous Fig. 5.08 Adenoma with undulating morphology.
adenoma (right).
Precursor lesions and benign tumours adenocarcinoma as the presenting fea- polyp with villous adenomatous changes
By analogy with the rest of the large intes- ture {1464}. and focal carcinoma in situ {1243}.
tine, an adenoma-carcinoma sequence is
assumed to occur in the appendix; the Hereditary non-polyposis colorectal can- Genetics
finding of a residual adenoma in some cer (HNPCC) Limited data are available on molecular
cases of adenocarcinoma supports this This familial cancer syndrome confers genetic alterations in appendiceal
contention {1548}. However, some ade- increased susceptibility to proximal tumours, and these data indicate similar-
nocarcinomas appear to arise from gob- colon cancer {1936}, but it is not yet clear ities to those in colorectal tumours. KRAS
let cell carcinoid tumours {209, 250}. whether there is also an increased risk of mutations have been identified in
Compared to adenomas of the colon, appendiceal neoplasms. approximately 70% of appendiceal muci-
adenomas of the appendix are more like- nous adenomas, mostly in codon 12 and
ly to be villous or serrated {250, 706, Other polyposis syndromes a few in codon 13 {1871}. In addition,
1548, 2115, 2110}. It is difficult to establish accurately the KRAS mutation has been identified in an
Many appendiceal serrated and villous risk of genetic susceptibility to tumours of appendix cystadenoma associated with
adenomas display minimal cytological the appendix in Peutz-Jeghers and juve- a long history of ulcerative colitis {1123}.
abnormalities; such lesions need to be nile polyposis syndrome on account of Tumour suppressor gene allelic imbal-
distinguished from hyperplastic polyps or the rarity of these conditions. Intussus- ances have been found in about half of
mucosal hyperplasia. Pedunculated ception with an ‘inside-out’ appendix in appendiceal mucinous adenomas with
hyperplastic polyps of the type seen in Peutz-Jeghers syndrome has been loss of heterozygosity (LOH) at several
the colon are unusual in the appendix, reported, caused by a hamartomatous chromosomal loci, including 5q22, 6q,
but diffuse hyperplasia is relatively com- polyp of the appendix or an appendiceal 17p13, and 18q21. LOH was most fre-
mon {2184}. The diagnosis of hyperplas-
tic polyp/diffuse hyperplasia should not
be made if there are cytological abnor-
malities in the epithelial cells; if any are
present, then the diagnosis of adenoma
should be considered. The presence of
villous structures is also a pointer towards
adenoma.
As they grow, adenomas of the appendix
typically become cystic, and the lining
epithelium becomes undulating rather
than villous. Such lesions may produce a
mucocoele and be given the descriptive
appellation of cystadenoma.
Genetic susceptibility
Familial adenomatous polyposis coli
(FAP)
A review of 71 000 appendix specimens
revealed 33 benign and 6 malignant
appendiceal tumours in patients with
familial polyposis coli {324}. Several
cases of adenocarcinoma of the appen-
dix have been reported in FAP patients,
including a patient with appendiceal Fig. 5.09 Hyperplastic polyp of appendix. Cytological abnormalities of intraepithelial neoplasia are absent.
Adenocarcinoma 97
05 19.7.2006 7:53 Page 98
quent at the 5q locus linked to the APC high-grade, and nonmucinous histology evidence of invasion of underlying struc-
tumour suppressor gene which in the {345, 1365, 1769}. The spread of mucus tures have been found to be poor prog-
colorectum is strongly associated with beyond the right lower quadrant of the nostic factors, whereas complete exci-
transition to adenoma {1871}. In cases of abdomen (whether or not cells are iden- sion of tumour is associated with pro-
pseudomyxoma peritonei (well differenti- tified within it) is an independent prog- longed disease-free survival {346, 1612,
ated mucinous adenocarcinoma), LOH nostic variable, as is the presence of 612}.
at one or two polymorphic microsatellite neoplastic cells outside the visceral peri- Cytological examination of aspirated
loci was seen in approximately half of the toneum of the appendix {250}. When mucus and DNA flow cytometry are
cases and was considered an indication pseudomyxoma peritonei is present, unhelpful in predicting prognosis {612,
of monoclonality. abdominal distension, weight loss, high 707}.
histological grade, and morphological
Prognosis and predictive factors
SEER data showed the 5-year survival Table 5.01
rates for localized adenocarcinoma to be Terminology of epithelial neoplasms of the appendix.
95%, compared with a 5-year survival of
80% for mucinous or cystadenocarcino- Diagnosis Criteria Significance
ma. When distant metastases were pres-
ent, the 5-year survival rates were 0% Adenoma Tumour confined to appendiceal mucosa Does not have the capacitiy to
and 51% respectively {1928}. This (Cystadenoma) and metastasize and can be cured by
No histological evidence of invasion complete local excision.
reflects the low aggressive potential of
mucinous tumours that spread to the Adenocarcinoma Histological evidence of mural invasion Can spread beyond the appendix
peritoneum {1769}. (Cystadenocarcinoma) or with peritoneal, lymph node or dis-
Features that have been associated with Presence of metastases, tant metastases.
a poor prognosis in appendiceal adeno- including spread to peritoneal cavity
carcinoma include advanced stage,
C. Capella
Endocrine tumours of the appendix E. Solcia
L.H. Sobin
R. Arnold
Definition
Tumours with endocrine differentiation
arising in the appendix.
Epidemiology
Incidence and time trends
Carcinoids account for 50-77% of all
appendiceal neoplasms {1252, 1131}.
Their incidence rate is 0.075 new cases
per 100,000 population per year and
appears to have been decreasing in the
time period 1950-1991 {1251}. Approx-
imately 19% of all carcinoids are located
in the appendix.
Endocrine tumours 99
05 19.7.2006 7:53 Page 100
A B
Fig. 5.14 EC-cell carcinoid tumour. A Chromogranin B. B S-100 immunohistochemistry demonstrating sustentacular cells.
Fig. 5.15 L-cell tumour showing trabecular pattern Fig. 5.16 Clear cell carcinoid. Fig. 5.17 Tubular carcinoid.
and glicentin immunoexpression.
A B C
Fig. 5.18 Goblet cell carcinoid tumour. A Typical concentric mural distribution of tumour with preservation of the appendiceal lumen. Mucin positive tumour nests
(green) are seen in this Movat stain. Lumen is compressed, but intact. B Typical clusters of goblet cells. C Chromogranin A positive cells.
and the argyrophil reaction in 89% of Unlike colonic adenocarcinomas, KRAS Location of tumours at the base of the
cases {2059}. Useful criteria for diagnos- mutations have not been detected either appendix with involvement of the surgi-
ing this tumour are origin from the base in typical or in goblet-cell carcinoid of the cal margin or of the caecum is prognos-
of the crypts, integrity of the luminal appendix {1556}, while in the same tically unfavourable, requiring at least a
mucosa, orderly arrangements, and study, TP53 mutations (mainly G:C to A:T partial caecectomy to avoid residual
absence of cytological abnormalities and transitions) were detected in 25% of gob- tumour or subsequent recurrence {1931}.
mitoses. Immunohistochemically, tumour let-cell carcinoids. The reported frequency of metastases
cells are often positive for chromogranin from appendiceal carcinoids ranged
A, glucagon, serotonin, and IgA, while Prognosis and predictive factors from 1.4% and 8.8% in older series
they are unreactive for S100 protein {586, The majority of patients with endocrine {1252, 1927, 1254, 1780}, while in a more
209}. tumours of the appendix have a recent study the frequency of regional
Mixed carcinoid-adenocarcinoma. This favourable prognosis. Clinically non- metastases was 27%, and that of distant
term has been proposed to designate functioning, non-angioinvasive lesions metastases 8.5% {1251}.
carcinomas of the appendix that arise by confined to the appendiceal wall, and The 5-year survival of patients with
progression from a pre-existing goblet- < 2 cm in diameter are generally cured appendiceal carcinoid is 94% for local-
cell carcinoid. These carcinomas occur by complete local excision, whereas ized disease, 85% for regional disease,
in the apparent absence of neoplastic invasion of the mesoappendix or beyond and 34% for distant metastases {1251}.
change in the mucosal epithelium {209}. or metastatic spread indicates that the Goblet-cell carcinoids are more aggres-
lesion is aggressive. The most important sive than conventional carcinoids, but not
Genetics risk factors appear to be tumour size as malignant as adenocarcinomas of the
Loss of heterozygosity at MEN-1 gene > 2 cm and invasion of the mesoappen- appendix. In one study the percentage of
locus in sporadic appendiceal carci- dix {1134}. Lesions confined to the patients dead of goblet cell carcinoids
noids was reported {829}, but has not appendiceal wall that show angioinva- was 12.5% {442}. Tubular carcinoids, in
been confirmed in more recent studies sion or are > 2 cm in size, carry an uncer- contrast, are clinically benign {209}.
{394, 1938}. tain malignant potential.
N.J. Carr
Miscellaneous tumours of the appendix L.H. Sobin
C. Niederau
CHAPTER 6
Hungary
Australia
Japan
France
United States
Spain
Finland
Incidence
Brazil
Mortality
South America
0 10 20 30 40 50 60
Fig. 6.01 Worldwide annual incidence (per 100,000) of colon and rectum cancer Fig. 6.02 Male incidence (blue) and mortality (orange) of colorectal cancer in
in males. Numbers on the map indicate regional average values. some selected countries.
From: Globocan, IARC Press, Lyon. From: Globocan, IARC Press, Lyon.
Adenocarcinoma 105
6a 19.7.2006 8:02 Page 106
A B C
Fig. 6.05 Endoscopic features of (A) polypoid, (B) flat, slightly elevated and (C) flat adenoma.
Clinical features
Signs and symptoms
Some patients are asymptomatic, espe-
cially when their neoplasm is identified
by screening or surveillance. Haemato-
chezia and anaemia are common pre- A B
senting features due to bleeding from
the tumour. Many patients experience
change in bowel habit; in the right colon,
the fluid faeces can pass exophytic
masses, whereas in the left colon the
solid faeces are more often halted by
annular tumours so that constipation is
more common. There may be associated
abdominal distension. Rectosigmoid
lesions can produce tenesmus. Other
symptoms include fever, malaise, weight C D
loss, and abdominal pain. Some patients Fig. 6.06 A Endoscopic view of two small flat adenomas highlighted with indigo-carmine to show the abnor-
present with the complications of mal tubular pit pattern. B Magnifying video endoscopy of a tubulovillous adenoma highlighted with indigo-
obstruction or perforation. carmine to show cribriform pattern. C Histological section of a flat elevated tubular adenoma showing low-
grade intraepithelial neoplasia. D Stereomicroscopic view with indigo-carmine dye spray of a depressed
Imaging adenoma with high-grade intraepithelial neoplasia containing very small round pits.
Modern imaging techniques permit non-
invasive detection and clinical staging.
Conventional barium enema detects large presence of regional and distant metas- ment. Colonoscopy allows observation of
tumours, while air-contrast radiography tases {2202}. Scintigraphy and positron the mucosal surface of the entire large
improves the visualization of less ad- emission tomography are also used. bowel with biopsy of identified lesions.
vanced lesions. Cross-sectional imaging Chromoendoscopy employing dyes to
by CT, MRI imaging and transrectal ultra- Endoscopy improve visualization of non-protruding
sonography permit some assessment of The development of endoscopy has had lesions and magnification, have been
the depth of local tumour invasion and the a major impact on diagnosis and treat- developed. The flat neoplastic lesions
A B
Fig. 6.07 A Small adenocarcinoma invading muscularis propria, arising in a depressed adenoma. B Early adenocarcinoma invading submucosa, arising in a flat ade-
noma.
Adenocarcinoma 107
6a 19.7.2006 8:02 Page 108
A B C
Fig. 6.08 Advanced colorectal carcinomas. A Small depressed invasive carcinoma (arrow) with a nearby protruding adenoma, B Advanced colorectal carcinoma,
depressed type. C Cross section of adenocarcinoma with extension into the submucosa (pT1).
have been designated by Japanese gas- lesions may be removed by endoscopic the peritoneal cavity when it is located
troenterologists as ‘type II’, with three mucosal resection {2121, 2122, 1164}. distal to the peritoneal reflection.
subtypes: IIa, ‘en plateau’ elevated; IIb, By contrast, colonic tumours can extend
completely flat; and IIc, ‘en plateau’ Macroscopy directly to the serosal surface. Perforation
depressed. The depressed lesions have, The macroscopic features are influenced can be associated with transcoelomic
despite a smaller diameter, a poor prog- by the phase in the natural history of spread to the peritoneal cavity (peritoneal
nosis with prompt penetration in the sub- tumours at the time of discovery. carcinomatosis). Involvement of the peri-
mucosa. The pit pattern of the surface at Carcinomas may be exophytic/fungating toneal surface should only be diagnosed
magnification 100 allows a reliable pre- with predominantly intraluminal growth, if the peritoneum is ulcerated or if tumour
diction of histology. Therapeutic endo- endophytic/ulcerative with predominantly cells have clearly penetrated the
scopy, including snare polypectomy and intramural growth, diffusely infiltrative/lini- mesothelium. Since the peritoneal sur-
endoscopic mucosectomy, can be used tis plastica with subtle endophytic face infiltrated by tumour cells may
to remove colorectal neoplasms, espe- growth, and annular with circumferential become adherent to adjacent structures,
cially adenomas, and carcinomas with involvement of the colorectal wall and direct extension into adjoining organs
minimal submucosal invasion. Protruded constriction of the lumen. Overlap among can also occur in colonic carcinomas that
neoplasms can usually be resected by these types is common. Pedunculated have invaded the peritoneal portion of the
snare polypectomy. Superficial lesions exophytic lesions have a mural attach- wall {62}. Implantation due to surgical
(flat and depressed) and some protruded ment narrower than the head of the manipulation occurs only occasionally,
tumour, with the stalk consisting of unin- but has been reported after laparoscop-
volved mucosa and submucosa, while ic colectomy for cancer {1106}.
sessile exophytic tumours have broad Spread via lymphatic or blood vessels
attachment to the wall. can occur early in the natural history and
Carcinomas of the proximal colon tend to lead to systemic disease. Despite the
grow as exophytic masses while those in presence of lymphatics in the colorectal
the transverse and descending colon are mucosa, lymphogenic spread does not
more often endophytic and annular. On
cut section, most colorectal carcinomas
have a relatively homogeneous appear-
ance although areas of necrosis can be
seen. Adenocarcinomas of the mucinous
Fig. 6.09 Small ulcerating adenocarcinoma of colon (colloid) type often have areas with
producing a depressed lesion. grossly visible mucus. Carcinomas with
high levels of microsatellite instability
(MSI-H) are usually circumscribed and
about 20% are mucinous {842}.
Mucinous adenocarcinoma
A B This designation is used if > 50% of the
lesion is composed of mucin. This vari-
ant is characterized by pools of extracel-
lular mucin that contain malignant
epithelium as acinar structures, strips of
cells or single cells. Many high-frequen-
cy micro-satellite instability (MSI-H) car-
cinomas are of this histopathological
type.
Adenocarcinoma 109
6a 19.7.2006 8:02 Page 110
Undifferentiated carcinoma
These rare tumours lack morphological
evidence of differentiation beyond that of
an epithelial tumour and have variable
histological features {1946}. Despite their
undifferentiated appearances, these
tumours are genetically distinct and typi-
Fig. 6.15 Adenocarcinoma within lymphatic vessel. cally associated with MSI-H. Fig 6.18 Signet-ring cell carcinoma invading a
nerve.
Other variants
Carcinomas that include a spindle cell
component are best termed spindle cell
carcinoma or sarcomatoid carcinoma.
The spindle cells are, at least focally,
immunoreactive for cytokeratin. The term
carcinosarcoma applies to malignant
tumours containing both carcinomatous
and heterologous mesenchymal ele-
ments. Other rare histopathological vari-
Fig. 6.16 Metastatic adenocarcinoma in regional ants of colorectal carcinoma include
lymph node. Fig. 6.19 Adenocarcinoma with venous invasion.
pleomorphic (giant cell), choriocarcino-
ma, pigmented, clear cell, stem cell, and
Medullary carcinoma Paneth cell-rich (crypt cell carcinoma). reactive for cytokeratin. The term carci-
This rare variant is characterized by Mixtures of histopathological types can nosarcoma applies to malignant tumours
sheets of malignant cells with vesicular be seen. containing both carcinomatous and het-
nuclei, prominent nucleoli and abundant erologous mesenchymal elements.
pink cytoplasm exhibiting prominent infil- Carcinosarcoma
tration by intraepithelial lymphocytes Carcinomas that include a spindle cell Grading
{856}. It is invariably associated with component are best termed sarcomatoid Adenocarcinomas are graded predomi-
MSI-H and has a favourable prognosis carcinoma or spindle cell carcinoma. The nantly on the basis of the extent of glan-
when compared to other poorly differen- spindle cells are, at least focally, immuno- dular appearances, and should be divid-
ed into well, moderately and poorly dif-
ferentiated, or into low-grade (encom-
passing well and moderately differentiat-
ed adenocarcinomas) and high-grade
(including poorly differentiated adeno-
carcinomas and undifferentiated carcino-
mas). Poorly differentiated adenocarci-
nomas should show at least some gland
formation or mucus production; tubules
are typically irregularly folded and dis-
torted.
A When a carcinoma has heterogeneity in
B
differentiation, grading should be based
on the least differentiated component,
not including the leading front of inva-
sion. Small foci of apparent poor differ-
entiation are common at the advancing
edge of tumours, but this feature is insuf-
ficient to classify the tumour as poorly dif-
ferentiated {1543}.
The percentage of the tumour showing
formation of gland-like structures can be
C D used to define the grade. Well differentiat-
Fig. 6.17 Mucinous adenocarcinoma. A Cut surface with glassy appearance. B Mucinous adenocarcinoma ed (grade 1) lesions exhibit glandular
beneath high-grade intraepithelial neoplasia in ulcerative colitis. C Well-differentiated tumour with large structures in > 95% of the tumour; moder-
mucin lakes. D Multilocular mucin deposits with well-differentiated adenocarcinoma. ately differentiated (grade 2) adenocarci-
A B C
Fig. 6.20 A Signet-ring cell carcinoma arising in an adenoma; intramucosal signet-ring cells adjacent to adenomatous glands. B Signet-ring cells infiltrating mus-
cularis propria. C Lymph node metastasis of a signet-ring cell carcinoma.
noma has 50-95% glands; poorly differen- mucosal sheets dissected from the epithelium from the base of the crypts,
tiated (grade 3) adenocarcinoma has bowel wall and stained with methylene where it normally occurs, toward or onto
5-50%; and undifferentiated (grade 4) blue, or mucosal examination with a the luminal surface {851, 1528}. Polyps
carcinoma has < 5%. Mucinous adeno- magnifying endoscope, reveal ACFs to appear to grow as a consequence of
carcinoma and signet-ring cell carcinoma have crypts of enlarged calibre and accelerated crypt fission resulting from
by convention are considered poorly dif- thickened epithelium with reduced mucin APC gene mutation {564}. Intraepithelial
ferentiated (grade 3). Medullary carcino- content. Microscopy shows two main neoplasia can be low-grade or high-
ma with MSI-H appears undifferentiated. types: ACFs with features of hyperplastic grade, depending on the degree of glan-
Additional studies of the biological behav- polyps and a high frequency of ras proto- dular or villous complexity, extent of
iour of MSI-H cancers are needed to oncogene mutations, and dysplastic nuclear stratification, and severity of
relate the morphological grade and ACFs (micro-adenomas) associated with abnormal nuclear morphology. Paneth
molecular subtypes of mucinous, signet- a mutation of the APC gene {1375}. cells, neuroendocrine cells and squa-
ring cell and medullary carcinoma to out- Progression from ACF through adenoma mous cell aggregates may be seen in
come since MSI-H carcinomas have an to carcinoma characterizes carcinogene- adenomas and may become a dominant
improved stage-specific survival {788, sis in the large intestine {1326}. constituent of the epithelium.
924, 1098}. Macroscopy. Colorectal adenomas can
Adenomas be classified into three groups: elevated,
Precursor lesions These precursor lesions are defined by flat, and depressed {973}. Elevated ade-
During the past decade the natural histo- the presence of intraepithelial neoplasia, nomas range from pedunculated polyps
ry of colorectal carcinomas has been histologically characterized by hypercel- with a long stalk of non-neoplastic
extensively studied in correlation with the lularity with enlarged, hyperchromatic mucosa to those that are sessile. Flat or
underlying accumulation of genetic alter- nuclei, varying degrees of nuclear strati- non-protruding adenomas and de-
ations. fication, and loss of polarity. Nuclei may pressed adenomas are recognized
be spindle-shaped, or enlarged and macroscopically by mucosal reddening,
Aberrant crypt foci (ACF) ovoid. Inactivation of the APC/beta- subtle changes in texture, or highlighting
The earliest morphological precursor of catenin pathway commonly initiates the by dye techniques. The term adenoma is
epithelial neoplasia is the aberrant crypt process and results in extension of applied even though the lesions are not
focus (ACF). Microscopic examination of epithelial proliferation in dysplastic polypoid because intraepithelial neopla-
MSI-H
* p<0.05; ** p<0.01 MSS
Fig. 6.21 Sporadic proximal colonic carcinomas. Comparison of pathology of MSI-H Fig. 6.22 Frequency of adenocarcinoma in adenomas relative to size and archi-
(red) and microsatellite stable MSS (blue) carcinomas. tecture.
Adenocarcinoma 111
6a 19.7.2006 8:02 Page 112
A B
Fig. 6.23 Clear cell carcinoma of colon. Fig. 6.26 A, B Crypt adenoma in a patient with FAP.
sia (dysplasia) is the hallmark of these Although tiny flat or depressed adeno-
lesions. Depressed adenomas are usual- carcinomas are well-described, it is diffi-
ly smaller than flat or protruding ones cult to determine if de novo adenocarci-
and tend to give rise to adenocarcinoma nomas without a benign histopathologi-
while still relatively small (mean diameter, cal precursor lesion ever occur in the
11 mm) due to a greater tendency to large bowel, because adenocarcinoma
progress {1628}. These adenomas have can overgrow the precursor lesion. The
a lower frequency of ras mutation than prolonged time interval usually required
polypoid adenomas {974}. for progression of intraepithelial to inva-
sive neoplasia offers opportunities for
Histopathology. Tubular adenomas are prevention or interruption of the process
usually protruding, spherical and pedun- to reduce mortality due to colorectal car-
culated, or non-protruding (flat). Micro- cinoma.
scopically, dysplastic glandular struc- Intraepithelial neoplasia can also occur
tures occupy at least 80% of the luminal in the absence of an adenoma, in a pre-
surface. Villous adenomas are typically existing lesion of another type (such as a
sessile with a hairy-appearing surface. hamartomatous polyp in juvenile polypo-
Microscopically, leaf-like projections lined sis syndrome and Peutz-Jeghers syn-
by dysplastic glandular epithelium com- drome), and in chronic inflammatory dis-
prise more than 80% of the luminal sur- eases.
face. Distinction of villous structures from
Fig. 6.24 Tubulovillous adenoma. Pedunculated elongated separated tubules is some- Hyperplastic (metaplastic) polyps
with long stalk of non-neoplastic mucosa. times problematical. Villous architecture The definition is a mucosal excrescence
is defined arbitrarily by the length of the characterized by elongated, serrated
glands exceeding twice the thickness of crypts lined by proliferative epithelium in
normal colorectal mucosa. Tubulovillous the bases with infolded epithelial tufts
adenomas have a mixture of tubular and and enlarged goblet cells in the upper
villous structures with a ratio between crypts and on the luminal surface,
80%/20% and 20%/80%. Serrated adeno- imparting a saw-tooth outline. In the
mas are characterized by the saw-tooth appendix, diffuse hyperplasia may occur
configuration of a hyperplastic (metaplas- as a sessile mucosal proliferation.
tic) polyp on low power microscopy, but The epithelial nuclei in the serrated region
the epithelium lining the upper portion of are small, regular, round and located at
the crypts and luminal surface is dysplas-
A tic. Serrated adenomas can also have a
tubular or villous component, but low-lev-
els of microsatellite instability (MSI-L) and
altered mucin are characteristic of these
serrated lesions {840}. By contrast, mixed
hyperplastic polyp/adenoma contains
separate identifiable areas of each histo-
pathological type {1092}. Occasionally,
some villous adenomas show in the
slopes of the villi closely packed small
B glands; those adenomas have been
Fig. 6.25 A Sessile villous adenoma. B Section referred to as villo-microglandular adeno-
through a villous adenoma. mas {972}. Fig. 6.27 Tubular adenoma of colon.
A B
Fig. 6.28 Tubulovillous adenoma, partly sessile, Fig. 6.29 A Adenoma with low-grade dysplasia and well-maintained glandular architecture. B Low-grade
partly pedunculated. dysplasia with regular but slightly elongated, hyperchromatic nuclei. Cytoplasmic mucin is retained.
the base of the cells adjoining the base- often oedematous granulation tissue that diseases including chronic inflammatory
ment membrane, which is often thick- surrounds cystically dilated glands con- bowel disease and diverticulitis.
ened beneath the surface epithelial cells. taining mucin. The glands are lined by Lymphoid polyps. These result from
The cytoplasm contains prominent mucin cuboidal to columnar epithelial cells with aggregates of reactive mucosa-associat-
vacuoles, which are usually larger than reactive changes. The juvenile polyps in ed lymphoid tissue with conspicuous
normal goblet cells. The proliferative zone patients with juvenile polyposis syn- germinal centres located in the mucosa
often shows increased cellularity and drome may have the macroscopic and and/or submucosa.
mitotic activity, which can be mistaken for microscopic appearances of sporadic Mucosal prolapse. On occasion, mucos-
adenoma. Hyperplastic polyps are tradi- juvenile polyps, but they often have a al prolapse can produce morphological
tionally considered non-neoplastic, but frond-like growth pattern with less stro- features that mimic neoplasia, including
ras mutation is common, clonality has ma, fewer dilated glands and more prolif- polyps, masses and ulcers character-
been demonstrated, and biochemical erated small glands (microtubular pat- ized histologically by elongated, distort-
abnormalities and epidemiological asso- tern) than their sporadic counterparts. ed, regenerative glands surrounded by a
ciations that occur in colorectal adeno- Intraepithelial neoplasia (dysplasia) is proliferation of smooth muscle fibres from
mas and carcinomas have been found rare in sporadic juvenile polyps. Intra- the muscularis mucosae, together with
{851, 663, 1178}. These lines of evidence epithelial neoplasia in this setting results superficial erosions, inflamed granulation
suggest that hyperplastic polyps may be from inactivation of the APC/beta-catenin tissue and fibrosis {159}. Widening of
neoplastic but have a molecular patho- pathway analogous to the genetic basis gland lumina at the surface is common.
genesis that differs from the adenoma- of adenoma formation {2145}. Examples of this phenomenon include
adenocarcinoma sequence due to inflammatory cloacogenic polyp {1083},
absence of inactivation of the APC/beta- Peutz-Jeghers polyps solitary rectal ulcer and cap polyp. The
catenin pathway. These are discussed in the small intes- process can extend into the bowel wall,
tine section. producing colitis cystica profunda.
Juvenile polyps
Sporadic juvenile polyps are typically Reactive lesions Neoplasia in chronic inflammatory
spherical, lobulated and pedunculated Inflammatory polyps. These non-neoplas- bowel disease
and considered hamartomatous. They tic polyps are composed of varying pro- There is evidence that the natural history
most commonly occur in children. The portions of reactive epithelium, inflamed of colorectal carcinomas associated with
surface is often eroded and friable, and granulation tissue and fibrous tissue, chronic colitis differs from that of ordinary
the cut surface typically shows mucin- often with morphological similarity to adenomas both morphologically and
containing cysts. On histology, the abun- juvenile polyps; inflammatory polyps are with respect to the type and sequence of
dant stroma is composed of inflamed, seen in a variety of chronic inflammatory genetic alterations.
A B C
Fig. 6.30 Adenomas with high-grade dysplasia. A Loss of normal glandular architecture, hyperchromatic cells with multi-layered irregular nuclei and loss of mucin,
high nuclear/cytoplasmic ratio. B Marked nuclear atypia with prominent nucleoli. C Adenoma with focal cribriform pattern .
Adenocarcinoma 113
6a 19.7.2006 8:02 Page 114
Li-Fraumeni syndrome
MIM No: Li-Fraumeni syndrome 151623;
TP53 mutations 191170
Li-Fraumeni syndrome is an autosomal
dominant disorder characterized by mul-
tiple primary neoplasms in children and
young adults, with a predominance of
soft tissue sarcomas, osteosarcomas
and breast cancer, and an increased
incidence of brain tumours, leukaemia
and adrenocortical carcinomas {1403}.
Criteria for proband identification are: (1)
occurrence of sarcoma before age 45,
(2) at least one first-degree relative with A B
any tumour before age 45, and (3) at Fig. 6.35 Proliferating cells demonstrated by immunohistochemistry for MIB1. A Hyperplastic polyp with pro-
least one first- or second-degree relative liferative cells restricted to the basal parts of the crypts. B Tubular adenoma with proliferating adenomatous
with cancer before age 45 or with sarco- epithelium also at the luminal surface.
ma at any age {717, 141, 1066}.
In about 70% of Li-Fraumeni kindreds,
affected family members carry a germline
mutation in TP53 {1151}. From 1990 to
1999, a total of 144 families with a TP53
germline mutation were identified. A data-
base of these mutations is available at
http://www.iarc.fr/p53/Germ. htm {699}.
As with somatic mutations, germline
mutations cluster in conserved regions of
exons 4 to 9, with major hotspots at
codons 175, 248 and 273. It has been
Fig. 6.36 Hyperplastic polyps. Typical sessile Fig. 6.37 Hyperplastic polyp with deep proliferative,
suggested that cancer phenotype corre- appearance. non-serrated zone protruding into submucosa.
lates with the position of the mutation
within the coding sequence, with lower
age of clinical manifestation in probands
with mutations falling in the DNA-binding
domain of the p53 protein {142}. The
most frequent type of germline mutation
is transition (GC to AT) at CpG dinu-
cleotides 556. The molecular basis of
tumour predispositions in families within
TP53 germline mutations is not known.
Recent studies have excluded tumour
suppressor genes such as PTEN and
CDKN2 {214}.
Gastrointestinal manifestations
Neoplasms of the digestive tract repre-
sent 7% of the tumours observed in Li-
Fraumeni families. Most of these tumours
are colorectal carcinoma, with a minority
of stomach carcinomas. The male:female
ratio is 1.5 and the mean age at clinical
manifestation is 45, which correspond to
a relatively long latency period as com-
pared to other types of cancers occurring A B
in Li-Fraumeni families {1403}. Preferen- Fig. 6.38 Hyperplastic polyp. A Pedunculated. B Short deep proliferative zone and superficial serrated
tial familial occurrence of stomach cancer mature zone.
Adenocarcinoma 115
6a 19.7.2006 8:02 Page 116
A B
Fig. 6.41 Reactive epithelial changes in ulcerative Fig. 6.42 Low-grade intraepithelial neoplasia in ulcerative colitis. A Patchy hyperbasophilic regular glands,
colitis. with dysplasia extending to the luminal surface. B Haphazardly arranged dysplastic glands.
A B C
Fig. 6.43 A – C High-grade intraepithelial neoplasia in ulcerative collitis with multilayered hyperchromatic elongated nuclei extending to the luminal surface.
tumour when compared to normal tissue. mutations in microsatellites within the match repair deficiency and in the
It has been recommended that a panel of coding region of some genes, such as absence of APC mutations. AXIN2
five microsatellites should be used as a the type II receptor for TGF-beta1 and mutant protein appears to be more sta-
reference standard (BAT25, BAT26, BAX {548}. In contrast to microsatellite- ble than the wild-type gene product, sug-
D5S346, D2S123, D17S250) for carcino- stable cancers, MSI-H cancers display gesting a dominant-negative effect
mas of the large intestine {164}. If two or nucleotide rather than chromosomal {1079A}.
more of these markers show MSI, the instability; allelic deletions are rare
lesion is classified as high-frequency {1044}. Prognosis and predictive factors
microsatellite instability (MSI-H); if only Recent studies indicate a functional link Morphology. Macroscopic and micro-
one marker shows MSI, it is classified as between defective DNA mismatch repair scopic features reportedly related to
low-frequency microsatellite instability and the Wnt-signalling pathway. Approxi- prognosis are summarized in Table 6.01
(MSI-L); if no markers show MSI it is clas- mately 25% of sporadic colorectal carci- {2348}.
sified as microsatellite stable (MSS). If nomas with defective mismatch repair Poor prognosis has been associated with
more than five markers are used, the cri- (MSI-H) were shown to contain frameshift both large and small tumour size, with
teria should be modified to reflect the per- mutations in the AXIN2 gene, which sessile and ulcerated configuration as
centage of markers demonstrating MSI. leads to a stabilization of β-catenin and contrasted with polypoid cancer, with
Thus, MSI-H lesions would exhibit MSI in activation of β-catenin/T-cell factor (TCF). extensive involvement of the bowel cir-
more than 30-40% of markers tested. This was associated with an accumula- cumference, with the presence of com-
MSI-H carcinomas are characteristic of tion in tumour cell nuclei which was plete bowel obstruction, with perforation,
hereditary nonpolyposis colorectal can- absent in colorectal cancer without mis- and with serosal deposits.
cer syndrome (HNPCC) due to germline
mutation of one of a group of DNA mis-
match repair genes followed by somatic
inactivation of the other allele. Sporadic
MSI-H tumours comprise about 15% of
colorectal carcinomas. They usually fol-
low transcriptional silencing of both alle-
les of the hMLH1 mismatch repair gene
due to aberrant methylation of cytosine
residues in the cytosine and guanine-rich
promoter region {886, 696}. The alter-
ations that accumulate during progres- A B
sion of both hereditary and sporadic neo- Fig. 6.44 Dysplasia associated lesion or mass (DALM). A Polypoid lesion. B Raised lesion simulating an ade-
plasms characterized by MSI-H include noma.
Adenocarcinoma 117
6a 19.7.2006 8:02 Page 118
Angiogenesis. Neovascularization of
tumour stroma is crucial in supporting
tumour growth, and high levels of
microvessel density have been interpret-
ed as an adverse prognostic feature
{2010}.
Inflammatory response. The presence of
an intense inflammatory infiltrate with
polymorphonuclear leukocytes (particu-
larly eosinophils), lymphocytes, plasma A
Fig. 6.45 Rectal carcinoma arising in ulcerative cells, mast cells and histiocytes, as well
colitis. Surface dysplasia overlies invasive carcino- as prominent desmoplasia have been
ma in this DALM. associated with improved prognosis
{1352}. In the regional lymph nodes,
Histopathological features related to hyperplasia of the paracortical T-lym-
poor prognosis include deep infiltration phocyte areas and the B-cell germinal
of the layers of the wall, extensive centers have also been reported as
involvement of a particular layer, an infil- favourable, as has sinus histiocytosis.
trative pattern of the invasive edge of the Other features of colorectal carcinomas
tumour as contrasted to an expansile that have been shown to be of prognostic
B
pattern, and poor differentiation, includ- value in some studies include angiolym-
Fig. 6.47 Solitary rectal ulcer. A, B Two deep ulcers
ing signet-ring cell and mucinous adeno- phatic invasion, perineural space involve-
macroscopically simulating carcinoma.
carcinoma, adenosquamous carcinoma, ment, extramural venous involvement,
small cell carcinoma and anaplastic car- peritumoural lymphocytic response, and
cinoma {1672, 1946, 220, 916, 266}. tumour-infiltrating lymphocytes. Some of
Mucinous adenocarcinomas of the rec- these features are evaluated in a classifi-
tum often present at a later stage and cation proposed by Jass {389}. A micro-
have the poorest overall prognosis acinar pattern of growth, defined as dis-
{1928}, but the MSI status influences the crete, small, relatively regular tubules, is
aggressiveness of this histopathological associated with reduced survival {559,
subtype {1221}. Other studies have 2100}.
shown no significant difference in prog- Extent of resection. A short longitudinal
nosis between mucinous and non-muci- surgical resection margin (2-5 cm),
nous varieties of adenocarcinoma reflecting the surgical technique
{1543}. employed, has been associated with
Lymph node metastasis. Metastasis to poor outcome. In rectal cancer, clear-
numerous nodes, those close to the ance from the circumferential margin is
mesenteric margin, at great distance important. The circumferential margin
from the primary tumour, or in retrograde represents the adventitial soft tissue mar-
lymph nodes, have been associated with gin closest to the deepest penetration of
poor prognosis while the prognostic the tumour. For all segments of the large
value of identification of micrometastasis intestine that are incompletely enveloped Fig. 6.48 Solitary rectal ulcer with reactive hyper-
in lymph nodes by immunohistochemical by peritoneum or not enveloped, the cir- plastic polyp due to prolapse. This lesion should not
or molecular techniques is still controver- cumferential margin is created by blunt be confused with a neoplasm.
sial {1564, 1387, 221}. or sharp dissection at operation. The
mesocolic margin in resection speci-
mens of colon cancer is usually well dis-
tant from the primary tumour, but the sta-
tus of the circumferential margin is par-
ticularly important in rectal carcinoma
due to the anatomic proximity of pelvic
structures {15}.
Genetic predictive markers. Some of the
genetic alterations identified in colorectal
cancers are markers for prognosis {313,
1206}. Allelic loss of chromosome 18q
was found to be an adverse prognostic
indicator. Other studies reported that loss
Fig. 6.46 Immunoexpression of p53 in intraepithelial of chromosomes 17p, 1p, 5q, 8p or 18q, Fig. 6.49 Inflammatory cap polyp in a patient with
neoplasia in ulcerative collitis. decreased DCC gene expression, p53 ulcerative collitis.
Table 6.01
Prognostic factors in colorectal carcinoma.
Features of the primary tumour Evidence of vessel invasion Evidence of host response Consequences of surgical technique
Anatomic extent of disease (TNM) Extramural venous involvement Angiogenesis Distance between resection margin
Extent of circumferential involvement Lymphatic vessel or Local inflammatory and desmo- and tumour
Bowel obstruction perineural space involvement plastic response to infiltrating Presence of residual tumour
Perforation tumour
Pattern of invasion Reactive changes in regional
Grade of differentiation lymph nodes
Adenocarcinoma 119
6b 24.7.2006 8:58 Page 120
I.C. Talbot
Familial adenomatous polyposis R. Burt
H. Järvinen
G. Thomas
Definition sis, Gardner syndrome, familial multiple ization of diminutive polyps may require
Familial adenomatous polyposis (FAP) is polyposis, multiple adenomatosis, famil- dye spray assisted endoscopy. Histo-
an autosomal dominant disorder charac- ial polyposis of the colon and rectum, logical confirmation requires examination
terized by numerous adenomatous col- familial polyposis of the gastrointestinal of several polyps. In the context of endo-
orectal polyps that have an intrinsic ten- tract, familial adenomatous polyposis scopic screening on the basis of definite
dency to progress to adenocarcinoma. It coli, etc. family history the detection of fewer ade-
is caused by a germline mutation in the nomas is sufficient at an early age. The
Adenomatous Polyposis Coli (APC) Incidence same applies on the attenuated disease
gene which is located on the long arm of Estimates of the incidence of FAP vary form (AAPC). Final diagnosis may be
chromosome 5 (5q21-22). Gardner syn- between 1 per 7000 and 1 per 30,000 achieved by demonstration of a mutated
drome is a variant of FAP that includes newborns. The mean annual incidence APC, but the detection rate of mutations
epidermoid cysts, osteomas, dental rate has been constantly from 1 to 2 per has only been between 60 and 80% of all
anomalies and desmoid tumours, in 1,000,000 in Denmark and Finland while FAP families. In patients where the clini-
addition to colorectal adenomas. Turcot the prevalence has increased to more cal criteria remain doubtful and genetic
syndrome is a variant that is associated than 25 per 1,000,000 since the creation diagnosis is not achieved the finding of
with a brain tumour (medulloblastoma). of preventive polyposis registries {205; extracolonic features of FAP (epidermoid
An attenuated FAP form has been distin- 836}. In general, FAP underlies less than cysts, osteomas, desmoid tumour, gas-
guished from classic FAP, where the 1% of all new colorectal cancer cases. tric fundic gland polyps, etc.) may give
number of adenomas is less than 100 in Between 30 and 50% of new FAP additional diagnostic support.
the colon. patients are solitary cases, probably rep- The following diagnostic criteria have
resenting new mutations of the APC been established: (1) 100 or more
MIM No.: FAP, including Gardner syn- gene. colorectal adenomas or (2) germline
drome, 175100; Turcot syndrome, 276300 mutation of the APC gene or (3) family
Diagnostic criteria history of FAP and at least one of the fol-
Synonyms Classical FAP is defined clinically by the lowing: epidermoid cysts; osteomas;
Adenomatous polyposis coli, familial finding of at least 100 colorectal adeno- desmoid tumour.
polyposis coli, Bussey-Gardner polypo- matous polyps {216}. Endoscopic visual-
Colorectal polyps
The colorectal polyps are adenomas,
most often tubular, and resemble their
sporadic counterparts.
Localization
Colorectal adenomas in FAP occur
throughout the colon but follow the gen-
eral distribution of sporadic adenomas,
with greatest density in the rectum and
sigmoid colon. The distribution of can-
A B cers follows that of the adenomas.
Clinical features
Age at clinical manifestation
Colorectal adenomas become detec-
table at endoscopic examination (sigmoi-
doscopy) between the age of 10 and 20
years, increasing in number and size with
age. The most important clinical feature
of FAP is the almost invariable progres-
C D sion of one or more colorectal adenomas
Fig. 6.52 Colectomy specimens from patients with familial adenomatous polyposis. A Hundreds of polyps of to cancer. The mean age of development
different size cover the entire mucosal surface. B Multiple adenomas in different stages of development. of colorectal cancer is about 40 years,
C Lateral view of polyps. D Numerous small early (sessile) adenomas. but the cancer risk is 1 to 6% already at
Proliferation
The histologically normal intestinal
mucosa in FAP shows no increase in the
rate of epithelial cell proliferation {2062}.
Mitotic activity is not increased {1315}
except in the adenomatous epithelium, in
which cell proliferation is identical with
that in sporadic adenomas.
A B
Fig. 6.58 Precursor lesion of mesenteric fibromatosis (desmoid tumour) in a patient with FAP. A The white band in the mesentery resembles a fibrous adhesion.
B Histology shows a band of fibromatosis in the mesenteric fat.
hypertrophy of retinal pigment epithelium Nervous system exon 1, a coding region for a heptad
(CHRPE) {280}. Ultrastructurally, they are The concurrent presence of a brain repeat that supports homodimerization
freckle-like plaques of enlarged melanin- tumour and multiple colorectal polyps of the APC protein.
containing retinal epithelial cells {1466}. constitutes Turcot syndrome. Some indi-
Their value for diagnosis is limited by viduals affected in this way are victims of Gene product and function
inconsistency and variation between FAP, with a germline defect of APC. The APC protein is a 2,843-amino acid
families. These are infants or young children who polypeptide that is a negative regulator in
present with medulloblastoma and col- the Wnt signaling pathway. The protein
orectal polyps {658}. contains several functional domains that
Other individuals present later in life with act as binding and degradation sites for
a glioma, usually an astrocytoma or β-catenin and control the β-catenin intra-
glioblastoma multiforme and are usually cellular concentration. A protein-binding
associated with hereditary non-polyposis domain near the carboxy-terminal of APC
colon cancer (HNPCC) rather than FAP mediates phosphorylation by glycogen
{262}. synthase kinase 3 β (GSK3b) and stabi-
lizes the formation of a complex between
Genetics the two proteins {1627}. In an unstimulat-
FAP is an autosomal dominant disease ed cell, GSK3b promotes phosphorylation
with almost complete penetrance by 40 of the protein conductin/axin which is
Fig. 6.59 Epidermoid cyst on the dorsal surface of years of age. APC germline mutations added to the APC GSK3b complex {2107;
the hand of an FAP patient. are the only known cause of FAP. 124}. Phosphorylated axin recruits
β-catenin, which is in turn phosphorylated
Gene structure and expression and targeted for degradation through an
Skin The APC gene was localized to chro- APC-dependent ubiquitin-proteasome
Epidermal cysts, usually of the face and mosome 5q21-22 by Bodmer et al. pathway {11}. Normal Wnt signalling
often multiple, were first described in {156} and Leppert et al. {1047}. It was inhibits GSK3b activity and dephosphory-
FAP by Gardner {565}. isolated by the group of White {868; lates axin. As a result, β-catenin is
629} and by the laboratories of Naka- released from the complex {2107}.
Endocrine system mura and Vogelstein {920; 1364}. It In the cytoplasm, β-catenin is involved in
There is a definite but relatively slight spans over a region of 120 Kb and is cytoskeletal organization with binding to
increase in the incidence of endocrine composed of at least 21 exons, 7 of microtubules. It also interacts with E-cad-
tumours in FAP, including neoplasia of which are alternatively expressed herin, a membrane protein involved in cell
pituitary, pancreatic islets and adrenal {1658}. 16 APC transcripts that differ in adhesion. Free β-catenin shuttles to the
cortex {1160}, as well as multiple endo- their 5’-most regions and arise by the nucleus where it binds to the transcription
crine neoplasia syndrome, type 2b alternative inclusion of 6 of these exons factors of the TCF/LEF family. The result-
{1500} but these are of insufficient fre- have been identified. ing complexes activate c-MYC {680} and
quency or gravity to form part of a routine The APC gene is ubiquitously expressed cyclin D1 transcription {1753; 1922}. Lack
screening protocol. The best document- in normal tissues, with highest levels in of functional APC causes unregulated
ed endocrine association is papillary car- the central nervous system. Tissue-spe- intracellular accumulation of β-catenin
cinoma of thyroid {268}, largely restricted cific differences were observed in the and thereby constitutive expression of
to women {202}. expression of APC transcripts without c-MYC and of the cyclin D1 gene (CDD1).
A B
Fig. 6.60 Mesenteric fibromatosis (desmoid tumour) in a patient with FAP. A The lesion entraps loops of small intestine. B Collagen bands and small vessels.
Gene mutations quent type of sporadic colon cancers not pholipase Pla2g2a is associated with a
The germline mutation rate leading to a associated with replication errors. TP53 decreased number and size of adenoma
new deleterious APC allele is estimated mutation and 17p allele loss have been in heterozygous mutant Apc mice {1283}.
to be 5 to 9 per million gametes. As a observed in 40% of invasive carcinomas Implication of PLA2G2A polymorphism in
result, most families exhibit unique muta- {910}. However, in some families TP53 FAP expressivity has not been demon-
tions, and individuals with no previous may not be involved {30}. Loss of alleles strated in humans.
family history of FAP are not uncommon. on chromosome 18 and 22 were
They may represent up to one fourth of observed in 46% and 33% respectively. Genotype / phenotype relationships
propositi {143}. The KRAS mutation frequency increases There are well documented relationships
A deleterious APC mutation may be from 11% inmoderately to 36% in severe- between the location of the mutation on
found in about 95% of FAP patients. The ly dysplastic adenomas {30}. KRAS the APC gene and the FAP phenotype.
vast majority of the mutant alleles lead to mutations may potentiate cyclin D1 tran- APC mutations in the first or last third of
the synthesis of a truncated protein. scription {680}. Interestingly, the type of the gene are associated with attenuated
About 10% of the mutations are large APC germline mutation may influence colorectal polyposis (AAPC) character-
interstitial deletions that may involve the the mode of inactivation of the second ized by the occurrence of less than 100
entire gene. Rare missense mutations, APC allele {30}. polyps and a late onset {1284}. Fundic
most with uncertain functional conse- gland polyposis is prevalent in the atten-
quences, have been described. Muta- Animal model uated form of FAP but desmoids may be
tions at codons 1061 and 1309 account Heterozygous mutant mice for a defec- present only if the AAPC causing muta-
for 20% of all identified germline muta- tive Apc allele develop multiple intestinal tion lies in the 3’ end of the APC gene.
tions in the APC gene. In up to 5% of fam- neoplasia {1245}. The homozygous Indeed, mutations after codon 1444 are
ilies, the genetic defect causing FAP is mutant embryos die prior to gastrulation associated with an increased suscepti-
not yet known {1003}. {1811}. Expression of the secretory phos- bility to desmoid tumours {340}. CHRPE
lesions are a consistent feature, except if bowel obstruction, or bloody diarrhoea. Screening in gene carriers is similar to
the APC mutation is located before exon In such cases, patient evaluation will fre- that in families where genetic testing is
9 and after codon 1387 {1810; 340}. quently find a colorectal carcinoma. not applied or does not work and usually
Mutations in the central region of the Occasionally, the extracolonic features of involves sigmoidoscopy every 1 to 2
gene, including the mutational hotspot at the condition may lead to presentation years, beginning between age 10 and 12
codon 1309, correlate with a severe phe- and diagnosis. Cases of new mutation years. If a genetic diagnosis is made
notype characterized by development of still present in these ways, but in areas after that age, full colonoscopy should
thousands of polyps at a young age with well organized registers, gene carri- probably be done in view of the risk of
{258}. In contrast to mutant APC proteins ers among relatives of affected patients lesions higher in the colon. Preventive
truncated at codon 386 or 1465, which are identified prior to symptoms either by total colectomy is proposed to gene car-
interfered only weakly with wild-type APC DNA-based genetic tests or by bowel riers when polyposis becomes conspicu-
activity in an in vitro system, a mutant examination. ous. Genotype/phenotype correlations
APC protein truncated at codon 1309 The most commonly used commercially may be used to adapt clinical manage-
was shown to be a strong inhibitor and available genetic testing for FAP involves ment to individual FAP patients.
may thus have dominant negative prop- identification of the mutant APC allele by A family member who has a negative
erties {1422}. These observations point in vitro detection of truncated APC pro- DNA based genetic test can forgo
to a possible mechanism that could con- tein {414}. This approach is referred to as screening if (1) the mutation found in
tribute to the genotype/phenotype rela- in vitro protein synthesis (IVPS) testing. other affected family members is obvi-
tionships observed in FAP. There may IVPS testing is able to detect mutation ously deleterious and (2) if the individual
also be a correlation between slow carriers in about 80% of families. Once with a negative test has been unambigu-
acetylation genotypes and extracolonic evidence of a disease-causing mutation ously shown to be a non-gene carrier by
manifestations of the disease {1308}. is found in an index case by this method, DNA testing. Such individuals need no
testing is near 100% predictive in other further screening as their risk to develop
Application of genetic testing family members. It is imperative that colon cancer is similar to that of the gen-
in the clinical setting genetic counselling be undertaken eral population.
In the absence of systematic, family throughout the process of genetic test-
based screening programs, the present- ing. Without this, genetic testing and the
ing features are usually those of malig- use of the results are poorly applied in
nancy, such as weight loss and inanition, the clinical setting {1703}.
A B
Fig. 6.63 Abundant lymphocytes infiltrate the neoplastic epithelium in these poorly differentiated (A) and moderately differentiated (B) adenocarcinomas from
patients with HNPCC.
A B
Fig. 6.65 Tubular adenoma from a patient with HNPCC immunostained for (A) MLH and (B) MSH2 . The neo-
plastic epithelium shows loss of MSH2 expression (upper portion of B)
A panel of five markers (BAT25, BAT26, (Postmeiotic segregation 2), and MSH6
D2S123, D5S346 and D17S250) has (MutS homologue 6). Structural charac-
been recommended for screening pur- teristics of these genes are given in Table
poses {164}. Bandshifts at two or more 6.04. Homozygous MLH1 mutations con-
microsatellite loci are indicative of MSI-H. fer to a neurofibromatosis 1 like pheno-
Around 60% of HNPCC adenomas are type {2048, 1580}.
MSI-H {2}.
Most MSI-H cancers are diploid or near Gene product
diploid and the frequency of loss of het- HNPCC genes are ubiquitously
erozygosity (LOH) is low for the tradition- expressed in adult human tissues, and
al loci 5q, 17p and 18q {962, 841}. The therefore, the expression pattern does Fig. 6.66 Microsatellite instability in HNPCC. Shifts
frequency of APC, KRAS and TP53 muta- not seem to explain the selective organ of allele size are evident in dinucleotide and
tion is reduced {962, 841}. Conversely, involvement in this syndrome. Expression mononucleotide markers. N = normal tissue,
mutations are encountered in TGFRII, is particularly prominent in the epithelium T = tumour.
IGF2R, BAX, E2F-4, MSH3, MSH6 and of the digestive tract as well as in testis
caspase 5 {548, 1165, 1699, 1793, 2156, and ovary {505, 1030, 2120}. In the intes- match binding, a heterodimeric complex
1558}. In general, the driving force for tine, expression is confined to the repli- of MutL-related proteins, MLH1-PMS2
colorectal cancer development and pro- cating compartment, i.e. the bottom half (and possibly another alternative com-
gression may be DNA instability (mutator of the crypts. Immunohistochemical plex formed by MLH1-MLH3) is recruit-
pathway) or chromosomal instability staining against these proteins is nuclear. ed, and this larger complex, together
(suppressor pathway). HNPCC cancers with numerous other proteins, accom-
and sporadic MSI-H cancers share the Function plishes mismatch repair. The observed
mutator pathway. The protein products of HNPCC genes functional redundancy in the DNA mis-
are key players in the correction of mis- match repair protein family may help
Mode of inheritance, matches that arise during DNA replica- explain why mutations in MSH2 and
chromosomal location, and structure tion {957}. Two different MutS-related het- MLH1 are prevalent in HNPCC families,
HNPCC is transmitted as an autosomal erodimeric complexes are responsible while mutations in PMS1, PMS2, and
dominant trait. It is associated with for mismatch recognition: MSH2-MSH3 MSH6 are much less frequent, and no
germline mutations in five genes with and MSH2-MSH6. While the presence of germline mutations in MSH3 or MLH3
verified or putative DNA mismatch repair MSH2 in the complex is mandatory, have been reported, so far (see below).
function, namely MSH2 (MutS homo- MSH3 can replace MSH6 in the correc- Mismatch repair deficiency gives rise to
logue 2), MLH1 (MutL homologue 1), tion of insertion-deletion mismatches, but microsatellite instability, and as such may
PMS1 (Postmeiotic segregation 1), PMS2 not single-base mispairs. Following mis- aid in the diagnosis of this syndrome {3}.
Table 6.04
Characteristics of HNPCC-associated human DNA mismatch repair genes.
Gene Chromosomal Length of cDNA (kb) Number of exons Genomic size (kb) References
location
MLH1 3p31-p23 2.3 19 58-100 {193, 660, 955, 1077, 1075, 1453}
However, microsatellite instability is not mutation leads to a nonconservative Prognosis and predictive factors
specific to HNPCC, occurring in 10 to amino acid change, the involved codon is HNPCC mutations generally have a high
15% of apparently sporadic colorectal evolutionarily conserved, the change is penetrance. There is no clear-cut corre-
and other tumours as well {164}. absent in the normal population, and it lation between the involved gene, muta-
Correction of biosynthetic errors in the segregates with the disease phenotype. tion site within the gene, or mutation type
newly synthesized DNA is not the only A subset of such mutations was directly vs. clinical features. MSH2 mutations
function of the DNA mismatch repair sys- assessed for pathogenicity using a yeast- may confer higher risk for extracolonic
tem. In particular, it is also able to recog- based functional assay, and there was a cancer as compared to MLH1 mutations
nize lesions caused by exogenous muta- good correlation {1745}. As a rule, the {2005}. MSH6 mutations may be associ-
gens, and has been shown to participate mutations are scattered throughout the ated with atypical clinical features,
in transcription-coupled repair {134, genes, but exon 12 in MSH2 and exon 16 including common occurence of
1215}. in MLH1 constitute particular hot spots endometrial cancer {2102} and late age
{1488}. of onset {29}. Finally, capability of the
Gene mutations Mutations in the five DNA mismatch mutant protein to block the normal homo-
The International Collaborative Group on repair genes account for two-thirds of all logue by a dominant negative fashion
HNPCC maintains a database for classical HNPCC families meeting the may lead to a severe phenotype, in
HNPCC-associated mutations and poly- Amsterdam criteria and showing MSI in which even normal cells may manifest
morphisms (http://www.nfdht.nl). The tumours {1078}. Occurrence of these mismatch repair deficiency {1475, 1348}.
great majority is found in MLH1 and mutations is clearly lower (< 30%) in Conversely, inability to do so may be
MSH2, with a few mutations in MSH6, HNPCC kindreds not meeting the associated with a milder phenotype and
PMS1 and PMS2. These mutations occur Amsterdam criteria {1379, 2103}. lack of extracolonic cancers {828}.
in over 400 HNPCC families from differ- Moreover, clinically indistinguishable Kindreds with the Muir-Torre phenotype
ent parts of the world {485}. phenotype (non-polypotic colon cancer {971} as well as a subset of those with
Most MSH2 and MLH1 mutations are plus variable extracolonic cancers) may Turcot syndrome {658} show mutations
truncating {1488}. However, one-third of be associated with germline mutations in similar to those observed in classical
MLH1 mutations is of missense type, genes that are not involved in DNA mis- HNPCC.
which constitutes a diagnostic problem match repair, such as TGFβ-RII {1103}
concerning their pathogenicity. Common- and E-Cadherin {1581}. As expected,
ly used theoretical criteria in support of tumours from such families do not char-
pathogenicity include the following: the acteristically show MSI.
A B
Fig. 6.68 A, B Juvenile polyposis. The bizarre architecture differs from the round, uniform structure of spo- Fig. 6.69 Juvenile polyp with intraepithelial neopla-
radic juvenile polyps. sia and early adenocarcinoma.
Histopathology
Smaller polyps are indistinguishable from
their sporadic counterparts. In the multi-
lobated or atypical variety the lobes may
be either rounded or finger-like. There is
a relative increase in the amount of
epithelium versus stroma. Glands show
more budding and branching but less
cystic change than the classical solitary
A B polyp {847}.
Fig. 6.70 A, B Intraepithelial neoplasia in a juvenile polyp.
Cancer in juvenile polyposis
There are two histogenetic explanations
for the well documented association
between colorectal cancer and juvenile
polyposis. Cancers could arise in co-
existing adenomas. Alternatively, they
may develop through dysplastic change
within a juvenile polyp. While both mech-
anisms may apply, pure adenomas are
uncommon in juvenile polyposis. By con-
trast, foci of low-grade dysplasia may be
demonstrated in 50% of atypical or multi-
lobated juvenile polyps. The dysplastic
areas may increase in size, generating a
mixed juvenile polyp/adenoma. The ade-
nomatous component may be tubular,
tubulovillous or villous. Carcinomas are
more likely to be poorly differentiated
and/or mucinous {847}.
Extraintestinal manifestations
Congenital anomalies have been report-
ed in 11 to 15% of JP patients {316, 727},
with the majority occurring in sporadic
cases {217}. These anomalies most
commonly involve the heart, central
nervous system, soft tissues, gastroin-
testinal tract and genitourinary system
{316, 1202}. Several patients have been
Fig. 6.71 TGF-β superfamily signaling through signal-transducing SMAD (1,2,3,4,5 and 8) and inhibitory
reported with ganglioneuromatous prolif-
SMAD (6 and 7) proteins. SMAD4, the protein defective in juvenile polyposis, plays a key role in the network.
After type I receptor activation, SMADs 1,2,3,5 and 8 become phosphorylated, form homomeric complexes
eration within juvenile polyps {428, 1218,
with each other, and assemble into heteromeric complexes with SMAD4. The complexes translocate into 1513, 2081}, and others with pulmonary
the nucleus, where they regulate transcription of target genes. Inhibitory Smads act opposite from R-Smads arteriovenous malformations and hyper-
by competing with them for interaction with activated type I receptors or by directly competing with SMADs trophic osteoarthropathy {348, 1760,
1,2,3,5 and 8 for heteromeric complex formation with SMAD4. From: E. Piek et al. FASEB J 13: 2105 (1999). 101, 333}.
Genetics have been described thus far, three stud- Prognostic factors
JP is autosomal dominant. Germline ies have confirmed, in different white pop- The most severe form of juvenile polypo-
mutations in SMAD4/DPC4 tumour sup- ulations, the frequent occurrence of a four sis presents in infancy, with diarrhoea,
pressor gene account for some of the base pair deletion in SMAD4 exon 9 {531, anemia, and hypoalbuminemia; these
cases {748, 751}. SMAD4 maps to chro- 751, 1622}. Haplotype analyses indicate patients rarely survive past 2 years of age.
mosome 18q21.1 {651}, i.e. a region that that this is due to a mutation hotspot, Although polyps in juvenile polyposis
is often deleted in colorectal carcinomas. rather than an ancient founder mutation patients have classically been described
{531, 751}. The families segregating this as hamartomas, they do have malignant
Gene structure and product particular mutation tend to be large, per- potential. The risk of colorectal carcinoma
SMAD4 has 11 exons, encoding 552 haps indicating high penetrance. is approximately 30-40% and that of
amino acids. It is expressed ubiquitously It seems likely that SMAD4 is not the only upper gastrointestinal carcinoma is
in different human organ systems, as well gene underlying JP since only a subset 10-15% {749}. Typical age of colon carci-
as during murine embryogenesis. The of the families have SMAD4 germline noma diagnosis is between 34 and 43
gene product is an important cellular mutations {531, 748, 751, 1622}, and years (range 15-68 years), and upper
mediator of TGF-β signals relevant for many families are not compatible with gastrointestinal carcinoma 58 years
development and control of cell growth 18q linkage {748, 751, 1622}. The PTEN (range 21-73 years) {749, 847, 834}. Most
and an obligate partner for SMAD2 and gene has also been proposed as under- cases occur in patients who have not
SMAD3 proteins in the signalling path- lying JP {1421}, but this report has not been screened radiologically or endo-
way from the TGF-β receptor complex to been confirmed by other studies and the scopically, suggesting that cancers may
the nucleus {2099}. present notion is that individuals with be preventable through close surveil-
PTEN mutations should be considered lance.
Gene mutations having Cowden syndrome, with a risk of
While relatively few germline mutations breast and thyroid cancer {469}.
A B
Fig. 6.72 A, B Colonic polyps in Cowden syndrome. Distorted glands and fibrous proliferation in lamina propria.
germline PTEN mutation, all 9 had hamar- general population, lifetime risks for and fibrocystic disease of the breast are
tomatous polyps {2075}. Several varieties breast and thyroid cancers are approxi- common signs in CS, as are follicular
of hamartomatous polyps are seen in this mately 11% (in women), and 1%, respec- adenomas and multinodular goitre of the
syndrome, including lipomatous and gan- tively. Breast cancer has been rarely thyroid. An unusual central nervous sys-
glioneuromatous lesions {2075}. Presu- observed in men with CS {1167}. In tem tumour, cerebellar dysplastic gan-
mably, these polyps can occur anywhere women with CS, lifetime risk estimates for gliocytoma or Lhermitte-Duclos disease,
in the gastrointestinal tract. Those in the the development of breast cancer range has recently been associated with CS
colon and rectum usually measure from 3 from 25 to 50% {1819, 665, 1096, 467}. {1445, 468, 932}.
to 10 millimetres but can reach 2 cen- The mean age at diagnosis is likely 10 Other malignancies and benign tumours
timetres in diameter. Some of the polyps years earlier than breast cancer occur- have been reported in patients or fami-
are no more than tags of mucosa but oth- ring in the general population {1819, lies with CS. Some authors believe that
ers have a more definite structure. Most 1096}. Although Rachel Cowden died of endometrial carcinoma could be a com-
are composed of a mixture of connective breast cancer at the age of 31 {196, ponent tumour of CS as well. It remains to
tissues normally present in the mucosa, 1081} and the earliest recorded age at be shown whether other tumours (sarco-
principally smooth muscle in continuity diagnosis of breast cancer is 14 {1819}, mas, lymphomas, leukaemia, menin-
with the muscularis mucosae {242}. the great majority of breast cancers are giomas) are true components of CS.
Examples containing adipose tissue have diagnosed after the age of 30-35 (range
been described. The mucosal glands 14 – 65) {1096}. The predominant histol- Genetics
within the lesion are normal or elongated ogy is ductal adenocarcinoma. Most CS Chromosomal location and mode of
and irregularly formed but the epithelium breast carcinomas occur in the context transmission
is normal and includes goblet cells and of DCIS, atypical ductal hyperplasia, CS is an autosomal dominant disorder,
columnar cells {242}. Lesions in which adenosis and sclerosis {1691}. with age related penetrance and variable
autonomic nerves are predominant, giv- Thyroid cancer. The lifetime risk for thy- expression {468}. The CS susceptibility
ing a ganglioneuroma-like appearance, roid cancer can be as high as 10% in gene, PTEN, resides on 10q23.3 {1071,
have been described but seem to be males and females with CS. Because of 1334, 1068}.
exceptional {1017}. The vast majority of small numbers, it is unclear if the age of
CS hamartomatous polyps are asympto- onset is truly earlier than that of the gen- Gene structure
matic. In a study of 9 CS individuals, eral population. Histologically, the thyroid PTEN/MMAC1/TEP1 consists of 9 exons
glycogenic acanthosis of the oesopha- cancer is predominantly follicular carci- spanning 120-150 kb of genomic dis-
gus was found in 6 of the 7 with PTEN noma although papillary histology has tance {1167, 1820, 1068}. It is believed
mutation {2075}. also been rarely observed {1819, 665, that intron 1 occupies much of this
Gastrointestinal malignancies are gener- 1152} (Eng, unpublished observations). (approximately 100 kb). PTEN is predict-
ally not increased in CS {1819, 468} Medullary thyroid carcinoma has not ed to encode a 403-amino acid phos-
although rare individual CS families been observed in patients with CS. phatase. Similar to other phosphatase
appear to have an increased prevalence Benign tumours. The most important genes, PTEN exon 5 specifically
of colon cancer (Eng, unpublished benign tumours are trichilemmomas and encodes a phosphatase core motif.
observations). papillomatous papules of the skin. Apart Exons 1 through 6 encode amino acid
from those of the skin, benign tumours or sequence that is homologous to tensin
Extraintestinal manifestations disorders of breast and thyroid are the and auxilin {1065, 1820, 1068}.
Breast cancer. The two most commonly most frequently noted and probably rep- Gene product
recognized cancers in CS are carcinoma resent true component features of this PTEN is virtually ubiquitously expressed
of the breast and thyroid {1819}. In the syndrome (Table 6.05). Fibroadenomas {1820}. Detailed expression studies in
development have not been performed. to 10-50% {1335, 1964, 1124}. A formal 60% of BRR families and isolated cases
However, early embryonic death in study which ascertained 64 unrelated combined carry a germline PTEN muta-
pten -/- mice would imply a crucial role CS-like cases revealed a mutation fre- tion {1170}. There were 11 cases classi-
for PTEN in early development {1526, quency of 2% if the criteria are not met, fied as true CS-BRR overlap families in
1868, 407}. even if the diagnosis is made short of this cohort, and 10 of these had a PTEN
PTEN is a tumour suppressor and is a one criterion {1168}. mutation. The overlapping mutation
dual specificity phosphatase {1304}. It is A single research centre study involving spectrum, the existence of true overlap
a lipid phosphatase whose major sub- 37 unrelated CS families, ascertained families and the genotype-phenotype
strate is phosphtidylinositol-3,4,5- according to the strict diagnostic criteria associations which suggest that the
triphosphate (PIP3) which lies in the PI3 of the Consortium, revealed a mutation presence of germline PTEN mutation is
kinase pathway {553, 1814, 1142, 364, frequency of 80% {1167}. Exploratory associated with cancer strongly suggest
1067}. When PTEN is ample, PIP3 is con- genotype-phenotype analyses revealed that CS and BRR are allelic and part of a
verted to 4,5-PIP2, which results in that the presence of a germline mutation single spectrum at the molecular level.
hypophosphorylated Akt/PKB, a known was associated with a familial risk of The aggregate term of PTEN hamartoma
cell survival factor. Hypophosphorylated developing malignant breast disease tumour syndrome (PHTS) has been sug-
Akt is apoptotic. Transient transfection {1167}. Further, missense mutations gested {1170}.
studies have shown that ectopic expres- and/or mutations 5’ of the phosphatase The identification of a germline PTEN
sion of PTEN results in apoptosis in core motif seem to be associated with a mutation in a patient previously thought
breast cancer lines mediated by Akt surrogate for disease severity (multi- to have juvenile polyposis {1421}
{1067} and G1 arrest in glioma lines {553, organ involvement). A small study com- excludes that diagnosis, and points to
554}. The G1 arrest is not fully explained prising 13 families with 8 PTEN mutation- the correct designation as CS or BRR
by the PTEN-PI3K-Akt pathway. It is also positive members could not find any {469, 751, 983, 750, 1171}.
believed that PTEN can dephosphorylate genotype-phenotype associations {1333}
FAK and inhibit integrin and MAP kinase but this may be due to the small sample Prognosis
signalling {637, 1892}. size. There have been no systematic studies
Gene mutations Bannayan-Riley-Ruvalcaba syndrome to indicate if CS patients who have can-
Approximately 70-80% of CS cases, as (BRR). Previously thought to be clinical- cer have a prognosis different from that
strictly defined by the Consortium crite- ly distinct, BRR (MIM 153480), character- of their sporadic counterparts.
ria, have a germline PTEN mutation ized by macrocephaly, lipomatosis, hae-
{1167, 1071}. If the diagnostic criteria are mangiomatosis and speckled penis, is
relaxed, then mutation frequencies drop likely allelic to CS {1169}. Approximately
Table 6.05
International Cowden Consortium diagnostic criteria for CS.
Diagnostic criteria Operational diagnosis in an individual Operational diagnosis in a family where one
individual is diagnostic for Cowden
Pathognomonic Criteria 1. Mucocutanous lesions alone if: 1. At least one pathognomonic criterion
Mucocutanous lesions: a) there are 6 or more facial papules, of
Trichilemmomas, facial which 3 or more must be trichilemmoma, or 2. Any one major criterion with or without
Acral keratoses b) cutaneous facial papules and oral mucos- minor criteria
Papillomatous papules al papillomatosis, or
Mucosal lesions c) oral mucosal papillomatosis and acral ker- 3. Two minor criteria
atoses, or
Major Criteria d) palmoplantar keratoses, 6 or more
Breast CA
Thyroid CA, esp. follicular carcinoma 2. Two major criteria but one must include
Macrocephaly (Megencephaly) ( * 97%ile) macrocephaly or LDD
Lhermitte-Duclos disease (LDD)
3. One major and three minor criteria
Minor Criteria
Other thyroid lesions 4. Four minor criteria
(e.g. adenoma or multinodular goiter)
Mental retardation (IQ )75)
Gastro-intestinal hamartomas
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumours (e.g. uterine fibroids) or
malformation
R. Burt
Hyperplastic polyposis J.R. Jass
A B
Fig. 6.81 Small cell carcinoma. A Typical oval or moulded nuclei with diffuse chromatin, scant cytoplasm and little stroma. B Neuroendocrine granules in elec-
tronmicrograph.
nant (non-localized) tumours represent- For rectal carcinoids, an overall malig- scopic fields, and DNA aneuploidy
ed 71% of the cases among colonic car- nancy rate of 11% to 14% has been cal- {1963}. Patients with rectal carcinoids
cinoids, and 14% of cases among rectal culated in some studies {1251, 488}. generally have a good prognosis, show-
carcinoids {1251}. The alleged poor Recognised malignancy criteria include: ing a 5-year survival rate of 72%-89%
prognosis of colonic carcinoids has been a size of the tumour greater than 2 cm {1251, 1931}, which is better than the
questioned as possibly the result of a {857, 1328, 930}, invasion of the muscu- 5-year survival rate of 60% for patients
proportion actually being poorly differen- laris propria {857, 212, 1328}, atypical with jejuno-ileal carcinoids {211}. The
tiated adenocarcinomas with carcinoid- histology {964}, presence of more than 2 prognosis is excellent if the tumour diam-
like growth patterns {1928}. mitoses per 10 high power (X 400) micro- eter is 1 cm or less {294}.
A B
Fig. 6.88 Leiomyosarcoma. A Cigar-shaped nuclei. B Pleomorphic cells with atypical mitosis.
CHAPTER 7
Although incidence rates are still low, there has been a signif-
icant increase in squamous cell carcinoma over the last 50
years. HIV infected homosexual men appear particularly at
risk. HPV DNA is detectable in most anal squamous cell car-
cinomas.
_________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through muscularis mucosae into
submucosa.
Definition appendages. There exists no generally 100,000 in women and between 0.3 and
Tumours that arise from or are predomi- accepted definition of its outer limit {62, 0.8 per 100,000 in men {1471}. Still a rel-
nantly located in the anal canal. The 66, 845}. The term anus refers to the dis- atively rare disease, anal SCC has shown
most frequent neoplams of this region tal external aperture of the alimentary a remarkable increase in incidence dur-
are human papilloma virus (HPV-)associ- tract. Anal margin tumours are classified ing the past half century {540, 600, 1213}.
ated squamous cell carcinomas and according to the WHO histological typing From being similar in the two sexes until
adenocarcinomas. of skin tumours {682}. approximately 1960 at 0.2 per 100,000,
annual age-adjusted incidence rates in
Topographic definition of anal canal Squamous cell carcinoma Denmark rose 2.5-fold in men and 5-fold
and anal margin in women during the period 1943-1994.
The anal canal is defined as the terminal Definition For both men and women, urban popula-
part of the large intestine, beginning at Squamous cell carcinoma (SCC) of the tions are at higher risk than rural popula-
the upper surface of the anorectal ring anal canal is a malignant epithelial neo- tions {540, 600, 1213}, and there are con-
and passing through the pelvic floor to plasm that is frequently associated with siderable racial differences in incidence.
end at the anus {68}. The most important chronic HPV infection. In the United States, blacks tend to have
macroscopic landmark in the mucosa is higher incidence rates than whites
the dentate (pectinate) line composed of ICD-O code 8070/3 {1213}, while Asians and Pacific Islanders
the anal valves and the bases of the anal appear to be at very low risk {70}.
columns. Histologically, the mucosa can Epidemiology Homosexual men appear to constitute a
be divided into three zones. The upper SCC of the anal canal and anal margin group at particular risk {368, 538, 140,
part is covered with colorectal type typically occurs among patients in their 96, 369, 540, 1213, 1690, 730}. In the
mucosa. The middle part is the anal tran- 6th or 7th decade of life {540}. However, United States, the incidence of anal SCC
sitional zone (ATZ), which is covered by a anal SCCs may occur in young adults, in homosexual men has been estimated
specialized epithelium with varying particularly in patients with cellular to be 11 to 34 times higher than in the
appearances; it extends from the dentate immune incompetence {1212}. Unselec- general male population and approxi-
line and on average 0.5-1.0 cm upwards ted, population-based studies show an mately as high as the incidence of cervi-
{490, 1929}. The lower part extends from approximate 2:1 female predominance cal cancer before the introduction of cer-
the dentate line and downwards to the among patients with anal SCC {540, 600, vical cytology screening {369, 1447}. HIV
anal verge and has formerly been called 1213}. infected homosexual men appear to be
the pecten. It is covered by squamous There are few published, histologically at particularly risk {1212, 1449, 598}.
epithelium, which may be partly kera- verified incidence rates of anal cancer Other sexual factors strongly associated
tinized, particularly in case of mucosal {540, 600, 1213}. Data from most popula- with anal SCC include number of sexual
prolapse. tion-based cancer registries worldwide partner, receptive anal intercourse, and
The perianal skin (the anal margin) is show age standardized incidence rates co-existence of sexually transmitted dis-
defined by the appearance of skin of anal SCC of between 0.5 and 1.0 per eases {368, 538, 730, 733}.
Aetiology
Sexually transmittable human papillo-
maviruses (HPVs) are detected by PCR
in the majority of anal SCC {355, 367,
538, 704, 732, 1448}. One large study
showed that SCCs involving the anal
Anorectal ring canal are more often high-risk HPV posi-
Anal columns tive (92%) than lesions confined to the
Anal valves and sinuses Surgical anal canal perianal skin (64%) {536}, suggesting
that HPV-unrelated pathways may apply
Histological anal canal particularly to cancers of the perianal
DENTATE LINE
skin. A strong association with tobacco
Intersphincteric groove Anatomical anal canal
smoking has been established in women,
Anal verge, ‘anus’ but the role of smoking in men is less
clear {367, 539, 730, 733}. States of cel-
Fig. 7.01 Anatomy of the anal canal. Printed with permission from ref 490. lular immunosuppression are associated
ular, and a lymphocytic infiltrate may be gies, i.e. size of predominant neoplastic
pronounced or absent. None of these fea- cell, basaloid features, degree of keratin-
tures have been shown to have any prog- isation, adjacent squamous intraepithe-
nostic significance, but poor keratiniza- lial neoplasia, or presence of mucinous
tion, prominent basaloid features and microcysts.
small tumour cell size are related to infec- Apart from the verrucous carcinoma
tion with ‘high risk’ HPV {536}. The keratin mentioned below, only two rare histolog-
profile of anal SCC is complex and vari- ical subtypes seem to have a different
able {2112, 2113}. The usual immunoex- biological course, both having a less
pression pattern is shown in Table 7.01. favourable prognosis {1734}. One is
The second edition of the WHO classifi- characterized by areas with well formed
Fig. 7.06 Well differentiated squamous cell carci-
noma composed of large cells showing keratiniza- cation of SCC in the anal canal included acinar or cystic spaces containing mucin
tion. the large-cell keratinizing subtype, the that reacts with Alcian dyes or PAS after
large-cell non-keratinizing subtype, and diastase digestion. This is termed squa-
the basaloid subtype {845}. The value of mous cell carcinoma with mucinous
tumour cells may be facilitated by this classification of anal SCC has been microcysts. The other is characterized
immunostaining for high molecular weight questioned in recent years. Many by a rather uniform pattern of small
cytokeratins (CKs). tumours show more than one subtype. tumour cells with nuclear moulding, high
In 15-20% of cases, the lesion may infil- Thus in a study of 100 cases of anal car- mitotic rate, extensive apoptosis and dif-
trate the lower rectum and the neigh- cinomas, 99 showed some features of fuse infiltration in the surrounding stro-
bouring organs including the rectovagi- squamous differentiation (keratinisation, ma. This has been called small cell
nal septum, bladder, prostate and poste- stratification and prickles), 65 showed (anaplastic) carcinoma, but should not
rior urethra, sometimes with suppuration basaloid features (small cell change, pal- be confused with small cell carcinoma
and fistulas. The vulva is usually spared. isading, retraction artefact and central (poorly differentiated neuroendocrine
Lymphatic spread occurs in up to 40 per- eosinophilic necrosis) and 26 showed carcinoma).
cent of cases {165, 1174, 1621, 1719, focal evidence of ductal proliferation and
2033}. Tumours proximal to the pectinate occasionally positive staining for PAS
line drain into the pelvis along the middle after diastase digestion {2111}. Further-
rectal vessels to the pelvic side walls and more, the diagnostic reproducibility of
internal iliac chains and superiorly via the these subtypes is low {492}. This is prob-
superior rectal vessels to the periaortic ably the reason that the proportion of
nodes. Tumours distal to the dentate line basaloid carcinoma in larger series has
drain along cutaneous pathways to the varied from 10 to almost 70 %, and that
inguinal and the femoral nodal chains. no significant correlation between histo-
Inguinal nodes are involved in about logical subtype and prognosis has been
10-20% of cases {230, 575, 1174, 1650, established. In addition, the histological
1692}. Inguinal lymph nodes can be diagnosis is nowadays nearly always per-
involved bilaterally in a small number of formed on small biopsies, that may not be Fig. 7.08 Squamous cell carcinoma showing a
cases at time of presentation. Retrograde representative for the whole tumour {492}. combination of basaloid and squamous features.
lymphatic drainage occurs in advanced Therefore, it is recommended that the
cases when the lymphatics are obstruct- generic term ‘squamous carcinoma’ be
ed by malignant spread {1621, 1719}. used for these tumours, accompanied by Squamous cell carcinoma of anal margin
a comment describing those histopatho- The distinction between anal canal and
Histopathology logical features that may possibly affect anal margin SCC may be difficult, as
Squamous cell carcinoma of anal canal the prognosis or reflect different aetiolo- tumours often involve both areas at the
Anal SCC may show a single predomi- time of diagnosis. This may account for
nant line of differentiation, but most exhib- the varying data on prognosis, but this is
it a mixture of areas with different histo- generally better for anal margin SCC
N
logical features. One pattern is that of than for anal canal SCC, in particular if
large, pale eosinophilic cells and kera- local resection is possible {392, 530,
tinization of either lamellar or single cell 1484}. Anal margin SCC is often of the
type. Another is that of small cells with large cell variant {536, 1484}.
palisading of the nuclei in the periphery
of tumour cell islands. The latter often Verrucous carcinoma
contain necrotic eosinophilic centres. In the anogenital area, this tumour is also
Intermediate stages between these two called giant (malignant) condyloma or
extremes are often present. Differentia- Buschke-Lowenstein tumour. It has a
tion into tubular or spindle cell configura- Fig. 7.07 Squamous cell carcinoma composed of cauliflower-like appearance, is larger
tion may be found. The invasive margin basaloid cells. Central necrosis (N) of tumour nests than the usual condyloma with a diame-
can vary from well circumscribed to irreg- is typical. ter up to 12 cm, and fails to respond to
Intraepithelial neoplasia
Precancerous anal intraepithelial neopla-
sia (AIN) in the anal transition zone (ATZ)
and the squamous zone, has also been
A termed dysplasia, carcinoma in-situ and
B
anal squamous intraepithelial lesion
Fig. 7.09 Squamous cell carcinoma of anus. A Combination of basaloid features and keratinization. B Large
(ASIL) {494, 1449}. The corresponding
cells, poorly differentiated.
lesions in the perianal skin are commonly
referred to as Bowen disease. This termi-
conservative treatment. In contrast to an 33 published anorectal cases, 42 per nology is complicated by the fact that the
ordinary condyloma, it is characterized cent have shown malignant transforma- precancerous changes are not always
by a combination of exophytic and endo- tion {133}. The presence of severe cyto- restricted to one area. Leukoplakia is a
phytic growth. Histologically, it shows logical changes, unequivocal invasion or clinical term and should not be used as a
acanthosis and papillomatosis with metastases should lead to the diagnosis histological diagnosis.
orderly arrangement of the epithelial lay- of SCC and to the appropriate therapy. Anal intraepithelial neoplasia (squamous
ers and an intact but often irregular base cell dysplasia in the anal canal). Most
with blunt downward projections and ker- Grading cases of AIN are incidental findings in
atin-filled cysts. The endophytic growth Poor prognosis has been related to poor minor surgical specimens for benign con-
is accompanied by destruction of the differentiation {165}, especially if this was ditions. When macroscopically detected,
underlying tissues. Cytologically, the defined only by the degree of dissocia- AIN may present as an eczematoid or
epithelial cells appear benign. Large tion of tumour cells {599}. However, such papillomatous area, or as papules or
nuclei with prominent nucleoli may be differences may be related to tumour plaques. The latter may be irregular,
present, but dysplasia is usually minimal stage in multivariate analysis {1734}. raised, scaly, white, pigmented or erythe-
and mitoses are restricted to the basal Grading on biopsies is not recommend- matous and occasionally fissured. Indur-
layers {162}. ed, as these may not be representative ation or ulceration may indicate invasion.
Some verrucous carcinomas contain for the tumour as a whole. Histologically, AIN is characterized by
HPV, the most common types being 6 varying degrees of loss of stratification
and 11. They are regarded as an inter- Precursor lesions and benign tumours and nuclear polarity, nuclear pleomor-
mediate state between the ordinary Chronic HPV infection phism and hyperchromatism, and in-
condyloma and SCC, and the clinical Warts in the perianal skin and lower anal creased mitotic activity with presence of
course is typically that of local destruc- canal (condyloma acuminatum) show the mitoses high in the epithelium. The sur-
tive invasion without metastases. Among same histology as their genital counter- face may or may not be keratinized, and
koilocytic changes may be present.
AIN has been graded into I, II or III, or
into mild, moderate and severe dysplasia
{494}. Reproducibility studies have
shown considerable observer variation
{254}. A two grade system (low- and
high-grade) may be more appropriate.
Squamous dysplasia at the anal margin -
Bowen disease. Clinically, this presents
as a white or red area in the perianal skin
that may be in continuity with dysplastic
lesions in the anal canal. HPV DNA is
sometimes identified, including types 16
and 18, among others. Histologically it
shows full thickness dysplasia of the
squamous and sometimes the piloseba-
ceous epithelium, with disorderly matura-
tion, mitoses at all levels and dyskerato-
sis. Occasionally, atypical keratinocytes
may resemble Paget cells, but are nega-
tive for low molecular weight CKs and for
mucin. In pigmented Bowen disease the
Fig. 7.10 Mucinous carcinoma of anus. Tumour extends to anal sphincter. neoplastic cells are invariably negative
B
Fig. 7.17 A, B Inflammatory cloacogenic polyp.
Dilated elongated hyperplastic glands showing
Fig. 7.15 Low-grade squamous intraepithelial neo- Fig. 7.16 High-grade squamous intraepithelial neo- regenerative atypia. Surface erosion is a constant
plasia with koilocytosis. plasia with hyperkeratosis. feature.
associated Paget disease of the anus from ordinary colorectal type adenocar- mucin composition {491} and keratin
(see below). Tumour spread and staging cinoma, and do not seem to represent a expression {2113}.
largely correspond to anal SCC. special entity except for their low loca- Adenocarcinoma within anorectal fistula.
tion. Adenocarcinoma in the anal transi- These tumours develop in pre-existing
Histopathology tional zone (ATZ) may develop after anal sinuses or in fistulae {74}. Some are
Adenocarcinoma arising in anal mucosa restorative proctocolectomy for ulcera- associated with Crohn disease {992}.
Most adenocarcinomas found in the anal tive colitis {1711}. Others may contain epithelioid granulo-
canal represent downward spread from Extramucosal (perianal) adenocarcinoma mas, often related to foci of inflammation
an adenocarcinoma in the rectum or Approximately two hundred cases of or extravasated mucin but without other
arise in colorectal type mucosa above extramucosal adenocarcinoma have signs of inflammatory bowel disease
the dentate line. Macroscopically and been reported, the largest series unfortu- {863}.
histologically, they are indistinguishable nately with insufficient histological data Rarely, the tumours may be related to fis-
{9}. A minimum criterion for the diagnosis tulae lined by normal rectal mucosa
is an overlying non-neoplastic mucosa, including muscularis mucosae, most
which may be ulcerated. Recent reports likely representing adenocarcinomas
indicate that about two thirds of these arising in congenital duplications {863}.
tumours manifest in men with a mean age Histologically, carcinomas arising in fistu-
about 60 years. Reliable data for the lae usually are of the mucinous type, but
prognosis for such patients have not tubular adenocarcinomas and squamous
been identified. Difficulties in establishing neoplasia can also be found {992, 2173}.
the correct diagnosis may delay proper Adenocarcinoma of anal glands. Only a
treatment. few cases have been reported in which
Extramucosal adenocarcinoma seem to convincing evidence for origin in an anal
fall into two groups, based on their asso- gland has been demonstrated by conti-
ciation with either fistulae or remnants of nuity between anal gland epithelium and
anal glands. At present, no laboratory tumour {118, 650, 1472, 2087, 2131}.
methods can distinguish between these With a single exception {650}, these
two. patients have had no history of previous
The epithelium of persistent anal fistulae or concomitant fistula. The tumours were
is most often of the same type as found all characterized by a combination of
in the anal glands and ATZ {1117}, and ductular and mucinous areas. Pagetoid
the epithelium in these two locations spread was present in at least one case
Fig. 7.18 Adenocarcinoma arising in a fistula. show the same profile with regard to {2131}.
A B
Fig. 7.21 Secondary Paget disease of the anus. A The underlying adenocarcinoma is present beneath the Fig. 7.22 Malignant melanoma of anus with typical
squamous epithelium. High molecular weight keratin immunostain is largely restricted to normal squamous polypoid appearance.
epithelium. B Low molecular weight keratins 8 and 13 immunostaining of tumour cells.
Malignant melanoma haematogenously to the liver and thence {902}, fibrosarcoma, neurilemmoma and
Anal melanoma is rare. It is a disease of to other organs. Metastases are frequent neurofibroma {571}, granular cell tumour
adults with a wide age range; most at time of presentation, and the progno- (myoblastoma) {862}, spindle cell lipoma
patients are white {339, 182}. Presen- sis is poor; the 5-year survival is less than and aggressive angiomyxoma {503} and
tation is usually with mass and rectal 10% {339, 157}. The chances of long- extraspinal ependymoma in a newborn
bleeding, but tenesmus, pain and term survival are increased if the lesion is {2074}. HIV infected persons may, in
change in bowel habit also occur {339}. small. addition to the increased risk of squa-
Macroscopy. Lesions may be sessile or mous neoplasia, develop Kaposi sarco-
polypoid. Pigmentation of the lesion is Mesenchymal and neurogenic ma in the perianal area {113}.
often appreciated. Satellite nodules may tumours
occur. These are all rare and the exact point of Malignant lymphoma
Histopathology. The features resemble origin may be difficult to establish. Primary lymphomas of the anorectal
those of cutaneous melanomas. The Recent reports on tumours in the anorec- region are rare in the general population,
majority shows a junctional component tal and perianal area include haeman- but much more common in patients with
adjacent to the invasive tumour, and this gioma, lymphangioma {372}, haeman- AIDS, particularly homosexual men. All
finding is evidence that the lesion is pri- giopericytoma {478}, leiomyoma, malig- are of B-cell type, the most common
mary rather than metastatic. The tumour nant fibrous histiocytoma and leio- types being large cell immunoblastic or
cells express S-100 and HMB-45. myosarcoma {1110}, rhabdomyoma in a pleomorphic {687, 786}. Langerhans cell
Prognosis. Anal melanomas spread by newborn {1014}, and rhabdomyosarco- histiocytosis has been described in chil-
lymphatics to regional nodes, and ma in childhood {1560} and adulthood dren {617, 874} and an adult {329}.
A B C
Fig. 7.23 Malignant melanoma of anus. A Polypoid growth is frequent. B Scattered tumour cells contain melanin. C Epitheloid melanoma cells with prominent nucleoli.
Table 7.01
Anal tumours, immunoreactivity profile (exceptions occur, especially among CK and mucin)1
CK CK CK
8+18 7/20 5+14 Mucin CEA Vim Special
––––––––––
1
Chrom = Chromogranin A PSA = Prostate specific antigen
CK = Cytokeratin PSAP = Prostate specific acid phosphatase
CRC = Colorectal carcinoma Synap = Synaptophysin
GCDFP = Gross cystic disease fluid protein Vim = Vimentin
CHAPTER 8
WHO histological classification of tumours of the liver and intrahepatic bile ducts
Epithelial tumours Others
Benign Miscellaneous Tumours
Hepatocellular adenoma (liver cell adenoma) 8170/01 Solitary fibrous tumour 8815/0
Focal nodular hyperplasia Teratoma 9080/1
Intrahepatic bile duct adenoma 8160/0 Yolk sac tumour (endodermal sinus tumour) 9071/3
Intrahepatic bile duct cystadenoma 8161/0 Carcinosarcoma 8980/3
Biliary papillomatosis 8264/0 Kaposi sarcoma 9140/3
Rhabdoid tumour 8963/3
Malignant
Others
Hepatocellular carcinoma (liver cell carcinoma) 8170/3
Intrahepatic cholangiocarcinoma 8160/3 Haemopoietic and lymphoid tumours
(peripheral bile duct carcinoma) Secondary tumours
Bile duct cystadenocarcinoma 8161/3
Epithelial abnormalities
Combined hepatocellular and cholangiocarcinoma 8180/3
Hepatoblastoma 8970/3 Liver cell dysplasia (liver cell change)
Undifferentiated carcinoma 8020/3 Large cell type (large cell change)
Small cell type (small cell change)
Non-epithelial tumours Dysplastic nodules (adenomatous hyperplasia)
Benign Low-grade
Angiomyolipoma 8860/0 High-grade (atypical adenomatous hyperplasia)
Lymphangioma and lymphangiomatosis 9170/0 Bile duct abnormalities
Haemangioma 9120/0 Hyperplasia (bile duct epithelium and peribiliary glands)
Infantile haemangioendothelioma 9130/0 Dysplasia (bile duct epithelium and peribiliary glands)
Intraepithelial carcinoma (carcinoma in situ) 8500/211
Malignant
Miscellaneous lesions
Epithelioid haemangioendothelioma 9133/1
Angiosarcoma 9120/3 Mesenchymal hamartoma
Embryonal sarcoma (undifferentiated sarcoma) 8991/3 Nodular transformation
Rhabdomyosarcoma 8900/3 (nodular regenerative hyperplasia)
Inflammatory pseudotumour
_________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded
/0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for in situ carcinomas and grade III intraepithelial neoplasia and /3 for malignant tumours.
_________
1
{1, 66}. This classification applies only to primary hepatocellular and cholangio-(intrahepatic bile duct) carcinomas of the liver.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
For classification, the plane projecting between the bed of the gallbladder and the inferior vena cava divides the liver in two lobes.
3.6
6.6 35.8
28.4
4.1
3.1
> 8% = high
2-7% = intermediate
< 3.6 < 5.4 < 10.8 < 20.9 < 48.9 < 2% = low
Fig. 8.01 Worldwide annual incidence (per 100,000) of liver cancer in males Fig. 8.02 Geographic distribution of the prevalence of chronic HBV infection,
(1995). Numbers on the map indicate regional average values. based on HBs Ag serology.
Alcohol
Among Western populations, alcohol-
induced liver injury is the leading cause
of chronic liver disease and liver cirrhosis
and constitutes the most important HCC
risk factor {426}. Regular daily consump-
tion of > 50g ethanol in females or
> 80g in males is generally considered
sufficient to induce liver cirrhosis,
although individual susceptibility can
vary considerably. Patients who abuse Fig. 8.07 Hepatocellular carcinoma, trabecular.
A B C
D E F
H G I
Fig. 8.08 Histological subtypes of hepatocellular carcinoma. A Pseudoglandular. B Clear cell. C Fatty change. D Spindle cell. E Scirrhous type. F Scirrhous type,
Masson trichrome stain. G Poorly differentiated, with numerous mitotic figures. H Pleomorphic. I Multinucleated giant cell.
tion in codon 249 of the TP53 tumour eral malaise, anorexia or weight loss, and development, AFP levels do not closely
suppressor gene, leading to an amino nausea or vomiting. The symptoms are correlate with clinical HCC stage. AFP
acid substitution of arginine to serine caused by the underlying chronic liver levels, therefore, have to be interpreted
{188}. In Southern China and disease or cirrhosis and its clinical com- individually in the context of other clinical
Subsaharan Africa, the two world regions plications, or by the HCC itself. The most symptoms and signs as well as imaging
with the highest levels of food contami- common clinical signs in HCC patients studies. Another HCC-specific marker is
nation with AFB1, this mutation is present are hepatomegaly, ascites, fever, jaun- des-gamma-carboxyprothrombin (DCP),
in > 40% of HCC {1265} and can be dice, and splenomegaly. which is roughly equivalent to AFP.
detected in serum DNA of patients with The laboratory findings are in part deter- Occasionally, HCC patients develop a
preneoplastic lesions and HCC {924}. In mined by the underlying liver disease, paraneoplastic syndrome, with erythrocy-
regions where AFB1 levels in food are which results in elevations of various liver tosis, hypoglycaemia or hypercalcaemia.
very low or undetectable, codon 249 enzymes, such as aspartate amino trans-
transversion mutations are either very ferase (AST), alanine aminotransferase Imaging
rare or absent. (ALT), alkaline phosphatase (AP), Imaging studies are important in patient
gamma-glutamyl-transpeptidase (GGT), management for the identification and
Clinical features and bilirubin. These laboratory parame- localization of HCC. Useful techniques
Symptoms and signs ters are not HCC-specific, however. A include ultrasonography of the liver and
Most HCC patients have a past or current significantly raised level of alpha-fetopro- the abdomen, colour Doppler ultra-
history of chronic liver disease from dif- tein (AFP) of > 500 ng/ml, or continuous- sonography, computed tomography
ferent causes {1681}. The major clinical ly rising values even if less than 100 (CT), lipiodol CT, magnetic resonance
risk factor for HCC development is liver ng/ml, strongly suggest HCC. However, imaging, angiography, and possibly
cirrhosis; 70–90% of HCCs develop in a not all cases of HCC are associated with positron emission tomography. The stan-
macronodular cirrhosis {452}. AFP elevation, and raised AFP may also dard imaging techniques are ultrasonog-
The presenting symptoms in patients be found in liver disease without HCC. raphy and CT. In most cases, these allow
with HCC include abdominal pain, gen- Furthermore, in the early stages of HCC HCC detection and staging. In patients
A B
Fig. 8.09 A Numerous Mallory bodies in a hepatocellular carcinoma (two examples indicated by arrows). B Hyaline inclusions in a hepatocellular carcinoma.
A B
Fig. 8.10 Pale bodies in hepatocellular carcinoma. A Haematoxylin and eosin. B Immunoreactivity for fibrinogen.
with suspected HCC metastases, a chest with liver cirrhosis tend to present as an nodules are distributed throughout the
X-ray, bone scan, or other imaging expansile tumour with a fibrous capsule liver and may be difficult to be distin-
modalities may be indicated. and intratumoural septa, while those guished from regenerative nodules in
without cirrhosis tend to be massive and liver cirrhosis.
Liver biopsy non-encapsulated. Varying degrees of Hepatocellular carcinomas are occasion-
The definitive diagnosis of HCC depends infiltrative growth, tumour thrombi in the ally pedunculated. Patients are usually
on the histological examination of the portal veins, and intrahepatic metas- females and the tumours are thought to
lesion, especially in AFP-negative tases, which are common in advanced arise in accessory lobes of the liver.
patients. Ultrasound- or CT-guided percu- tumours, modify the gross appearance. Following surgical resection, the progno-
taneous biopsy with a 22-gauge needle Occasionally, numerous minute tumour sis is excellent.
usually provides sufficient tissue for diag-
nosis with minimum risk of bleeding or
seeding of tumour cells along the needle Table 8.01
tract. However, in patients with signifi- Immunohistochemistry of HCC.
cantly elevated AFP levels who are poten- Antigen Result
tially eligible for HCC resection or liver
transplantation, liver biopsy is not recom- Hepatocyte (Dako) Positive (most useful in diagnosis)
mended to eliminate the residual risk of Polyclonal carcinoembryonic antigen Positive (canalicular pattern)
tumour cells spreading before surgery. Alpha fetoprotein Positive or negative
Fibrinogen Positive or negative
Cytokeratins 8 and 18 Usually positive
Macroscopy
Cytokeratins 7 and 19 Usually negative
Macroscopic features of HCCs vary
Cytokeratin 20 Usually negative
depending on the size of the tumour and Epithelial membrane antigen Negative
the presence or absence of liver cirrho- BER EP4 Negative
sis. In general, most HCCs associated
A B
Fig. 8.11 Hepatocellular carcinoma in a 17-year old patient with Fanconi anaemia. A Green bile staining and extensive necrosis and haemorrhage. B Trabecular and
pseudoglandular pattern with bile plugs.
Tumour spread entiated tumours {1894}. HCCs vary Scirrhous. This uncommon type is char-
Invasion into the blood vessels, in partic- architecturally and cytologically. The dif- acterised by marked fibrosis along the
ular into the portal vein, is a characteris- ferent architectural patterns and cytolog- sinusoid-like blood spaces with varying
tic of HCC. Tumour thrombi in the portal ical variants frequently occur in combina- degrees of atrophy of tumour trabeculae.
veins are present in more than 70% of tion. Immunohistochemical features of It is observed even in small tumours. The
autopsies of advanced HCCs. Intra- HCC are summarized in Table 8.01. scirrhous type should not be confused
hepatic metastases is caused mostly by with cholangiocarcinoma or fibrolamellar
tumour spread through the portal vein Architectural patterns carcinoma. Similar fibrotic changes
branches. Tumour invasion into the major Trabecular (plate-like). This pattern is the occur following chemotherapy, radiation,
bile ducts is infrequent clinically, but most common in well and moderately dif- and transchemo arterial embolization.
found in about 6% of autopsy cases. ferentiated HCCs. Tumour cells grow in Such post-therapeutic fibrosis should be
Extrahepatic metastasis is mostly cords of variable thickness that are sep- distinguished from the scirrhous variant.
haematogenous, the lungs being the arated by sinusoid-like blood spaces. The term 'sclerosing hepatic carcinoma'
most common target. Regional lymphatic Well-differentiated tumours have a thin
metastasis is frequent though distant trabecular pattern and trabeculae
lymph nodes are rarely involved. become thicker with de-differentiation.
Sinusoid-like blood spaces often show
Histopathology varying degrees of dilatation, and pelio-
HCCs consist of tumour cells that resem- sis hepatis-like change are occasionally
ble hepatocytes. The stroma is com- observed in advanced HCCs.
posed of sinusoid-like blood spaces lined Pseudoglandular and acinar. HCC fre-
by a single layer of endothelial cells. quently has a glandular pattern, usually
Unlike the sinusoidal endothelial cells in admixed with the trabecular pattern. The
normal liver tissue, those of HCC are glandular structure is formed mostly by a
immunohistochemically positive for single layer of tumour cells, and some
CD34 and factor-VIII-related antigen. glandular or acinar structures are formed Fig. 8.12 Immunostaining for polyclonal CEA
Ultrastructural observation shows a base- by dilatation of the bile canaliculus-like demonstrates canaliculi in a hepatocellular carci-
ment-membrane-like structure between structure between cancer cells. Pseudo- noma.
the endothelial cells and tumour cell tra- glands frequently contain proteinaceous
beculae, and basement-membrane-like fluids, which often stain with PAS but do
materials are immunohistochemically not stain with mucicarmine or Alcian blue.
positive with antibodies for laminin and Bile may be present. Cystic dilatation of
type IV collagen. Thus, the sinusoid-like the pseudoglands sometimes occurs,
blood spaces resemble capillary vessels. such dilated glands are occasionally
This phenotypic change of sinusoids is formed by degeneration of thick trabecu-
called 'capillarization' {472, 919, 917}. lae. Generally, the glandular structure is
In the sinusoidal blood spaces, varying smaller in well differentiated tumours than
numbers of macrophages, which show in moderately differentiated tumours.
immunohistochemical positivity with anti- Compact. Sinusoid-like blood spaces
lysozyme and CD68, are also present are inconspicuous and slit-like, giving Fig. 8.13 Bile production in a hepatocellular carci-
and resemble Kupffer cells in well differ- the tumour a solid appearance. noma.
{1424}, which has been used to desig- alpha-fetoprotein. Some are also positive patients. They stain with modified orcein,
nate a variety of tumours arising in non- for cytokeratin. Victoria blue, or aldehyde fuchsin, and
cirrhotic livers and associated with Fatty change. Diffuse fatty change is show immunohistochemical positivity
hypercalcemia, does not constitute a dis- most frequent in small, early-stage with anti-HBsAg antibody. They are not
tinct histopathological entity {806}, some tumours less than 2 cm in diameter. Its seen in tumour casts in the portal vein or
of these tumours appear to be hepato- frequency declines as tumour size in extrahepatic metastases, and most are
cellular, but others are intrahepatic increases, and fatty changes are rather thought to be HBsAg-positive hepato-
(peripheral) cholangiocarcinomas. infrequent in advanced tumours. Meta- cytes entrapped in a tumour.
bolic disorders related to hepatocarcino-
Cytological variants genesis and insufficient blood supply in Fibrolamellar HCC
Pleomorphic cell. Tumour cells show the early neoplastic stage have been This variant usually arises in non-cirrhotic
marked variation in cellular and nuclear suggested as a possible mechanism for livers of adolescents or young adults
size, shape, and staining. Bizarre the development of fatty change in small {353}. It is rare in Asian and African coun-
multinucleated or mononuclear giant tumours, but a definite mechanism has tries but not so rare in Western countries.
cells are often present, and osteoclast- not yet been determined. The tumour cells grow in sheets or small
like giant cells may be seen rarely. Bile production. Bile is occasionally trabeculae that are separated by hyalin-
Generally, pleomorphic tumour cells lack observed, usually as plugs in dilated ized collagen bundles with a character-
cohesiveness and do not show a distinct canaliculi or pseudoglands. When bile istic lamellar pattern. They are large and
trabecular pattern. Pleomorphic cells are production is prominent, the tumour is polygonal and have a deeply eosino-
common in poorly differentiated tumours. yellowish in color and turns green after philic and coarsely granular cytoplasm
Clear cell. The tumour consists predom- formalin fixation. and distinct nucleoli. The eosinophilic
inantly of cells with clear cytoplasm due Mallory hyaline bodies are intracytoplas- granularity is due to the presence of a
to the presence of abundant glycogen. mic, irregular in shape, eosinophilic and large number of mitochondria. Pale bod-
This type is sometimes difficult to distin- PAS-negative. They consist of aggregat- ies are frequently present, and stainable
guish from metastatic renal cell carcino- ed intermediate filaments and show copper, usually in association with bile,
ma of clear cell type. immunohistochemical positivity with anti- can occasionally be shown.
Sarcomatous change. HCC occasionally ubiquitin antibodies.
appears sarcomatous, characterised by Globular hyaline bodies are small, round, Undifferentiated carcinoma
the proliferation of spindle cells or bizarre homogeneous, and strongly acidophilic Undifferentiated carcinoma is rare,
giant cells. When the tumour consists intracytoplasmic bodies. They are accounting for less than 2% of epithelial
solely of sarcomatous cells, it is difficult PAS-positive and stain orange to red with liver tumours. There is male preponder-
to distinguish from sarcomas such as Masson trichrome stain. Immunohisto- ance but data on geographical distribu-
fibrosarcoma and myogenic sarcoma. chemically, they are often positive for tion are not available. Localization, clini-
When sarcomatous features are predom- alpha-1-antitrypsin. cal features, symptoms and signs, and
inant, the tumour is called sarcomatoid Pale bodies are intracytoplasmic, round diagnostic procedures display no differ-
HCC or sarcomatous HCC. In many to ovoid, amorphous and lightly eosino- ence as compared to hepatocellular car-
cases, however, the sarcomatous philic. They represent an accumulation cinoma. Undifferentiated carcinomas are
change is present in a part of the tumour, of amorphous materials in cystically postulated to have a worse prognosis
and transitional features between dilated endoplasmic reticulum, and (compared to HCC), although greater
trabecular HCC and sarcomatous com- show distinct immunohistochemical pos- case numbers to support this are not
ponents are frequent. Sarcomatous itivity with anti-fibrinogen {1846}. They available {351, 806}.
change is more frequent in cases with are commonly seen in the fibrolamellar
repeated chemo-therapy or transchemo variant of HCC but are also found in the Grading
arterial embolization {953}, but it is also common types of HCC, especially in According to histological grade, HCC is
seen in small tumours. Most sarcoma- scirrhous HCC. classified into well differentiated, moder-
tous cells are positive for vimentin or Ground glass inclusions are rarely ately differentiated, poorly differentiated,
desmin but negative for albumin and observed in tumours of HBsAg-positive and undifferentiated types.
A B C
Fig. 8.14 Nodule-in-nodule type of hepatocellular carcinoma. The border between early and advanced components is shown in C.
A B
Fig. 8.15 A, B Fibrolamellar type of hepatocellular carcinoma.
Well differentiated HCC. This is most abundant eosinophilic cytoplasm and HBV integration pattern, chromosomal
commonly seen in small, early-stage round nuclei with distinct nucleoli. A allele loss, and mutational inactivation of
tumours less than 2 cm in diameter and pseudoglandular pattern is also frequent, tumour suppressor genes has indicated
is rare in advanced tumours. The lesions and pseudoglands frequently contain multicentric independent development of
are composed of cells with minimal atyp- bile or proteinaceous fluid. these nodules {1647, 1392}. These stud-
ia and increased nuclear/cytoplasmic Poorly differentiated HCC. This prolifer- ies have shown that nodules apparently
ratio in a thin trabecular pattern, with fre- ates in a solid pattern without distinct growing from portal vein tumour thrombi
quent pseudoglandular or acinar struc- sinusoid-like blood spaces, and only - or satellite nodules surrounding a large
tures and frequent fatty change. In most slitlike blood vessels are observed in main tumour represent intrahepatic
tumours larger than 3 cm in diameter, large tumour nests. Neoplastic cells metastases, whereas other nodules can
well-differentiated carcinoma is observed show an increased nuclear/cytoplasmic be considered multicentric HCCs if they
only in the periphery if at all. ratio and frequent pleomorphism, includ- satisfy any of the following three criteria:
Moderately differentiated HCC. The mod- ing bizarre giant cells. Poorly differentiat- (1) multiple, small early-stage HCCs or
erately differentiated type is the common- ed HCC is extremely rare in small early- concurrent small early-stage HCCs and
est in tumours larger than 3 cm in diame- stage tumours. classical HCCs; (2) presence of periph-
ter and is characterized by tumour cells Malignant progression of HCC. HCC is eral areas of well differentiated HCC in
arranged in trabeculae of three or more known to vary histologically even within a both lesions or in the smaller ones; and
cells in thickness. Tumour cells have single nodule. From the viewpoint of his- (3) multiple HCCs of obviously different
tological grade, most cancer nodules histology.
less than 1 cm in diameter have a uniform Multicentric HCCs are associated with a
distribution of well differentiated cancer- high rate of tumour recurrence, even
ous tissues, whereas approximately 40% after curative resection, making treat-
of cancer nodules 1.0-3.0 cm in diameter ment difficult and the prognosis poor.
consist of more than 2 types of tissue of The presence of hyperplastic foci, small-
different histological grades {900}. Less cell dysplasia, an increase in the prolifer-
differentiated tissues are always located ative activity of non-tumourous liver tis-
inside, surrounded by well differentiated sue, or the progression of background
tumour on the outside. The area of well liver disease are risk factors for multicen-
differentiated neoplasm diminishes as the tric HCC development {1902, 1859}.
A tumour size increases, and they are com-
pletely replaced by less-well-differentiat-
ed cancerous tissues when the tumour
size reaches a diameter of around 3 cm.
When less-well-differentiated areas within
a well differentiated tumour nodule are
growing expansively, the nodule often
has a 'nodule-in-nodule' appearance
{1275}.
ed and explant livers have revealed new In contrast, classical HCCs, even if small
information about the morphological and well differentiated, show tumour
characteristics of small early-stage HCC blushing without portal flow {1883}.
and equivocal nodular lesions. The most Invasion into the stromal tissue can be
striking information is that HCC associat- sometimes identified, but vascular inva-
ed with cirrhosis probably evolves from sion and intrahepatic metastases are
precancerous lesions, and well differenti- exceptional {1942}. Moreover, these
ated HCC further progresses to a less lesions are locally curable, have a favor-
differentiated form {952, 1646, 1882, able long-term outcome, and can be
1645, 81}. defined clinically as 'early HCC'. B
Histological features of small early-stage Adenomatous hyperplasia (dysplastic
HCC nodules)
Although some small HCCs show fea- This lesion is characterized by marked
tures of classical HCCs, most less than enlargement of individual cirrhotic nod-
1.5 cm in diameter are vaguely nodular ules that show thick liver cell plates.
with indistinct margins macroscopically Small nodular lesions, most of which are
and have a uniform distribution of well below 1.5 cm in size, have been noticed
differentiated cancerous tissues. They in the livers of patients with HCCs that
are characterized by increased cell den- have been resected surgically and in
sity with increased nuclear/cytoplasmic explant cirrhotic livers. The nodules show
C
Fig. 8.19 A–C Atypical adenomatous hyperplasia
ratio, increased staining intensity variable atypia but lack features of defi-
with mild atypia and extensive fatty change.
(eosinophilic or basophilic), irregular thin nite malignancy. Macroscopically, most
trabecular pattern with a frequent acinar lesions are vaguely nodular and are not
or pseudoglandular pattern, and fatty much different from small, well differenti- pattern. There are many portal tracts
change {959, 1324}. Diffuse fatty change ated HCC with indistinct margins; it is within the nodules but no invasion into
of tumour cells is present in approxi- almost impossible to distinguish them the portal tracts. These nodules some-
mately 40% of tumours less than 2 cm in from cancer on the one hand or from times contain distinct, well differentiated
diameter. Many portal tracts are present large regenerative nodules on the other cancer foci. Many of them gave rise to
within the tumour nodule, and tumour cell hand. Microscopically, they are charac- distinct HCC in clinical follow-up studies
invasion into some portal tracts can be terized by a moderate increase in cell {1882, 1645} and are, therefore, consid-
seen. At the tumour boundary, neoplastic density with a slightly irregular trabecular ered precancerous lesions. Some of
A B
Fig. 8.18 Adenoma. A Extensive central haemorrhage. B Benign appearing hepatocytes arranged in plates, one or two cells thick.
A B
Fig. 8.20 Focal nodular hyperplasia. A Solitary lobulated nodule with typical central stellate scar. B Masson trichrome stain shows extensive blue connective tissue
component.
these nodules contain areas with a nodule, high grade) and early-stage hypothesis that small cell dysplasia,
marked increase in cell density, a more HCC are still under discussion, mainly rather than large cell dysplasia, is the
irregular trabecular pattern, and frequent due to the lack of objective phenotypic or precancerous lesion in man.
fatty change, characteristic of well differ- genotypic markers {1080, 64, 805}.
entiated HCC but insufficient in extent to Hepatocellular adenoma
warrant such a diagnosis. Focal liver cell dysplasia (LCD) A benign tumour composed of cells
These foci have been designated adeno- Large cell dysplasia. The term liver cell closely resembling normal hepatocytes,
matous hyperplasia {1080, 806} or dys- dysplasia (LCD) was first coined by which are arranged in plates separated
plastic nodule {64}. Additional terms Anthony et al. {73} to describe a change by sinusoids. On gross examination,
used for these lesions include macrore- characterized by cellular enlargement, adenomas are soft, rounded, yellow or
generative nodule, hyperplastic nodule nuclear pleomorphism and multinucle- tan masses, often with areas of necrosis,
and borderline lesions. ation of liver cells occurring in groups or haemorrhage, and fibrosis. A fibrous
Morphological criteria for the differential occupying whole cirrhotic nodules. The capsule is uncommon. Lesions are soli-
diagnosis of adenomatous hyperplasia change was found in only 1% of patients tary in two-thirds of cases {511}. When
(dysplastic nodule, low grade), atypical with normal livers, in 7% of patients with more than 10 lesions are encountered, a
adenomatous hyperplasia (dysplastic cirrhosis and in 65% of patients with cir- diagnosis of 'adenomatosis' has been
rhosis and HCC. There was a strong rela- recommended {511}.
tionship between LCD and HBsAg Adenoma is histologically composed of
seropositivity {73}. They concluded that benign-appearing hepatocytes arranged
the presence of LCD identified a group of in plates one or two cells in thickness
patients at high risk for development of {64, 803, 351, 71}. Portal tracts are
HCC, and that such patients should be absent; the lesion is supplied by arteries
followed by serial alpha-fetoprotein and veins. In most cases, the tumour
determinations. cells are uniform in size and shape, but
Small cell dysplasia. Watanabe et al. occasionally, mild to moderate cytologi-
{2068} have expanded the original defi- cal variation may be seen. Mitotic activi-
nition of LCD to include a 'small cell' vari- ty is almost never found. Lipofuscin, fat
A ant. The nuclear/cytoplasmic ratio is and clear cell change (due to water or
increased in small cell dysplasia, the glycogen accumulation) are often pres-
ratio being between that of liver cancer ent in the cytoplasm. Haemorrhage,
and normal hepatocytes. This is in con- infarction, fibrosis, and peliosis hepatis
trast to large cell dysplasia that has nor- may be seen.
mal nuclear/cytoplasmic ratio. Also, The differential diagnosis may be difficult
multinucleation and large nucleoli are with small biopsies. Features suggesting
characteristic of large cell dysplasia but hepatocellular carcinoma include mito-
not small cell dysplasia. The small dys- ses, high nuclear/cytoplasmic ratio, and
plastic cells have more of a tendency to plates more than 2 cells in thickness.
B form small round foci than large dysplas- Loss of a normal reticulin pattern is com-
Fig. 8.21 Nodular regenerative hyperplasia. tic cells. On the basis of their morpho- mon in HCC whereas it is preserved in
A Multiple pale nodules of varying size. B Reticulin logical and morphometric studies hepatocellular adenoma. HCC typically
stain showing mild distortion of liver architecture. Watanabe et al. {2068} proposed the also shows diffuse capillarization using
EBM
EBM
EBM
EBM
EBM
EBM
EBH
EBH
EBH
EBH
EBH
EBH
EB
EB
Extrahepatic inherited conditions.
Several cases of HCC have been report-
ed in familial adenomatous polyposis of
2.6 kb
the colon {1000}. Occasional cases have
also been described in neurofibromato-
E, EcoRI; B; BamHI; M, Mspl; H, Hpall; C1 and 2, cases with liver metastatic lesions sis, Soto syndrome, and situs inversus
of primary colonic cancer; H99 and 103, HCC cases. {2082}. Cases of hepatocellular adeno-
mas and HCC in young patients with
= normal liver tissue = cirrhotic liver tissue = HCC Fanconi anaemia have been also
described {1033}.
Genetics
Clonal expansion and subclonal progres-
sion during multistage carcinogenesis
Most HCCs are associated with HBV or
HCV infection. Clonal expansion of hepa-
tocytes is initiated during regeneration in
damaged livers; a clonal integration pat-
Chronic hepatitis HCC HCC tern of HBV was identified in cirrhotic
nodules {2170}. Advanced HCCs often
Fig. 8.23 CpG methylation around E-cadherin promoter in HCCs and non-tumorous liver showing chronic emerge as ‘nodule-in-nodule’ HCCs; the
hepatitis or cirrhosis. CpG methylation was detected in 46% of liver tissues showing chronic hepatitis or cir- early and advanced HCC components of
rhosis and 67% of HCCs. Heterogenous E-cadherin expression was detected in hepatocytes in 7 (41%) of the a ‘nodule-in-nodule’ type HCC showed
17 liver tissues showing chronic hepatitis or cirrhosis; small focal areas of hepatocytes showed only slight identical integration patterns of HBV
E-cadherin immunoreactivity. Reduced E-cadherin expression was observed in 10 (59%), in which over 50% {1968, 1647}. Ordinary HCCs with in-
of the HCC cells in each patient lacked or showed only slight E-cadherin immunoreactivity, of the 17 HCCs. creased cell proliferation and neovascu-
larization are subsequently formed.
Protein metabolism disorders are occasionally associated with HCC TP53 mutations
In alpha-1-antitrypsin deficiency (A1ATD) {1073, 53}. Point and frameshift mutations of the
{1501}, only male A1ATD homozygotes TP53 tumour suppressor gene are fre-
are at high risk for HCC, even in the Chronic cholestatic syndromes. quent in areas with low exposure to afla-
absence of cirrhosis {473}. Further-more, HCC may complicate paucity of intra- toxin B1 {1393}. TP53 mutations were
cholangiocarcinomas and combined hepatic bile ducts {1028, 99, 898}, most frequent and were clustered in
hepatocellular and cholangiocarcinomas biliary atresia {2082}, congenital hepatic domains IV and V in poorly differentiated
in non-cirrhotic livers of adult patients fibrosis {2082}, and Byler syndrome HCCs, but were less frequent and equal-
with heterozygous A1ATD of PiZ type are {1550}. ly distributed in domains II to V in well or
well documented {2207}. HCC occurs in moderately differentiated HCCs in one
18%-35% of patients with hereditary Metal-storage diseases. study {1393}. Analysis of ‘nodule-in-nod-
tyrosinaemia {2082, 1996}. The non- The relative risk for the development of ule’ type HCC shows that TP53 mutation
tumourous liver is cirrhotic and often dys- primary liver cancer in inherited is associated with the progression of
plastic {808}. HCC has further been haemochromatosis has been calculated HCC from an early to a more advanced
reported in 14% of adult-onset cases of as being greater than 200 {181, 1351, stage {1392, 1391}.
hypercitrullinaemia in the absence of cir- 487}. HCC develops usually in patients In areas with high exposure to AFB1,
rhosis {1324A}. with cirrhosis {403, 951}, even after iron mutation of the third nucleotide in codon
depletion {403}. Iron-free foci (defined as 249 of TP53 is frequent {758, 188}, sug-
Disorders of porphyrin metabolism. The clear-cut, sublobular, hepatocytic nod- gesting that some TP53 mutations can be
prevalence of HCC in porphyria cutanea ules free of iron or having significantly fingerprints of past exposure to a given
tarda (PCT) ranges from 7% to 47% less iron than the surrounding parenchy- carcinogen (see 'Aetiology', above).
{1755, 1073}. Almost all HCCs occur in ma) may represent an early step of HCC
male patients older than 50 years with in genetic haemochromatosis {403}. In HBV X
preexisting cirrhosis and a long-standing Wilson’s disease, HCC is present only The HBV X open reading frame is fre-
history of symptomatic PCT. The involve- exceptionally {293}. quently integrated and expressed. HBV
ment of additional risk factors is likely X [MLS1] can bind to the C terminus of
{396}. Rarely, PCT evolves as a para- Hepatic vascular anomalies. p53, inhibits its sequence-specific DNA
neoplastic syndrome associated with Cases of HCC have been occasionally binding and transcriptional activation
HCC {1389}. Other hepatic porphyrias reported in hereditary haemorrhagic and suppresses p53-induced apoptosis
the evidence for the role of opisthorchia- Epstein-Barr virus (EBV) infection
sis in the induction of ICC is compelling Rare examples of ICC have a lymphoep-
{2009, 2008}. Carcinogenesis is proba- itheliomatous, undifferentiated pattern.
bly related to the length and severity of Clonal EBV has been found in such
infection, the host’s immune response, cases {757, 2025}.
and other variables such as ingestion of
dietary carcinogens, for example nitro- Non-biliary cirrhosis
samines. In northeast Thailand, several There are several reports of ICC arising in
carcinogenic N-nitroso compounds and non-biliary cirrhosis, particularly hepatitis
their precursors exist at low levels in the virus-related liver cirrhosis {2159, 1940}.
daily diet {1230}. In addition, endo- HCV is frequent in such cases and ICC is
Fig. 8.30 Ultrasonography of an intrahepatic
genous nitrosamine formation by liver usually of a smaller, mass-forming type. cholangiocarcinoma. A hyperechoic mass is pres-
fluke infection has been reported {1673}. Such ICC and combined hepatocellular- ent in a dilated bile duct.
Both exogeneous and in situ nitrosamine cholangiocarcinomas share apomucin
formation may lead to DNA alkylation profiles {1669}, suggesting that these two
and deamination {1346}. It seems that tumours have a similar or common histo- or obstruction of the biliary tree are
the presence of parasites induces DNA genesis, or that ICC associated with cir- responsible for the variable clinical fea-
damage and mutations as a conse- rhosis might be the result of exclusive tures of ICC.
quence of the formation of carcino- proliferation of the cholangiocellular com-
gens/free radicals and of cellular prolif- ponent of the combined type. Genotypes Symptoms and signs
eration of the intrahepatic bile duct of hepatitis B and C viruses have been General malaise, mild abdominal pain
epithelium. shown in cholangiocarcinoma cells and weight loss are frequent clinical
{2049, 1787}. symptoms. When the carcinoma infil-
Hepatolithiasis trates the hilar region, jaundice and
Hepatolithiasis (recurrent pyogenic Deposition of Thorotrast cholangitis become manifest. ICCs, par-
cholangitis), which is not uncommon in Thorotrast is a radioactive α-particle ticularly those arising from the small bile
the Far East, is also associated with ICC emitter that was widely used as a radio- ducts, may go unnoticed until they
{1857, 1321}. It is frequently observed in opaque intra-arterial contrast medium have attained a large size. The liver is
clonorchiasis {746} but not in opisthor- between 1930 and 1955. ICC has been enlarged to a lesser extent, ascites
chiasis. Most of these cases are associ- recorded in many patients with prior is less common, and signs of portal
ated with calcium bilirubinate stones; a exposure to Thorotrast. The data suggest hypertension are absent or minimal.
few cases with cholesterol stones have that the chronic alpha-irradiation may be Patients with unrelieved obstruction of
also been reported. Patients with intra- the causative factor, with latent periods the intrahepatic large bile ducts may die
hepatic stones and ICC have a signifi- ranging from 25 to 48 years. from complications, e.g. liver failure or
cantly longer duration of symptoms and sepsis.
a higher frequency of previous biliary Biliary malformations and other lesions
surgery. ICC may arise rarely in solitary unilocular Imaging
or multiple liver cysts, congenital seg- Advanced cases of ICC show mixed
Inflammatory bowel disease and primary mental or multiple dilatation of the bile growth and spreading patterns with
sclerosing cholangitis ducts (Caroli disease), congenital hepat- intrahepatic metastases. Computerized
Patients with primary sclerosing cholan- ic fibrosis, and von Meyenburg complex- tomography (CT) images of ICC usually
gitis (PSC) and ulcerative colitis (UC) es {736, 2165}. show a lobulated or fused hypodense
have a predisposition to develop col- space-occupying lesion with peripheral
orectal neoplasia and also bile duct Clinical features enhancement, probably due to central
carcinoma, including ICC {672, 1993, The site of the tumour, its growth pattern hypocellular dense fibrosis. Secondary
194, 2078}. and the presence or absence of stricture dilated ducts around the tumour are
detectable by CT and ultrasonography. A
focal area of carcinoma involving the bile
duct wall is identifiable by spiral CT.
Endoscopic retrograde, transhepatic or
magnetic resonance cholangiography is
a useful adjunct for the identification of
the level of biliary obstruction and sec-
ondary bile duct dilatation.
ICCs at relatively early and surgically
resectable stages are classifiable into
three representative types of growth pat-
A B terns {1080}, and these patterns, which
Fig. 8.31 Cholangiocarcinoma, CT images. A The right lobe contains a mass and shows peripheral bile duct are evaluable by imaging studies, can be
dilation. B Arrows indicate a peribiliary spreading type. useful for the preoperative staging of
A B C
Fig. 8.32 Macroscopic features of intrahepatic cholangiocarcinoma. A Cut surface shows massive tumour and multiple intrahepatic metastatic nodules.
Surrounding liver is non-cirrhotic. B White, scar-like mass in a normal liver (mass forming types) together with dilated peripheral bile ducts. C Intraductal growth
type of intrahepatic cholangiocarcinoma.
tumour extent and for designing the sur- beyond the bile duct walls. Some ICC in endemic areas of liver fluke infec-
gical procedure. The mass forming type tumours of this type of ICC might have tion is similar to that described in non-
is an expansile nodule and is the most arisen from biliary papillomatosis after endemic regions; liver flukes are rarely
common. The tumour borders between malignant transformation. Marked local- seen nowadays due to mass treatment.
the cancerous and noncancerous por- ized dilatation of the affected duct is In hepatolithiasis-associated ICC, the
tions are relatively clear. The contrast detectable by ultrasound or CT. Cholan- tumour tends to proliferate and spread
enhanced CT scan shows a low- giography shows filling defects in the bil- along the stone-containing ducts. The
density tumour with peripheral ring-like iary tract, due to polypoid tumours and liver lobe or segments containing stones
increased density. The periductal-infiltrat- mucin. involved by ICC are atrophic in some
ing type, which is usually associated with cases.
biliary stricture, is relatively common. The Macroscopy
tumour exhibits diffuse infiltration along ICC can arise from any portion of the Tumour spread
the portal pedicle. This type resembles intrahepatic bile duct epithelium {61, ICC shows direct spread into the sur-
hilar or extrahepatic bile duct carcinoma. 1418}. Lesions are gray to gray-white, rounding hepatic parenchyma, portal
The contrast enhanced CT demonstrates firm and solid, although some tumours pedicle and bile duct. Intrahepatic
a small cancerous enlargement of the show intraductal growth, sometimes with metastases develop in nearly all cases at
portal pedicle, or a mass central to the polyp formation. Typical tumours consist a relatively advanced stage.
dilated peripheral ducts. The anatomical of variably sized nodules, usually coales- Vascular invasion is a frequent histologi-
location of the involved ducts can be cent. Portal tract infiltration is also seen. cal finding relatively early, suggesting the
evaluated by caliber changes or the Central necrosis or scarring are common, development of early metastasis. The
rigidity of the bile duct on high-quality and mucin may be visible on the cut sur- incidence of metastases in regional
cholangiographic images. The intraduc- faces. ICC cases involving the hepatic lymph nodes is higher than in HCC.
tal growth type (intraductal papillary hilum are hardly distinguishable from hilar Blood-borne spread occurs later, to the
cholangiocarcinoma) is less common cholangiocarcinoma, and such cases lungs in particular; other sites include
{351}. These tumours are confined within show cholestasis, biliary fibrosis, and bone, adrenals, kidneys, spleen, and
the dilated part of an intrahepatic large cholangitis with abscess formation. ICC pancreas.
bile duct, with no or mild extension is not often noted in a non-cirrhotic liver.
A B
Fig. 8.33 Intrahepatic cholangiocarcinoma. A Well differentiated tubular adenocarcinoma. B Moderately differentiated tubular adenocarcinoma.
A B
Fig. 8.34 A Intrahepatic cholangiocarcinoma showing papillary growth pattern involving the peribiliary glands . The bile duct lumen (top and center) is free of car-
cinoma. B Papillary cholangiocarcinoma invading the bile duct wall.
On rare occasions, the tumour shows Adenocarcinoma ICC arising from the large intrahepatic
extensive intraluminal spread of bile This common type of ICC growing in the bile ducts shows intraductal micropapil-
ducts throughout the liver. The tumour hepatic parenchyma and portal pedicle lary carcinoma and in situ like spread
cells can also infiltrate into the peribiliary reveals a significant heterogeneity of his- along the biliary lumen. Once there is
glands of the intrahepatic large bile tological features and degree of differen- invasion through the periductal tissue,
ducts and their conduits. It may be diffi- tiation. At an early stage, a tubular pat- the lesion may be well, moderately, or
cult to distinguish this lesion from reac- tern with a relatively uniform histological poorly differentiated adenocarcinoma,
tive proliferated peribiliary glands histo- picture is frequent. Cord-like or micro- with considerable desmoplasia and
logically. papillary patterns are also seen. The stenosis or obliteration of the bile duct
cells are small or large, cuboidal or lumen.
Histopathology columnar, and can be pleomorphic. The Infrequently, a papillary tumour growing
Most ICCs are adenocarcinomas show- nucleus is small and the nucleolus is in the duct lumen is supported by fine
ing tubular and/or papillary structures usually less prominent than that of HCC. fibrovascular cores. Cholangio-carcino-
with a variable fibrous stroma {326}. The majority of cells have a pale, ma arising from the intrahepatic peribil-
There is no dominant histological type of eosinophilic or vacuolated cytoplasm; iary glands {1914} mainly involves these
ICC in cases associated with liver flukes sometimes, the cells have a clear and glands, sparing the lining epithelial cells
or hepatolithiasis when compared to abundant cytoplasm or resemble goblet at an early stage.
those in non-endemic areas. cells. An abundant fibrous stroma is an impor-
tant characteristic of ICC. Activated
perisinusoidal cells (myofibroblasts) are
incorporated into the tumour, producing
extracellular matrix proteins that lead to
fibrosis {1913}. Usually, the central parts
of the tumour are more sclerotic and
hypocellular, while the peripheral parts
show more actively proliferating carcino-
ma cells. On rare occasions, the tumour
cells are lost in a massive hyaline stroma,
which may be focally calcified.
The secretion of mucus in one form or
another can be demonstrated in the
majority of tumours by mucicarmine, dia-
stase-PAS and Alcian blue staining.
Mucus core (MUC) proteins 1, 2, and 3
are detectable in the carcinoma cells
{1264, 1670}. ICC cells can immunoex-
press cytokeratins 7 and 19, CEA, epithe-
lial membrane antigen, and blood group
antigens. Bile may be present occasion-
ally in ICC as a result of destruction of the
Fig. 8.35 High-grade intraepithelial neoplasia of a peribiliary gland in a patient with hepatolithiasis. bile ducts or entrapment of non-neoplas-
A B
Fig. 8.38 Intrahepatic cholangiocarcinoma, in a patient with heterozygous alpha-1 antitrypsin deficiency of the Piz type. A Tubular adenocarcinoma. B Cytokeratin 7
immunohistochemistry demonstrates tumour cells spreading along bile ducts and infiltrating liver tissue.
ICCs are diffusely positive for cytokeratin Grading lining with subsequent hyperplasia,
7 and 19, whereas only a few cases of ICCs can be graded into well, moderate- periductal fibrosis, inflammation and
HCC are positive. The hepatocyte anti- ly, and poorly differentiated adenocarci- goblet cell metaplasia {2008, 913}. The
gen (Dako) is expressed by HCC but not noma according to their morphology. In neoplastic transformation from hyperpla-
by ICC. the case of the common type of adeno- sia in bile ducts to ICC through dysplas-
Metastatic carcinoma. ICC cannot be carcinoma, well-differentiated lesions tic changes is demonstrable in opisthor-
distinguished histologically from meta- form relatively uniform tubular or papil- chiasis. In hepatolithiasis, the findings
static adenocarcinoma of biliary tract or lary structures, moderately differentiated are those of cholangitis, with proliferation
pancreatic origin. Occasionally, dysplas- tumours show moderately distorted tubu- of the biliary epithelial lining and peri-
tic changes in neighbouring bile ducts lar patterns with cribriform formations biliary glandular cells, and multiple foci
suggest intrahepatic origin. In addition, and/or a cord-like pattern, while the poor- of biliary intraepithelial neoplasia {1323}.
diffuse expression of cytokeratin 20 ly differentiated show severely distorted Hyperplasia and intraepithelial neoplasia
favours metastatic adenocarcinoma, par- tubular structures with marked cellular of the duct epithelium in livers with
ticularly from colon {1141}. While cyto- pleomorphism. Thorotrast-deposition and congenital bil-
keratin 7 is common in ICC, it is not so iary anomalies may be also related to the
common in metastatic carcinoma. Precursor and benign lesions development of ICC {1626, 2165}.
Sclerosing cholangitis. Periductal Biliary intraepithelial neoplasia (dysplasia) It has been reported in patients with PSC
spread of ICC may be difficult to distin- This is characterized by abnormal that biliary intraepithelial neoplasia could
guish from sclerosing cholangitis, partic- epithelial cells with multilayering of nuclei evolve from papillary hyperplasia {2078,
ularly when only biopsy material is and micropapillary projections into the 1107}. However, recent experience at
available. The most important criteria for duct lumen {2078, 1322}. The abnormal orthotopic liver transplantation of PSC
the diagnosis of malignancy are severe cells have an increased nuclear/cyto- has detected hardly any in situ or inva-
cytological atypia, random and diffuse plasmic ratio, a partial loss of nuclear sive neoplastic foci.
infiltration of the duct wall by the polarity, and nuclear hyperchromasia.
neoplastic cells, and perineural invasion. They are divisible into low-grade and Biliary papillomatosis
high-grade lesions. Some peribiliary Dilated intrahepatic and extrahepatic bile
glands may also be dysplastic. ducts are filled with papillary or villous
Cell kinetic studies have disclosed prolif- excrescences, which microscopically are
erative activity of intraepithelial neoplasia papillary or villous adenomas with deli-
between that of hyperplasia and ICC, cate fibrovascular stalks covered with a
and telomerase activity is demonstrable columnar or glandular epithelium {806,
in both intraepithelial and invasive carci- 351}. They are soft and white, red or tan.
noma {1915, 1440}. Carcinoembryonic In some cases, there are variable degrees
antigen (CEA) is focally detectable in bil- of cellular atypia and multilayering of
iary intraepithelial neoplasia and more so nuclei. Occasionally, foci of in situ or inva-
in carcinoma {1322}. These findings sup- sive carcinoma are encountered {1340}.
port the concept of a hyperplasia-dys-
plasia-carcinoma sequence in the biliary Von Meyenburg complex (biliary micro-
tree {1989}. hamartoma)
Fig. 8.39 Immunoexpression of atz11 demonstrates In liver fluke infestations, the bile ducts The lesions are small, up to several mm
alpha-1 antitrypsin deficiency of piz type. first show desquamation of the epithelial in diameter. They are usually multiple and
A B
Fig. 8.40 Bile duct adenoma. A Frozen section. B Cytokeratin immunostain showing characteristic branching pattern of bile ducts.
are adjacent to a portal area. Within a biliary anomalies, and also in normal liv- nosis of a well-differentiated cholangio-
fibrous or hyalinized stroma, they present ers, multiple cysts may be seen around carcinoma. It occurs in apparently nor-
as irregular or round ductal structures the intrahepatic large bile ducts {1319, mal livers and also in acquired liver dis-
that appear somewhat dilated and have 1320}. They are visible by ultrasound or eases.
a flattened or cuboidal epithelium. The CT. These cysts are derived from peribil-
lumina contain proteinaceous or bile- iary glands and should be differentiated Molecular genetics and genetic sus-
stained secretion. These lesions carry lit- from ICC clinically and histologically. ceptibility
tle or no malignant potential {736, 673}. Mutations of the RAS and TP53 genes are
Diffuse and multifocal hyperplasia of peri- the most common genetic abnormalities
Bile duct adenoma (BDA) biliary glands identified in ICC. The incidence of KRAS
BDA is usually single and subcapsular, Diffuse, severe, macroscopically recog- mutations ranges from 100% and 60%
and is white and well circumscribed but nizable dilatation and hyperplasia of the among British {1054} and Japanese
non-encapsulated. BDA is usually less peribiliary glands of intrahepatic and patients respectively {1878, 1402}, to 4%
than 1 cm in size, and is composed of a extrahepatic bile ducts is a rare condition among Thai patients {1510}. Taiwanese
proliferation of small, normal appearing {1319, 437}. Some ducts may be cysti- and Korean patients show an intermedi-
ducts with cuboidal cells that have regu- cally dilated. Lack of familiarity with this ate frequency {1037, 887}. The most fre-
lar nuclei and lack dysplasia {44}. These lesion could lead to an erroneous diag- quently mutated position in the KRAS
ducts have no or little lumen and can
elaborate mucin. Their fibrous stroma
shows varying degrees of chronic inflam-
mation and collagenization. Enclosed in
the lesion are normally spaced portal
tracts. They are considered to be a focal
reaction to injury.
BDA and peribiliary glands share com-
mon antigens, suggesting a common line
of differentiation {136}. Occasionally, BDA
contains periductular endocrine cell clus-
ters {1384}.
In addition, there are several atypical
BDA with a neoplastic nature. Biliary
adenofibroma is characterized by a com-
plex tubulocystic biliary epithelium with-
out mucin production, together with
abundant fibroblastic stromal compo-
nents {1972}. Its expansive growth, and
foci of epithelial tufting, cellular atypia
and mitoses favor a neoplastic process.
Intrahepatic peribiliary cysts Fig. 8.41 Bile duct adenoma. Small, normal appearing proliferating bile ducts associated with a small con-
In chronic advanced liver disease and nective tissue component and lymphocytic infiltration.
gene is codon 12 involving GGT (glycine) of E-cadherin, alpha-catenin, and beta- Histologically, squamous cell or sarco-
to GAT (aspartic acid). Less frequent catenin is reduced in a majority of ICC matous elements and mucinous variants
mutations have been identified in codon and this down-regulation correlates with confer a poor prognosis {1312, 1313}.
13, involving GGT (glycine) to GAT ICC at high-grade {91}. Patients with well differentiated ICC seem
(aspartic acid) and codon 61, involving Overexpession of MET, the receptor for to survive longer than those with moder-
CAA (glutamine) to CAC (histidine) {1402, hepatocytes growth factor, occurs in ICC ately or poorly differentiated ones. A few
1969, 1511}. and correlates with tumour differentia- cases of well differentiated ICC with
TP53 mutations occur between exons 5 tion, being poorly expressed in poorly bland features resembling bile duct ade-
to 8, the most common change being G differentiated tumours {1912}. It also cor- noma show a good prognosis {522}.
to A transitions {887, 1511, 907, 1848}. relates with the markedly increased pro- MUC 2 protein expression is relatively
The mutations are random with no spe- liferation indices seen in precancerous frequent in well differentiated ICC, sug-
cific hot spot, being mostly missense glands and cholangiocarcinoma. Biliary gesting a somewhat more favourable
mutations and less frequently nonsense epithelial cells are continuously exposed prognosis {1915}.
mutations {887}. p53 protein is immuno- to genotoxic insults such as chronic Lymph node metastasis is a significant
histochemically detectable in carcinoma inflammation and hydrophobic bile prognostic factor {2160}. The 5-year sur-
cells in more that 70% of ICC cases. acids, predisposing to oncogenic muta- vival rate in patients with lymph node
KRAS and TP53 mutations correlate with tions. Progression to malignancy may be metastases is significantly lower than
the gross morphology of ICC {1969, due, in part, to failure in activating apop- that in patients without lymph node
1401}; a higher prevalence of KRAS tosis and deleting cells with genetic metastasis (51%).
gene alterations is found in the periduc- damages {263}. The anti-apoptotic pro- In liver fluke-associated ICC, survival
tal and spicular forming infiltrating sub- tein bcl-2, is overexpressed in ICC {281} after right hepatectomy is better than
type compared to the slower growing, and telomerase activity is detectable in after left hepatectomy, and is not associ-
non-invasive mass-forming type. TP53 carcinoma cells of almost all ICC cases. ated with tumour size {1990}. In addition,
mutations are prominent in the mass- multiple tumour masses have a poor
forming type of ICC. Prognosis and predictive factors prognosis. Concomitant hepatolithiasis
The variable incidence of KRAS muta- Early detection of ICC is difficult, and the prevents precise diagnosis preoperative-
tions in different populations of ICC may overall prognosis after resection is poor ly, and precipitates biliary sepsis. Long-
reflect different aetiologies. O. viverrini compared with that of HCC. Lymph node term post-surgical survival of patients
infection and increased consumption of spread, vascular invasion, positive mar- with stone-containing ICC compared to
nitrates and nitrites are contributing fac- gins and bilobar distribution are associ- ICC alone is controversial {291, 1849}.
tors in Thailand where the incidence of ated with a high recurrence rate and a ICC found in non-biliary cirrhosis is usual-
KRAS abnormalities is low {2025, 1446}. poor prognosis. One study found the ly detectable as a small nodule during fol-
Overexpression of c-erbB-2 occurs in one 5-year survival rate was 39% in patients low-up of hepatitis virus-related cirrhosis,
fourth to about two thirds of carcinoma of with mass-forming tumours and 69% for and is treatable with hepatectomy {2159}.
the biliary tract, and may be used as a intraductal tumours while no patients with
phenotypic marker for neoplastic transfor- mass-forming plus periductal-infiltrating
mation {1912}. Membranous expression tumours survived > 5 years {2161}.
C. Wittekind
Combined hepatocellular H.P. Fischer
and cholangiocarcinoma T. Ponchon
Histopathology
Combined hepatocellular and cholangio-
carcinoma is the term preferred for a
A tumour containing both hepatocellular A
and distinct or separate cholangiocarci-
noma. The presence of both bile and
mucus should be sought in the com-
bined tumour. This category should not
be used for tumours in which either form
of growth is insufficiently differentiated
for positive identification.
Hepatocytes preferentially express cytok-
eratins 8 and 18 and, like duct epithelial
B cells, cytokeratins 7 and 19. However, the B
Fig. 8.42 Combined hepatocellular carcinoma and different patterns of expression are not as Fig. 8.43 Combined hepatocellular and cholangio-
cholangiocarcinoma arising in non-cirrhotic liver clear-cut in these tumours. For practical cellular carcinoma. A Microtrabecular HCC and
tissue in a patient with heterozygous Piz type alpha- purposes, demonstration of bile canaliculi cholangiocarcinoma with desmoplastic response.
1 antitrypsin deficiency. A Pale, homogeneous cut by polyclonal CEA (mixed biliary glyco- B Border zone between HCC and cholangiocarci-
surface. B Microscopic, showing glandular areas. proteins) combined with Hep Par immu- noma.
Definition solid areas of grey-white tumour in a females and has been likened to ovarian
A cystic tumour either benign (cystade- thickened wall. stroma. The stromal cells express
noma) or malignant (cystadenocarcino- vimentin, and there are many cells that
ma), lined by epithelium with papillary Tumour spread and staging express smooth muscle actin. A xan-
infoldings that may be mucus-secreting Cystadenocarcinomas show intrahepatic
or, less frequently, serous. Lesions arise spread and metastasis to regional lymph
from ducts proximal to the hilum of the nodes in the hepatoduodenal ligament.
liver. They differ from tumours that arise Distant metastases occur most frequent in
in cystic congenital malformation and in the lungs, the pleura and the peritoneum.
parasitic infections and hepatolithiasis. Staging is performed according to the
TNM Classification of liver tumours {66}.
Epidemiology
Bile duct cystadenoma and cystadeno- Histopathology
carcinoma are rare {809}. Cystadenoma Cystadenomas are usually multilocular
is seen almost exclusively in females, and are well defined by a fibrous cap-
with cystadenocarcinoma appearing sule, which may contain smooth muscle
equally in males and females. The aver- fibres. The contents of the locules are Fig. 8.44 Biliary cystadenoma. The lining epithelium
age age of patients is 50-60 years. either thin, opalescent or glairy fluid, or is cuboidal and lies on ovarian-like stroma, beneath
mucinous semisolid material. which is a band of dense tissue.
Clinical features Two histological variants are recognized.
Patients often present with abdominal The mucinous type is more common and
pain and mass. A few patients have jaun- is lined by columnar, cuboidal, or flat-
dice. Elevated serum levels of tumour tened mucus-secreting epithelial cells
marker CA 19-9 may occur. Imaging resting on a basement membrane; poly-
techniques show multilocular cystic poid or papillary projections may be pres-
tumour(s), occasionally with tiny papillary ent. About 5% of the tumours reveal neu-
folds in the cystic wall. roendocrine differentiation, as identified
by expression of chromogranin and
Macroscopy synaptophysin. Subjacent to the base-
The cysts are usually multilocular and ment membrane is a cellular, compacted
typically range from 5 to 15 cm diameter mesenchymal stroma, which in turn is Fig. 8.45 Severe dysplasia in the epithelium of an
{809}. In cystadenocarcinoma, a large surrounded by looser fibrous tissue. This intrahepatic large bile duct in a case of hepatolithi-
papillary mass may occur as well as mesenchymal component is seen only in asis.
A B
Fig. 8.46 Bile duct cystadenoma. A Large peribiliary cysts in the connective tissue of the hilus; the background liver shows advanced cirrhosis. B Variably sized cysts
are intermingled with peribiliary glands.
oping fetal liver. These cells contain a by more abundant cytoplasm and larger
small round nucleus with fine nuclear nuclei. Although the trabeculae resemble
chromatin and an indistinct nucleolus. those seen in the pseudoglandular type
The cytoplasm varies from finely granular of hepatocellular carcinoma, the cells
to clear, reflecting variable amounts of display only mild hyperchromasia and
glycogen and lipid which can impart a anisocytosis, and mitotic activity is low.
'light and dark' pattern to the lesion when The term 'macrotrabecular' is applied to
viewed at lower magnifications. Cana- only those cases in which macrotrabecu-
liculi may be seen between hepatocytes lae are a prominent feature of the lesion.
of the 2-3 cell layer trabeculae, but only If only an isolated focus is present, the
Fig. 8.49 Epithelial hepatoblastoma presenting as a rarely is bile stasis present. In biopsies
large, well demarcated lesion with central haemor- taken before preoperative chemothera-
rhage. py, foci of extramedullary haemato- Table 8.04
poiesis (EMH) composed of clusters of Clinical syndromes, congenital malformations and
other conditions that have been associated with
erythroid and myeloid precursors may be
hepatoblastoma.
veins and inferior vena cava. The lung is present in the sinusoids {2023}.
the most frequent site of metastases; Sinusoids are lined by endothelial and Absence of left adrenal gland
approximately 10-20% of patients have Kupffer cells which show a more diffuse Acardia syndrome
pulmonary metastases when first diag- staining with UEA-1 and anti-CD34 than Alcohol embryopathy
nosed. Hepatoblastomas also spread to the focal staining of the sinusoidal Beckwith-Wiedemann syndrome
bone, brain, ovaries, and the eye {179, endothelial cells of normal liver {1630}. Beckwith-Wiedemann syndrome with opso-
1600, 619, 463}. The fetal phenotype has been signifi- clonus, myoclonus
cantly associated with both diploid DNA Bilateral talipes
Histopathology nuclear content and low proliferative Budd-Chiari syndrome
Hepatoblastomas display a distinct vari- activity assessed by flow cytometry and Cleft palate, macroglossia, dysplasia of ear
ety of histological patterns that may be PCNA labeling index {1640}. lobes
present in varying proportions. Some Cystothioninuria
tumours are composed entirely of uni- Combined fetal and embryonal epithelial Down syndrome, malrotation of colon, Meckel
form fetal epithelial cells or small undif- Approximately 20% of cases display a diverticulum, pectum excavatum, intrathoracic
ferentiated cells, while others contain a pattern combining fetal epithelial cells kidney, single coronary artery
variety of tissue types including hepatic and sheets or clusters of small, ovoid to Duplicated ureters
fetal epithelial and embryonal cells, angulated cells with scant amounts of Fetal hydrops
fibrous connective tissue, osteoid-like dark granular cytoplasm surrounding a Gardner syndrome
material, skeletal muscle fibers, nests of nucleus with increased nuclear chro- Goldenhar syndrome – oculoauriculovertebral
squamous epithelial cells, and cells with matin. The cells display little cohesive- dysplasia, absence of portal vein
melanin pigment. ness but may cluster into pseudorosette, Hemihypertrophy
glandular or acinar structures. These Heterotopic lung tissue
Pure fetal epithelial differentiation small, round, blue cells resemble the Heterozygous α1-antitrypsin deficiency
Accounting for nearly one third of cases, blastemal cells seen in nephroblastomas, HIV or HBV infection
the fetal epithelial pattern is composed of neuroblastomas and other 'embryonal' Horseshoe kidney
thin trabeculae of small cuboidal cells tumours in children. While often inter- Hypoglycemia
resembling the hepatocytes of the devel- mixed with the fetal epithelial cells, the Inguinal hernia
foci of embryonal cells, which are devoid Isosexual precocity
of glycogen and lipid, can be identified Maternal clomiphene citrate and Pergonal
Table 8.03 by their absence of staining with PAS or Meckel diverticulum
Staging of Hepatoblastoma according to the oil red-O stains. Mitotic activity is more Oral contraceptive, mother
Children's Cancer Study Group (CCSG) classifica-
pronounced in the embryonal areas, and Oral contraceptive, patient
tion.
associated with a low TGF-alpha expres- Osteoporosis
Stage I Complete resection sion. EMH, in the absence of preopera- Persistent ductus arteriosus
tive chemotherapy, may also be noted Polyposis coli families
Stage II Microscopic residual {925}. Prader-Willi syndrome
Negative nodal Renal dysplasia
involvement Macrotrabecular Right-sided diaphragmatic hernia
No spilled tumour
In about 3% of cases of fetal or fetal and Schinzel-Geidion syndrome
Stage III Gross residual or
embryonal epithelial hepatoblastomas, Synchronous Wilms tumour
Nodal involvement or areas containing broad trabeculae (6-12 Trisomy 18
Spilled tumour or more cells in thickness) are present. Type 1a glycogen storage disease
These macrotrabeculae are composed Umbilical hernia
Stage IV Metastatic disease of fetal and embryonal epithelial cells Very low birth weight
and a third, larger cell type characterized
Hepatoblastoma 185
8b 19.7.2006 8:18 Page 186
A B
Fig. 8.50 Pure fetal epithelial hepatoblastoma. Variable concentrations of glycogen and lipid within tumour cells create dark and light areas.
A B
Fig. 8.51 Pure fetal hepatoblastoma. A Cuboidal cells form trabeculae. B Immunoreactivity for alpha-fetoprotein is present in most tumour cells. A cluster of
hematopoietic cells is present at lower center.
classification is based on the epithelial or bling the small blue cells of neuroblas- Mixed epithelial and mesenchymal
mixed epithelial/mesenchymal compo- toma, Ewing sarcoma, lymphoma, and The largest number of hepatoblastomas
nents present. rhabdomyosarcoma are called small cell (44%) display a pattern combining fetal
undifferentiated hepatoblastomas and and embryonal epithelial elements with
Small cell undifferentiated amount to about 3% of the tumours. This primitive mesenchyme and mesenchy-
Hepatoblastomas composed entirely of type is believed to represent the least dif- mally derived tissues. Of these mixed
noncohesive sheets of small cells resem- ferentiated form of hepatoblastoma tumours, 80% have only immature and
{602}.
While often difficult to identify as hepatic
in origin, the presence of small amounts
of glycogen, lipid and bile pigment,
along with cytoplasmic cytokeratin, helps
separate this lesion from metastatic small
cell tumours. The cells are arranged as
solid masses with areas of cellular
pyknosis and necrosis and high mitotic
activity. Sinusoids are present but
decreased in amount compared to the
fetal epithelial pattern, and there is pro-
Fig. 8.52 Fetal and embryonal epithelial hepatoblas-
toma. Fetal epithelial cells with a high cytoplasmic nounced intracellular expression of
lipid concentration are separated by a band of extracellular matrix proteins and large Fig. 8.53 Fetal and embryonal hepatoblastoma.
fibrous connective tissue from a vascular mass of numbers of fibers immunoreactive for Embryonal epithelial cells occur singly and in gland-
embryonal cells. collagen type III {1629}. like structures.
Staging
These is no official TNM classification for
hepatoblastoma but a TNM-type system Fig. 8.55 Fetal and embryonal hepatoblastoma. The embryonal cells may resemble other blastemal cells, e.g.
has been proposed {332}. The Children's those encountered in nephroblastoma or neuroblastoma.
Hepatoblastoma 187
8b 19.7.2006 8:18 Page 188
Fig. 8.56 Macrotrabecular hepatoblastoma. On the left, the tumour consists of Fig. 8.57 Mixed epithelial and mesenchymal hepatoblastoma. Areas showing
macrotrabeculae. The one to two-cell thick trabeculae of fetal epithelial hepa- mesenchymal tissue and foci of osteoid-like material are present, together with
toblastoma pattern are seen on the right. areas of epithelial hepatoblastoma.
years of life and presents as a rapidly nia, and other disparate malformations somy for all or parts of chromosome 2,
enlarging mass due to accumulation of such as absent adrenal gland and het- trisomy for chromosome 20 and loss of
fluid within cysts formed in the mes- erotopic lung tissue. Other syndromes heterozygosity (LOH) for the telomeric
enchymal portion of the lesion {1841}. CT with an increased incidence of hepato- portion of 11p (11p15.5). The material
and MRI are useful in defining the cystic blastoma include Beckwith-Wiedemann lost on 11p is always of maternal origin
nature of the lesion. Focal nodular hyper- syndrome, trisomy 18, trisomy 21, {43}. LOH has also been observed on the
plasia and nodular regenerative hyper- Acardia syndrome, Goldenhar syndrome, short and long arms of chromosome 1
plasia may be seen in the first few years Prader Willi syndrome, and type 1a glyco- with a random distribution of parental ori-
of life but are more common in older chil- gen storage disease {1585}. gin for chromosome arm 1p and a pater-
dren {1839}. Hepatocellular adenoma is Hepatoblastoma and familial adenoma- nal origin for chromosome arm 1q {970}.
rarely seen in the first 5-10 years of life, tous polyposis (FAP) are associated due TP53 overexpression has been
but may be difficult to differentiate from a to germline mutation of the adenomatous described in several cases, but TP53
pure fetal epithelial hepatoblastoma. polyposis coli (APC) gene. FAP kindreds mutations in exons 5 to 9 are infrequent
include patients with hepatoblastoma {1406}. Increased copy numbers of c-met
Genetic susceptibility who have an APC gene mutation at the and K-sam proto-oncogenes and cyclin
Congenital anomalies are noted in 5' end of the gene {267, 578}. Alterations D1 genes have been described in a case
approximately 5% of patients (Table 8.04) in APC have also been noted in cases of of hepatoblastoma in an adult patient
and include renal malformations such as hepatoblastoma in non-familial adeno- {977}.
horseshoe kidney, renal dysplasia and matous polyposis patients {1390}. The presence of oval cell antigen has
duplicated ureters, gastrointestinal mal- been demonstrated in hepatoblastomas,
formations such as Meckel diverticulum, Molecular genetics which supports the stem cell origin of
inguinal hernia and diaphragmatic her- Cytogenetic abnormalities include tri- these tumours {1631}.
A B
Fig. 8.58 Mixed epithelial and mesenchymal hepatoblastoma with teratoid features. A Squamous differentiation. B Skeletal muscle fibres.
Fig. 8.59 Mixed epithelial and mesenchymal hepatoblastoma. Fetal epithelial Fig. 8.60 Mixed epithelial and mesenchymal hepatoblastoma with teratoid fea-
cells upper left and embryonal epithelial cells upper right lie adjacent to a focus tures. This area resembling fetal hepatoblastoma contains black melanin pig-
of osteoid-like material. ment.
Prognosis and predictive factors Survival in Stage I is nearly 100% and > 1,000,000ng/mL. Other factors posi-
Prognosis is directly affected by the abil- Stage II survival approaches 80%. tively influencing prognosis include
ity to resect the lesion entirely, i.e. to AFP levels are useful in predicting out- tumour confined to one lobe, fetal epithe-
attain Stage I or II following the initial sur- come by observing their response to sur- lial growth pattern, and multifocal dis-
gery {332, 446, 648, 2024}. Chemo- gery and chemotherapy {1997}. AFP lev- semination (rather than unifocal growth
therapy and transplantation have els of 100 to 1,000,000 ng/mL at initial pattern in the liver with distant metas-
allowed resectability in 90% of cases, diagnosis are associated with a better tases and vascular invasion) {2022}.
increasing the overall survival to 65-70%. prognosis than if they are < 100 or
Hepatoblastoma 189
8b 19.7.2006 8:18 Page 190
Definition
Benign and malignant tumours arising in
the liver, with vascular, fibrous, adipose
and other mesenchymal tissue differenti-
ation.
ICD-O codes
ICD-O codes, terminology, and defini-
tions largely follow the WHO ‘Histological
Typing of Soft Tissue Tumours’ {2086}. A B
Imaging
Imaging studies establish the presence
of a space-occupying lesion or lesions in
the liver, and may provide a diagnosis or
differential diagnosis {1565}. Biopsy of a
mass is, however, needed for a definitive
diagnosis {806}.
Mesenchymal hamartoma
Mesenchymal hamartoma is a ‘tumour C D
malformation’ that develops in utero. It Fig. 8.61 Mesenchymal hamartoma. A Cut surface shows cysts and tan-white tissue. B Mixture of bile ducts,
accounts for 8% of all liver tumours and mesenchymal tissue and blood vessels. C Bile ducts display a ductal plate malformation; the primitive mes-
pseudotumours from birth to 21 years of enchymal tissue consists of loosely arranged stellate cells. In addition to blood vessels, the tumour also con-
age, but during the first two years of life tains liver cells (top). D Fluid accumulation in the mesenchyme mimics lymphangioma, but the spaces lack
it represents 12% of all hepatic tumours an endothelial lining.
and pseudotumours, and for 22% of the
benign neoplasms {1839}. It usually
manifests in the first two years of life and Table 8.05
there is a slight male predominance. Presentation of mesenchymal tumours of the liver.
Lesions involve the right lobe in 75% of Mode of Presentation Examples
cases, the left lobe in 22% and both
lobes in 3%. Asymptomatic (incidental finding) Any
Presentation is typically with abdominal Upper abdominal mass +/- hepatomegaly Any
swelling, but rapid accumulation of fluid Sudden increase in size of tumour Mesenchymal hamartoma,
in the tumour can cause sudden enlarge- cavernous haemangioma
ment of the abdomen {1841}. Macrosco- Febrile illness with weight loss Inflammatory pseudotumour,
pically, it is usually a single mass that can embryonal sarcoma, angiosarcoma
Acute abdominal crisis from rupture Cavernous haemangioma, angiosarcoma,
attain a large size (up to 30 cm or more).
epithelioid haemangioendothelioma
Mesenchymal hamartoma has an excel-
Budd-Chiari syndrome Epithelioid haemangioendothelioma
lent prognosis after resection. The fate of Congestive heart failure Infantile haemangioendothelioma
untreated lesions is not known but there Cardiac tumour syndrome Embryonal sarcoma
is no convincing evidence of malignant Consumption coagulopathy Cavernous haemangioma,
transformation. infantile haemangioendothelioma
Histopathology. This tumour-like lesion is Hypoglycaemia Solitary fibrous tumour
composed of loose connective tissue and Portal hypertension Epithelioid haemangioendothelioma,
epithelial ductal elements in varying pro- inflammatory pseudotumour
portions. Grossly, the cut surfaces exhib- Liver failure Epithelioid haemangioendothelioma,
angiosarcoma
it solid, pink-tan areas and cysts contain-
Obstructive jaundice Inflammatory pseudotumour
ing a clear fluid. Histologically, the con-
Lung metastases Epithelioid haemangioendothelioma,
nective tissue is typically loose and oede- angiosarcoma
matous with a matrix of acid mucopoly-
Angiomyolipoma
The lesion is defined as a benign tumour
composed of variable admixtures of adi-
pose tissue, smooth muscle (spindled or
epithelioid), and thick-walled blood ves-
sels. The age range of angiomyolipoma
is from 30-72 years, with a mean of 50 A B
years {1373}. It is seen equally in males
and females {604}. A small number are
associated with tuberous sclerosis.
Angiomyolipomas are usually single, with
60% located in the right lobe, 30% in the
left lobe, 20% in both lobes and 8% in the
caudate lobe {1373}. They are sharply
demarcated but not encapsulated, fleshy
or firm and, when sectioned, with a
homogeneous yellow, yellow-tan or tan
appearance, depending on their content
C D
of fat.
Histopathology. Angiomyolipomas are
composed of adipose tissue, smooth
muscle and thick-walled, sometimes
hyalinized blood vessels in varying pro-
portions. Morphologically and phenotyp-
ically they are believed to belong to a
family of lesions characterized by prolif-
eration of perivascular epithelioid cells
{2197}. The smooth muscle is composed E F
of spindle-shaped cells arranged in bun- Fig. 8.66 Angiomyolipoma. A Fat within the tumour imparts a yellow colour. B Fat and smooth muscle are
dles, or larger more rounded cells with present. C Two characteristically thick-walled arteries are surrounded by fat. D This tumour is composed
an ‘empty’ (glycogen-rich) cytoplasm or predominantly of smooth muscle. The clear cytoplasm is due to glycogen that was lost during processing.
an eosinophilic, epithelioid appearance. E Large smooth muscle cells show perinuclear condensation of cytoplasm. F Marked extramedullary
The nuclei of the spindle cells are elon- haematopoiesis.
A B C
Fig. 8.68 Kaposi sarcoma. A Multiple dark brown lesions centered in large portal areas. B, C Spindle cells and slit-like vascular spaces.
to phenytoin {148}. Symptoms include eral years with some patients living five Histologically, lesions resemble those
abdominal enlargement, fever, weight or more years after combined modality occurring in other sites with spindle cells
loss, and nonspecific gastrointestinal therapy (surgical resection, radiothera- showing elongated or ovoid, vesicular
complaints {1840}. Rarely, the tumour py, and chemotherapy). nuclei with rounded ends and inconspic-
invades the vena cava and grows into uous nucleoli. Eosinophilic, PAS-positive
the right atrium, mimicking a cardiac Kaposi sarcoma globules may be seen in the cytoplasm.
tumour {561}. This lesion is defined as a tumour com- The tumour cells are separated by slit-
Macroscopy. Embryonal sarcoma is posed of slit-like vascular channels, spin- like vascular spaces . Aggregates of
usually located in the right lobe of dle cells, mononuclear inflammatory haemosiderin granules may be present.
the liver, and varies from 10-20 cm in cells, with an admixture of haemosiderin- The spindle cells express endothelial cell
diameter. It is typically well-demarcated laden macrophages. markers (CD31, CD34).
but not encapsulated. Gross sections Kaposi sarcoma involves the liver in
reveal a variegated surface with glisten- 12-25% of fatal cases of the acquired Epithelioid haemangioendothelioma
ing, solid, grey-white tumour tissue alter- immunodeficiency syndrome (AIDS), but A tumour of variable malignant potential
nating with cystic, gelatinous areas is not known to contribute significantly to that is composed of epithelioid or spindle
and/or red and yellow foci of haemor- its morbidity and mortality. In patients cells growing along preformed vessels or
rhage or necrosis. with AIDS, it is aetiologically related to forming new vessels.
Histopathology. Embryonal sarcoma is HHV-8 infection {276, 1367}. It involves Epithelioid haemangioendothelioma pre-
composed of malignant stellate or spin- portal areas but can infiltrate the adja- sents between 12 and 86 years (mean 47
dle cells that are compactly or loosely cent parenchyma for short distances, years) {807, 1150}. Its overall incidence is
arranged in a myxoid stroma. Tumour and is characterized grossly by irregular, unknown, but more are reported in
cells often show prominent anisonucleo- variably-sized, red-brown lesions scat- females (61%) than in males (39%) {807,
sis with hyperchromasia; giant cells that tered throughout the liver. 1150}. Risk factors are not known; the
may be multinucleated are seen in many
cases. A characteristic feature is the
presence of eosinophilic globules of var-
ied size, sometimes many per cell, in the
cytoplasm. They are PAS-positive, resist
diastase digestion, and express alpha-1
antitrypsin, though the larger globules
may only be immunoreactive at the
periphery. Entrapped bile ducts and
hepatocellular elements are often pres-
ent in the peripheral areas of these
tumours. The spindle, stellate and giant
cells typically show no morphological
evidence of differentiation, but immuno-
histochemical studies in a few cases
have demonstrated widely divergent dif-
ferentiation into both mesenchymal and
epithelial phenotypes, probably from a
primitive stem cell {1460}.
Prognosis. Until recently the prognosis
of embryonal sarcoma has been very
poor, with a median survival of less than
one year after diagnosis {1840}. The sur- Fig. 8.69 Epithelioid haemangioendothelioma. There is extensive destruction of liver cell plates. Note the
vival has greatly improved in the last sev- intracellular vascular lumina (arrow).
C D Angiosarcoma
Fig. 8.70 Epithelioid haemangioendothelioma. A, B Tumour cells form polypoid projections in dilated peri- A malignant tumour composed of spindle
portal sinusoids. C Dendritic tumour cells, some having intracellular vascular lumina appearing as small vac- or pleomorphic cells that line, or grow
uoles. A terminal hepatic venule is infiltrated by tumour. D Tumour cells express factor VIII-related antigen. into, the lumina of preexisting vascular
spaces, such as liver sinusoids and
small veins.
suggestion of a relationship to oral con- Neoplastic cell are either ‘dendritic’, with Worldwide, about 200 cases of angiosar-
traceptive use has not been validated spindle or irregular shapes and multiple coma are diagnosed annually {848, 59}.
{1270}. Epithelioid haemangioendothe- interdigitating processes, ‘epithelioid’, During the period 1973-87, the SEER
lioma causes systemic symptoms (weak- with a more rounded shape and an abun- database of the US National Cancer
ness, malaise, anorexia, episodic vomit- dant cytoplasm, or ‘intermediate’. Institute contained 6,391 histologically-
ing, upper abdominal pain, and weight Nuclear atypia and mitoses are mainly confirmed primary liver cancers; of these
loss) and hepato-splenomegaly {807, observed in the epithelioid cells. Cyto- only 65 (1%) were angiosarcomas {252}.
1150}. Some patients develop jaundice plasmic vacuoles, representing intracel- The peak incidence is in the 6th and 7th
and liver failure. Uncommon modes of lular vascular lumens, are often identified decades of life. The male to female ratio
presentation include the Budd-Chiari syn- and may contain erythrocytes. The is 3:1 {1085}.
drome {2040} or portal hypertension. tumour cells synthesize factor VIII-related 75% of angiosarcomas of the liver have
Macroscopy. Macroscopically, lesions antigen (von Willebrand factor), which no known aetiology {484}. The remainder
are usually multifocal; ill-defined lesions can be demonstrated in the cytoplasm or have been linked to prior administration
scattered throughout the liver vary from a in the neoplastic vascular lumens. Other of Thorotrast (a radioactive material con-
few millimeters to several centimeters in endothelial cell markers, such as CD31 taining thorium dioxide, that was used as
greatest dimension. They are firm, tan to and CD34, are also positive. an angiography contrast medium from
white on sectioning, and often have a The stroma can have a myxoid appear- the 1930s to the early 1950s), exposure
hyperaemic periphery; calcification may ance due to an abundance of sulphated to vinyl chloride monomer (VCM) or inor-
be evident grossly. mucopolysaccharide. Reticulin fibres sur- ganic arsenic, and the use of andro-
Histopathology. The tumour nodules are round nests of tumour cells. Basement genic-anabolic steroids {484}.
ill-defined, and often involve multiple membrane can be demonstrated around Patients with angiosarcoma present in
contiguous acini. In actively proliferating the cells by the PAS stain, as well as ultra- one of several ways: 61% have symp-
lesions the acinar landmarks, such as structurally and immunohistochemically. toms referable to the liver (e.g. hepato-
terminal hepatic venules (THV) and por- Variable numbers of smooth muscle cells megaly, abdominal pain, ascites); 15%
tal areas, can be recognized despite surround the basement membrane. have an acute abdominal crisis due to
extensive infiltration by the tumour. The As the lesions evolve they are associated haemoperitoneum from rupture of the
cells grow along preexisting sinusoids, with progressive fibrosis and calcification. tumour; 15% have splenomegaly, often
THV, and portal vein branches, and often Eventually, tumour cells (and indeed, the with pancytopenia; and 9% present due
invade Glisson capsule. Growth within vascular nature of the lesion) may be diffi- to distant metastases {804}. The progno-
the acini is associated with gradual atro- cult if not impossible to recognize in the sis of angiosarcoma is very poor, with
phy and eventual disappearance of liver densely sclerosed areas. Needle biopsy most patients dying within 6 months of
cell plates. Intravascular growth may be specimens taken from such areas often diagnosis.
in the form of a solid plug, or a polypoid pose diagnostic problems. The histopa- Macroscopy. Angiosarcoma typically
or tuft-like projection. thological differential diagnosis includes affects the entire liver. Grayish-white
A B
C D
Fig. 8.71 Angiosarcoma. A Multiple dark brown tumour foci scattered throughout the liver. B Solid portion showing spindle cells and numerous small vascular
channels. C Intravascular papillary structure covered by neoplastic endothelial cells. D Tumour cells express CD34.
A B
Fig. 8.72 Angiosarcoma. A Sinusoidal spread of tumour cells with destruction of hepatocyte plates. B Disrupted liver cells act as scaffolding for the tumour cells.
tumour alternates with red-brown haem- Histopathology. Tumour cells grow along cular channels and eventually the devel-
orrhagic areas. Large cavities with preformed vascular channels (sinusoids, opment of cavities of varied size. These
ragged edges, filled with liquid or clotted THV and portal vein branches). Sinus- cavities have ragged walls lined by
blood, may be present. A reticular pat- oidal growth is associated with progres- tumour cells, sometimes with polypoid or
tern of fibrosis is seen in cases related to sive atrophy of liver cells and disruption papillary projections, and are filled with
prior exposure to Thorotrast. of the plates, with formation of larger vas- clotted blood and tumour debris. Reti-
A B
Fig. 8.73 Angiosarcoma. A Closely packed elongated tumour cells. B Pink-brown granular deposits of Thorotrast in a portal area adjacent to an angiosarcoma.
culin fibres and, less often, collagen lumen, and readily explains the frequent- exposure found TP53 mutations to be
fibres support the tumour cells. Perithelial ly encountered areas of haemorrhage, uncommon, thus supporting previous
cells, reactive for alpha-smooth muscle infarction, and necrosis. Haematopoietic evidence of the carcinogenic potential of
actin, may also be present. The tumour activity is observed in the majority of chloroethylene oxide, a metabolite of
cells are sometimes packed solidly in tumours. VCM {1776}. A high rate of KRAS-2 muta-
nodules that resemble fibrosarcoma. Cases related to Thorotrast and vinyl tions has been found in both sporadic
The cells of angiosarcoma are spindle- chloride monomer are often associated and Thorotrast-induced angiosarcomas
shaped, rounded or irregular in outline, with considerable periportal and sub- of the liver {1542}.
and often have ill-defined borders. The capsular fibrosis. Thorotrast deposits are Malignant mesenchymal tumours other
cytoplasm is lightly eosinophilic, and readily recognized in reticuloendothelial than angiosarcoma may have cytogenet-
nuclei are hyperchromatic and elongated cells, in connective tissue of portal areas, ic aberrations similar to those of soft tis-
or irregular in shape. Nucleoli can be in Glisson capsule, or in the walls of THV. sue tumours {513, 1812}.
small, or large and eosinophilic. Large, The deposits are coarsely granular and
bizarre nuclei and multinucleated cells refractile, and in an H&E-stained section Carcinosarcoma
may be seen, and mitotic figures are fre- they have a pink-brown hue. They are This neoplasm is defined as a malignant
quently identified. The spindled cells readily visualized by scanning electron tumour containing an intimate mixture of
have ill-defined outlines, a lightly eosino- microscopy, and thorium can be defini- carcinomatous (either hepatocellular or
philic cytoplasm, and vesicular nuclei tively identified by energy dispersive cholangiocellular) and sarcomatous ele-
with blunt ends. Factor VIII-related anti- X-ray microanalysis {804}. ments; such lesions have also been
gen can be identified in tumour cells Genetics. Analysis of six hepatic angio- called ‘malignant mixed tumour’ of the
immunohistochemically. Other useful sarcomas associated with VCM expo- liver. Carcinosarcoma should be distin-
markers include CD31 and CD34; the for- sure found three TP53 mutations, all guished from carcinomas with foci of
mer is believed to be the most sensitive A:T→T:A transversions, which are other- spindled epithelial cells and from the rare
immunostain {1224}. wise uncommon in human cancers {728}. true ‘collision’ tumours.
Invasion of THV and portal vein branch- Another study of 21 sporadic angiosar-
es leads to progressive obstruction of the comas not associated with vinyl chloride
P.P. Anthony
Secondary tumours of the liver P. DeMatos
Definition
Malignant neoplasms metastasized to
the liver from extrahepatic primary
tumours.
Epidemiology
In Europe and North America, metas-
tases predominate over primary hepatic
tumours in a ratio of 40:1 {130, 1517}. In
Japan the ratio is 2.6:1 {1517}. In South- A B
East Asia and sub-Saharan Africa, pri-
mary hepatic tumours are more common
than metastases {1909} owing to the high
incidence of hepatocellular carcinoma, a
shorter life span (common extrahepatic
carcinomas affect older age groups) and
the low incidence of certain tumour types
(e.g. carcinomas of the lung and col-
orectum). Autopsy studies in the USA
and Japan have shown that about 40%
of patients with extrahepatic cancer have C D
hepatic metastases {351, 1517}.
Aetiopathogenesis
The liver has a rich systemic (arterial)
and portal (venous) blood supply, pro-
viding a potentially abundant source of
circulating neoplastic cells. Circulating
tumour cell arrest is controlled by Kupffer
cells in the sinusoids {881, 121} and may
be enhanced by growth factors such as
transforming growth factor alpha (TGFα) E F
{385}, tumour necrosis factor (TNF) Fig. 8.74 Secondary tumours in the liver. A Metastatic colon carcinoma showing umbilication and hyper-
{1431}, and insulin-like growth factor-1 emic borders. B Metastatic small cell carcinoma of lung forming inumerable small nodules. C, D Metastatic
(IGF-1) {1091}. As tumour deposits large intestinal carcinoma, cut surfaces. E Metastatic gastric adenocarcinoma, cut surface. F A metastasis
lies adjacent to a Zahn infarct.
enlarge, they induce angiogenesis using
native sinusoidal endothelium; this
enhances their chances of survival and is In the majority of cases, metastases to gallbladder, pancreas): 44-78%; colon:
often macroscopically evident {1919}. the liver are a manifestation of systemic, 56-58%; lung 42-43%; breast 52-53%;
Most metastases from unpaired abdomi- disseminated disease. Colorectal carci- oesophagus 30-32% and genito-urinary
nal organs reach the liver via the portal noma, neuroendocrine tumours, and organs 24-38% {130, 1517, 351}.
vein, and from other sites via the systemic renal cell carcinoma are exceptions as Carcinomas of the prostate and the
arterial circulation. Lymphatic spread is these neoplasms sometimes produce ovaries preferentially spread to the lymph
less common and extension to the liver isolated, even solitary deposits {1517}. nodes and the spine, and to the peri-
via the peritoneal fluid is rare {351}. toneal cavity, respectively.
Cirrhosis provides some relative protec- Origin of metastases Hodgkin and non-Hodgkin lymphomas
tion against seeding by secondary The majority of secondary liver neo- may involve the liver in up to 20% of
tumours {1983, 1211}. It has also been plasms are carcinomas, involvement by cases on presentation and 55% at autop-
suggested that metastasis is rare in fatty lymphomas is next and sarcomas are sy {1620, 826}. Sarcomas are much less
livers {676}, but excess alcohol con- uncommon. The order of frequency by common but 6% had hepatic metastases
sumption apparently enhances hepatic primary site in Western populations is: at presentation (mostly intra-abdominal
metastases {1140}. upper gastrointestinal tract (stomach, leiomyosarcomas) in one study {833},
Imaging
Ultrasound (US) can identify tumours
measuring 1-2 cm in size, can differenti-
ate solid from cystic lesions, and provide
guidance for percutaneous needle biop-
sy. However, it provides poor anatomical
A B definition and frequently misses smaller
Fig. 8.76 Metastatic colorectal carcinoma. A Tumour is necrotic and cell type is typically columnar. lesions.
B Necrosis may result in calcification. Computed tomography (CT), using both
contrasted and non-contrasted images,
can also serve as a screening tool. The
while 34% had hepatic metastases at ness, hepatic pain, jaundice, anorexia, administration of intravenous contrast
autopsy in another {1517}. and weight loss. Constitutional symp- permits the detection of tumours as small
In a study of randomly selected liver toms, such as malaise, fatigue, and fever as 0.5 cm in diameter {1763}. Most meta-
biopsies from England and Wales {852}, may be present. On examination, nod- stases display decreased vascularity in
the commonest histological type of ules or a mass are felt in up to 50% of the comparison to the surrounding hepatic
metastasis was adenocarcinoma (39%), cases, and a friction bruit may be heard parenchyma and appear as hypodense
followed by carcinoma not otherwise on auscultation. Unfortunately, sympto- defects. Tumours that are hypervascular
specified (36%); the rest were undifferen- matic presentation is associated with (e.g. melanoma, carcinoids and some
tiated small cell carcinoma, other special bulky, rapidly progressive tumours with a breast cancers) or calcified (e.g. colorec-
types of carcinoma, and lymphomas. poor prognosis {2035}. tal carcinoma) are better delineated by
Rarely, patients present with fulminant noncontrast views.
Clinical features hepatic failure, obstructive jaundice, or Magnetic resonance imaging (MRI) is
Symptoms and signs intraperitoneal haemorrhage. Function- more sensitive than CT in the detection of
Hepatic metastases produce clinical ing neuroendocrine tumours produce syn- hepatic tumours and can demonstrate
manifestations in about two-thirds of dromes of hormonal excess. ‘Carcino- additional lesions, too small to be seen
cases and they generally reveal them- matous cirrhosis’ with jaundice, ascites, on CT.
selves through symptoms referable to the and bleeding varices due to diffuse infil- Positron emission tomography (PET) can
liver. Afflicted patients often present with tration of the liver, usually by metastatic detect metastatic disease in the liver and
ascites, hepatomegaly or abdominal full- breast carcinoma, has been described elsewhere. Using 2-(18)fluoro-2-deoxy-
{174}. D-glucose (F-18 FDG), a radiolabeled
glucose analogue, PET highlights meta-
Laboratory studies bolically active tissues. Through co-reg-
The alkaline phosphatase (ALP) and istration with anatomical studies like CT
serum glutamic-oxaloacetic transami- or MRI, viable malignant tumours can be
nase (SGOT) levels, although non-spe- differentiated from benign or necrotic
cific, are elevated in approximately 80% lesions {54}.
and 67% of patients respectively, and CT arterial portography performed pre-
most likely represent the effects of hepat- operatively, and intraoperative ultra-
ic parenchymal infiltration by tumour and sound are associated with the highest
of generalized wasting. Elevated lactic sensitivities {1796}. The former is capa-
dehydrogenase (LDH) levels are relative- ble of detecting lesions as small as
Fig. 8.77 Metastatic breast carcinoma. ly specific for the presence of metastatic 15 mm, although a false positive rate of
A B
Fig. 8.78 Metastatic islet cell carcinoma of pancreas. A Haematoxylin and eosin. B Somatostatin immunoreactivity.
17% has been reported {1795}. Its suc- creas or colorectum. A vascular rim Histopathology
cess relies on the fact that tumours are around the periphery is often seen. Liver biopsy samples can be obtained by
not fed by portal vein blood, so that Highly mucin secreting adenocarcino- percutaneous or transjugular routes with
metastases appear as filling defects. The mas appear as glistening, gelatinous or without imaging techniques for guid-
latter, capable of detecting lesions 2-4 masses whilst well differentiated kera- ance, as a wedge during laparotomy, or
mm in diameter delineates the anatomi- tinizing squamous cell carcinomas are a fine needle can be used to aspirate
cal location of tumours in relationship to granular. Metastatic carcinoid tumours material for cytology. Each of these meth-
major vascular and biliary structures and can form pseudocysts {401}. Haemor- ods has advantages and drawbacks but
provides guidance for intraoperative rhagic secondary deposits suggest a guided percutaneous needle biopsy
needle biopsies. It is the definitive step in angiosarcoma, choriocarcinoma, carci- producing a core of liver for histology is
determining resectability at the time of noma of thyroid or kidney, neuroen- the one most frequently used. It pro-
exploratory laparotomy or laparoscopy. docrine tumour, or vascular leiomyosar- duces a tissue sample that is usually
Angiography use has declined in recent coma. Some diffusely infiltrating carcino- adequate for all purposes, including the
years. It remains useful for defining vas- mas (e.g. small cell carcinoma), lym- use of special stains, immunohistochem-
cular anatomy for planned hepatic resec- phomas and sarcomas may have a soft, istry and molecular biological tech-
tions, selective chemotherapy, chemo- opaque ‘fish flesh’ appearance. Meta- niques. Touch preparations for cytology
embolization, or devascularization pro- static breast carcinoma in particular can can also be prepared from needle cores
cedures, for assessing whether there is produce an intensely fibrous, granular before fixation and may provide an
metastatic involvement of the portal liver (‘carcinomatous cirrhosis’) either instant diagnosis {1523}.
venous system and/or hepatic veins, and before {174} or after {1693} treatment.
for differentiating between benign vascu- Calcification of secondary deposits is a Differential diagnosis
lar lesions, such as haemangiomas and feature of colorectal carcinoma but it is Hepatocellular carcinoma can usually be
metastases, when other imaging studies seldom excessive and has no effect on distinguished from metastatic tumours by
have yielded equivocal results. prognosis {653}. Metastatic melanoma is its trabecular structure, sinusoids, lack of
often, but not always, of a brown-black stroma, bile production, absence of
Macroscopy colour. Secondary tumours may appear mucin secretion, and the demonstration
The distribution of metastases from col- in the liver long after the removal of the of bile canaliculi by polyclonal CEA anti-
orectal carcinoma was found to be primary. sera, which is specific for a liver cell ori-
homogenous, regardless of the primary gin. Other useful immunophenotypic fea-
site of origin {1695} but in another study, tures in this differentiation are the pres-
it was suggested that right sided cancers ence of liver export proteins (albumin,
predominantly metastasize to the right fibrinogen, alpha-1-antitrypsin), the cyto-
lobe of the liver and left sided cancers to keratin pattern, and the expression of
both lobes {1749}. Hep Par 1 antigen {1046}. Metastatic
Metastases are nearly always multinodu- tumours that often mimic hepatocellular
lar or diffusely infiltrative, but may rarely carcinoma are adrenal cortical and renal
be solitary and massive (e.g. from colo- cell carcinomas. Amelanotic melanoma
rectal and renal cell carcinomas). may also cause difficulties but it is easily
Umbilication (a central depression on the identified by positive immunostaining for
surface of a metastatic deposit) is due to S100 protein and HMB45 .
necrosis or scarring and is typical of an Fig. 8.79 Systemic non-Hodgkin lymphoma involv- The distinction between primary cholan-
adenocarcinoma from stomach, pan- ing the liver. giocarcinoma and metastatic adenocar-
CHAPTER 9
_________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded
/0 for benign tumours, /1 for unspecified, borderline, or uncertain behaviour, /2 for in situ carcinomas and grade III intraepithelial neoplasia and /3 for malignant tumours.
_________
1
{1, 66}. The classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
_________
1
{1, 66}. The classification applies to carcinomas of extrahepatic bile ducts and those of choledochal cysts.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
_________
1
{ 1, 66}. The classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
205
09 19.7.2006 8:20 Page 206
A B C
Fig. 9.05 Intestinal type adenocarcinoma. A Tubular glands similar to colonic adenocarcinoma. B Goblet cell type of adenocarcinoma. C Numerous serotonin con-
taining cells in a neoplastic gland.
Carcinoma 207
09 19.7.2006 8:20 Page 208
Adenosquamous carcinoma
This tumour consists of two malignant
components, one glandular and the
other squamous. The extent of differenti-
ation of the two components varies, but
in general they tend to be moderately dif- CA
ferentiated {1357, 1867}. Keratin pearls
are often present in the squamous com-
ponent, and mucin is usually demonstra-
ble in the neoplastic glands.
Fig. 9.12 Carcinosarcoma of gallbladder. The Carcinosarcoma Fig. 9.14 Clear cell carcinoma of extrahepatic bile
tumour shows malignant glandular elements and a This malignant tumour consists of a mix- duct. The overlying biliary epithelium is non-neo-
sarcomatous component with osteoid formation. ture of two components: carcinomatous plastic.
Carcinoma 209
09 19.7.2006 8:20 Page 210
component, which helps to distinguish association with the Peutz-Jeghers syn- including somatostatin, pancreatic
carcinosarcomas from spindle and giant drome {521} or with Gardner syndrome polypeptide, and gastrin have been
cell carcinomas. {1900, 2041}. Adenomas of the extrahep- detected in the cytoplasm of these cells.
atic bile ducts are usually symptomatic Smaller lesions show low-grade intraep-
Grading and cause biliary obstruction. These ithelial neoplasia, but larger adenomas
Adenocarcinomas can be divided into benign tumours are not associated with may have high-grade changes or foci of
well, moderately, or poorly differentiated lithiasis. invasive carcinoma. As they enlarge,
types. The diagnosis of well differentiat- According to their pattern of growth, they most adenomas develop a pedicle and
ed adenocarcinoma requires that 95% of are divided into three types: tubular, pap- project into the lumen. Rarely, they
the tumour contains glands. For moder- illary, and tubulopapillary. Cytologically, extend into or arise from Rokitansky-
ately differentiated adenocarcinoma 40 they are classified as: pyloric gland type, Aschoff sinuses, a finding that should not
to 94% of the tumour should be com- intestinal type, and biliary type. Tubular be mistaken for carcinoma {42}.
posed of glands and for poorly differenti- adenomas of pyloric gland type are more
ated adenocarcinomas 5 to 39% of the common in the gallbladder while intestin- Tubular adenoma, intestinal type. This
tumour should contain glands. Undiffer- al type adenomas are more common in benign tumour is composed of tubular
entiated carcinomas display less than the extrahepatic bile ducts {42}. glands lined by cells with an intestinal
5% of glandular structures. phenotype, and closely resembles
Tubular adenoma, pyloric-gland type. A colonic adenomas. It consists of tubular
Precursor lesions benign tumour composed of closely glands lined by pseudostratified colum-
Adenoma packed short tubular glands that are sim- nar cells with elongated hyperchromatic
Adenomas are benign neoplasms of ilar to pyloric glands. Early lesions nuclei, and high-grade dysplastic
glandular epithelium (intraepithelial neo- appear as well demarcated nodules changes are frequent. The glands lack
plasia) that are typically polypoid, single embedded in the lamina propria and invasive properties and focally are
and well-demarcated. They are more covered with normal biliary epithelium. arranged in well defined lobules. The
common in women than in men {42}. They are composed of lobules that con- adenomatous epithelium may extend into
There is a wide age range; although tain closely packed pyloric-type glands, the Rokitansky-Aschoff sinuses, a finding
mostly a disease of adults rare gallblad- some of which may be cystically dilated. that should not be confused with stromal
der adenomas occur in children {1256, The epithelial cells are columnar or invasion. Clusters of goblet, Paneth, and
2126}. They are more common in the cuboidal with vesicular or hyperchromat- endocrine cells are usually mixed with
gallbladder than in the extrahepatic bile ic nuclei and small nucleoli and variable the columnar cells. Serotonin and, less
ducts, and are found in 0.3-0.5% of gall- amounts of cytoplasmic mucin. Nodular frequently, peptide hormones have been
bladders removed for cholelithiasis or aggregates of cytologically bland spin- identified in the endocrine cells by
chronic cholecystitis. A small proportion dle cells with eosinophilic cytoplasm but immunohistochemistry. Hyperplasia of
of adenomas progress to carcinoma {42, without keratinization or intercellular metaplastic pyloric type glands is often
909, 967}. bridges known as squamoid morules seen at the base of the adenomas.
Adenomas are often small, asympto- {984, 1361} are present in about 10% of Papillary adenoma, intestinal type. This
matic, and usually discovered incidental- the cases, whereas frank squamous benign tumour consists predominantly of
ly during cholecystectomy, but they can metaplasia is exceedingly rare. Paneth papillary structures lined by dysplastic
be multiple, fill the lumen of the gallblad- cells and endocrine cells are often pres- cells with an intestinal phenotype. These
der and be symptomatic. Occasionally, ent. By immunohistochemistry, serotonin adenomas, which usually arise in a back-
adenomas of the gallbladder occur in and a variety of peptide hormones ground of pyloric gland metaplasia, may
B
A
Fig. 9.15 Papillary adenoma of gallbladder, intestinal type. A Numerous papillary structures project into lumen. B Pseudostratified columnar cells with scattered gob-
let and Paneth cells.
A B
Fig. 9.16 A, B Tubular adenoma of gallbladder, pyloric gland type.
occur in the gallbladder or the extrahep- comprise more than 20% of the tumour, characterized by multiple recurring papil-
atic bile ducts. In a series of five intestin- the term tubulo-papillary adenoma is lary adenomas, that may involve exten-
al type papillary adenomas of the gall- applied. Two subtypes are recognized: sive areas of the extrahepatic bile ducts
bladder, one progressed to invasive car- one is composed of tubular glands and and even extend into the gallbladder and
cinoma {42}. The predominant cell is papillary structures similar to those of intrahepatic bile ducts. The disease
columnar with elongated hyperchromatic tubulovillous intestinal adenomas; the affects both sexes equally. Most patients
nuclei and little or no cytoplasmic mucin. other subtype consists of tubular glands are adults between 50 and 60 years.
The cells are pseudostratified, mitotically similar to pyloric glands and papillary Complete excision of the multicentric
active, and indistinguishable from those structures often lined by foveolar epithe- lesions is difficult and local recurrence is
of villous adenomas arising in the large lium. Paneth and endocrine cells are common. The lesion consists of numer-
intestine. Tubular glands lined by the present in some. Rarely, tubulo-papillary ous papillary structures as well as com-
same type of epithelium, but represent- adenomas arise from the epithelial plex glandular formations. Because
ing less than 20% of the tumour, may also invaginations of adenomyomatous hyper- severe dysplasia is often present, papillo-
be found. Dysplastic changes are more plasia. matosis is difficult to distinguish from
extensive than in pyloric-gland type ade- papillary carcinoma. Some regard this
nomas. Also present are goblet, Paneth, Other benign biliary lesions lesion as a form of low-grade multicentric
and serotonin-containing cells. Some of Biliary cystadenoma. These lesions intraductal papillary carcinoma. Papil-
the endocrine cells are immunoreactive resemble their intrahepatic counterparts lomatosis has a greater potential for
for peptide hormones. (see chapter on bile duct cystadenoma malignant transformation than solitary
and cystadenocarcinoma). Cystadeno- adenomas.
Papillary adenoma, biliary type. This mas are seen predominantly among Intraepithelial neoplasia (dysplasia)
lesion consists predominantly of papil- adult females and are usually sympto- If intraepithelial neoplasia is found, multi-
lary structures lined by cells with a biliary matic. Some of the tumours may meas- ple sections should be taken to exclude
phenotype. It is well demarcated and ure up to 20 cm in diameter leading to invasive cancer. Cholecystectomy is a
consists of papillary structures lined by obstructive jaundice or cholecystitis-like curative surgical procedure for patients
tall columnar cells, which except for the symptoms. More common in the extra- with in situ carcinoma or with carcinoma
presence of more cytoplasmic mucin hepatic bile ducts than in the gallblad- extending into the lamina propria {35}.
show minimal variation from normal gall- der, cystadenomas are multiloculated Epidemiology. The rate of intraepithelial
bladder epithelium. Endocrine or Paneth neoplasms that contain mucinous or neoplasia of the gallbladder reflects that
cells are not found. Only mild dysplastic serous fluid and are lined by columnar of invasive carcinoma. In countries in
changes are noted. In situ or invasive epithelium reminiscent of bile duct which carcinoma of the gallbladder is
carcinoma has not been reported in or foveolar gastric epithelium {404}. endemic, the prevalence is higher than in
association with these adenomas. This is Occasionally endocrine cells are pres- countries in which this tumour is spo-
the rarest form of adenoma of the gall- ent. The cellular subepithelial stroma radic. Studies from different countries
bladder; we have seen only one case. resembles ovarian stroma and shows have shown that the incidence of high-
Most papillary lesions composed of nor- immunoreactivity for estrogen and prog- grade dysplasia or carcinoma in situ in
mal-appearing gallbladder epithelium esterone receptors {2029}. The stroma gallbladders with lithiasis has varied from
are examples of hyperplasia secondary also shows variable fibrosis. Malignant 0.5-3% {35}. This variation in the inci-
to chronic cholecystitis. transformation (cystadenocarcinoma) dence of intraepithelial neoplasia is also
can occur {404}. attributable to other factors such as lack
Tubulo-papillary adenoma. When tubular Papillomatosis (adenomatosis). Papillo- of uniformity in morphological criteria
glands and papillary structures each matosis is a clinicopathological condition and sampling methods.
Carcinoma 211
09 19.7.2006 8:20 Page 212
A B
Fig. 9.17 High-grade intraepithelial neoplasia (carcinoma in situ) of gallbladder.
A B C
Fig. 9.19 Biliary papillomatosis. A Large, thickened intrahepatic and extrahepatic bile ducts. B Villous pattern. C There is no invasion by tumour cells.
els. The neoplastic columnar cells alterations are considered early events, ing on the study, the incidence of KRAS
extend into the epithelial invaginations while RAS mutations and LOH at 3p, RB, mutations in extrahepatic bile duct carci-
and the antral-type glands. Formation of and 5q occur less frequently and are nomas has varied from 0-100% {1586},
cribriform structures in the lamina propria considered late events, probably related but most likely, the true incidence is
occurs. This tumour also has scattered to tumour progression. Amplification of around 56% {2067}. However, the inci-
endocrine cells, most of which are the c-erbB-2 gene, that codes for a gly- dence of KRAS mutations is greater in
immunoreactive for serotonin. coprotein structurally similar to the epi- gallbladder carcinomas associated with
Two examples of in situ signet-ring cell dermal growth factor receptor was an anomalous junction of the pancreati-
carcinoma confined to the surface detected in 30 of 43 invasive gallbladder cobiliary duct than in carcinomas not
epithelium and to the epithelial invagina- carcinomas {1036}. However, no correla- associated with this congenital anomaly
tions of the gallbladder have been tion between c-erbB-2 gene amplifica- {661}. These molecular pathology find-
reported {40}. These in situ signet ring tion and prognosis was found. ings support the concept that gallbladder
cell carcinomas represented incidental In contrast to lesions of the gallbladder, carcinogenesis requires a number of
findings in cholecystectomy specimens the incidence of TP53 mutations in extra- genetic alterations involving activation of
and were cytologically similar to those hepatic bile duct carcinomas is lower oncogenes or inactivation of tumour sup-
reported in the stomach. This unusual and appears to be a late molecular pressor genes.
form of carcinoma in situ should be dis- event. The molecular pathology of adenomas of
tinguished from epithelial cells which Although the frequency of KRAS muta- the gallbladder differs from that of carci-
acquire signet-ring cell morphology tions in gallbladder carcinomas has nomas. None of 16 adenomas showed
when desquamated within the lumen of ranged from 0%-34% in different studies, TP53 or p16 Ink4/CDKN2a gene muta-
dilated metaplastic pyloric glands in most investigators have found these tions, which are common in carcinomas
cases of chronic cholecystitis and from mutations to be significantly higher in {2126}. Four adenomas had KRAS muta-
mucin-containing histiocytes (muci- extrahepatic bile duct tumours than in tions (2 in codon 12 and 2 in codon 61)
phages). gallbladder carcinomas {2067}. Depend- which are considered rare and late
The morphological type of in situ carci-
noma does not always correspond with
that of the invasive carcinoma. For exam-
ple, we have seen conventional adeno-
carcinoma in situ in the mucosa adjacent
to invasive squamous, small cell, and
undifferentiated carcinomas.
The wall of the gallbladder with dysplasia
or carcinoma in situ usually shows vari-
able inflammatory changes, typically with
a predominance of lymphocytes and
plasma cells, although lymphoid follicles
with germinal centers, xanthogranuloma-
tous inflammation or an acute inflamma-
tory reaction may be present.
Molecular pathology
Mutations of TP53 are found in the vast
majority of invasive gallbladder carcino-
mas {2124, 2127}. Loss of heterozygosi-
ty (LOH) at chromosomal loci 8p (44%),
9p (50%) and 18q (31%) are also fre-
quently detected {2127}. These genetic Fig. 9.20 Papillomatosis of extrahepatic bile duct.
Carcinoma 213
09 19.7.2006 8:20 Page 214
events in the pathogenesis of carcino- most likely contributing factors in the histologically often prove to be papillary
mas of the gallbladder. Only one adeno- pathogenesis of gallbladder carcinoma. carcinomas) have the best prognosis.
ma of intestinal type showed loss of het- However, KRAS mutations were not Non-invasive papillary carcinomas are
erozygosity at 5q22 {2126}. detected in intraepithelial neoplasia associated with a better prognosis than
Intraepithelial neoplasia (both dysplasia {2125}. other types of invasive carcinomas.
and carcinoma in situ) shows a high inci- Perineural invasion and lymphatic per-
dence of loss of heterozygosity at the Prognosis and predictive factors meation are common in the extrahepatic
TP53 gene locus. Other molecular abnor- The prognosis of tumours of the extra- bile duct carcinoma and are significant
malities include loss of heterozygosity at hepatic biliary tract depends primarily on prognostic factors {2150, 376}.
9p and 8p loci and the 18q gene. These the extent of disease and histological
abnormalities are also early events and type {694, 695}. Polypoid tumours (which
C. Capella
Endocrine tumours of the gallbladder E. Solcia
and extrahepatic bile ducts L.H. Sobin
R. Arnold
eral hormones including serotonin {115, ing the cases reviewed by Yamamoto et
57}, gastrin {1175, 1156}, and somato- al. {2157}, are in fact mixed endocrine-
statin {603, 57}. exocrine carcinomas. These are com-
Cases showing regional or distant posite tumours in which areas of adeno-
metastases {177, 926, 1205, 57} or signs carcinoma intermingle with areas of
of local aggressive growth, including endocrine cell carcinoma formed by
invasion of the entire wall {1205, 57} and solid and/or trabecular structures with
neural invasion {1205}, should be con- cells which are argyrophylic and
sidered as well differentiated endocrine immunoreactive for endocrine markers,
carcinomas (malignant carcinoids). including NSE, chromogranin, serotonin
Fig. 9.22 Small cell carcinoma lying below normal and gastrin {2157, 2030, 1405, 1575}.
Small cell carcinoma (poorly differentiat- gallbladder epithelium. The adenocarcinoma component is usu-
ed endocrine carcinoma) ally tubular or papillary, formed by
The cell population and growth patterns those of adenocarcinomas, and foci of columnar cells, goblet cells and some-
of this tumour are similar to those of small squamous differentiation are seen {40, times Paneth cells, but a case of a com-
cell carcinoma of the lung {38, 40, 1359}. 774, 40, 1359}. Mitotic figures are fre- bined diffuse type tumour in which
Small cell carcinomas appear to be more quently observed and they are reported mucin-containing signet-ring cells were
common in the gallbladder than in the to range from 15 to 206 (mean 75) per 10 admixed with clear endocrine cells has
extrahepatic bile ducts. Some mimic car- high power fields {1359}. also been reported {1455}.
cinoid tumours. Most small cell carcinomas show scat- These tumours behave as adenocarcino-
Most tumours are composed of round or tered Grimelius positive cells. In addition, mas and, therefore, are clinically more
fusiform cells arranged in sheets, nests, tumour cells immunoexpress epithelial aggressive than carcinoids. Adenocar-
cords, and festoons. Rosette-like struc- markers such as EMA, AE1/AE3 and cinoma with endocrine cells should not
tures and tubules are occasionally pres- CEA, and endocrine markers such as be included in this category.
ent. Extensive necrosis and subepithelial NSE, chromogranin A, Leu7, serotonin,
growth are constant features. In necrotic somatostatin, and ACTH {1359, 34}. Genetic susceptibility
areas, intense basophilic staining of the Ultrastructurally, a small number of Carcinoids of the gallbladder and extra-
blood vessels occurs. The tumour cells dense core secretory granules can be hepatic bile ducts are infrequently asso-
have round or ovoid hyperchromatic found {34, 37}. ciated with the Zollinger-Ellison, MEN I,
nuclei with inconspicuous nucleoli. A few or the carcinoid syndromes. One patient
tumour giant cells can be observed in Mixed endocrine-exocrine carcinoma with von Hippel-Lindau syndrome and a
some cases {1359, 34}. Occasionally, A significant number of cases reported in carcinoid tumour of the extrahepatic bile
focal glandular configurations similar to the older literature as carcinoids, includ- ducts has been reported.
A B C
Fig. 9.21 Carcinoid tumour of common bile duct. A A band of fibrous tissue separates the tumour from normal bile duct epithelium. B Carcinoid cells with round nuclei
and eosinophilic cytoplasm. C The tumour cells are immunoreactive for serotonin.
Genetics metastases has been estimated as chemotherapy. In one study, the survival
Overexpression of TP53 has been found approximately 44% and 11%, respective- rates differed significantly between
in 64% of small cell carcinomas of the ly {1251}. The 5-year survival rate was stages I, II, III and stage IV {1359}. The
gallbladder {1359}, compared with a fre- 41% in SEER data. Carcinoid tumours survival of patients with small cell carci-
quency of 44% in small cell carcinomas larger than 2 cm often extend into the noma of the gallbladder appears to be
of the lung {773} and 75% in small cell liver or metastasize. Complete excision shorter than that of patients with papillary
carcinomas of the stomach {1589}. of small tumours is usually curative. The adenocarcinoma {1359}.
prognosis of small cell carcinoma of the
Prognostic factors gallbladder is poor, with only one of 18
The percentage of gallbladder carci- patients {34} surviving 11 months follow-
noids showing regional and distant ing cholecystectomy, radiotherapy, and
Paraganglioma lar cell tumours may be multicentric or iary tract is an incidental autopsy finding
This benign tumour is composed of chief may coexist with one or more granular in the acquired immune deficiency syn-
cells and sustentacular cells arranged in cell tumours in other sites, especially the drome. The haemorrhagic lesions are
a nesting or zellballen pattern. The chief skin. usually located in the subserosa or mus-
cells are argyrophilic and stain for neu- cular wall of the gallbladder or in the
ron-specific enolase and chromogranin. Ganglioneuromatosis periductal connective tissue of the bile
The sustentacular cells are S-100 protein Ganglioneuromatosis of the gallbladder ducts. Other malignant non-epithelial
positive. The tumour is located in either is a component of the type Ilb multiple tumours are leiomyosarcoma, malignant
the subserosa or muscular wall of the endocrine neoplasia syndrome. The his- fibrous histiocytoma and angiosarcoma.
gallbladder and apparently arises from tological changes consist of Schwann Leiomyoma, lipoma, haemangioma, and
normal paraganglia. This rare and small cell and ganglion cell proliferation in the lymphangioma have been described. A
tumour is usually an incidental finding in lamina propria as well as enlarged and benign stromal tumour of the gallbladder
cholecystectomy specimens. Paragan- distorted nerves in the muscle layer and with interstitial cells of Cajal phenotype
gliomas also occur in the extrahepatic subserosa. Neurofibromatosis is exceed- has been reported recently {35}.
bile ducts, where they may be sympto- ingly rare in the gallbladder but has been
matic. reported in association with multiple neu-
rofibromatosis.
Granular cell tumour Embryonal rhabdomyosarcoma (‘sarco-
Granular cell tumours are the most com- ma botryoides’) is the most common
mon benign non-epithelial tumours of the malignant neoplasm of the biliary tract in
extrahepatic biliary tract. They are more childhood. It occurs more frequently in
common in the bile ducts than in the gall- the bile ducts than in the gallbladder.
bladder. Although usually single, granu- Kaposi sarcoma of the extrahepatic bil-
A. Wotherspoon
Lymphoma of the gallbladder
In common with lymphoma elsewhere in reported {282, 1201, 94, 138}. Two cases surrounded by an infiltrate of centrocyte-
the digestive system, primary lymphoma of low-grade B-cell MALT lymphoma like (CCL) cells showing variable plasma
of the gallbladder is defined as an extra- have been described {1201, 138}, while cell differentiation. Infiltration of the
nodal lymphoma arising in the gallblad- the majority of the remainder have been epithelium with the formation of lym-
der with the bulk of the disease localized large B-cell lymphomas. MALT lym- phoepithelial lesions is a typical feature.
to this site {796}. Contiguous lymph node phomas may arise within acquired MALT Characteristically, the CCL cells show
involvement and distant spread may be that is frequently encountered within gall- expression of the pan-B-cell markers
seen but the primary clinical presenta- bladders associated with chronic chole- CD20 and CD79a, and there is frequent
tion is in the gallbladder with therapy cystitis {1943}. The morphology of pri- expression of bcl-2 protein. Tumour cells
directed at this site. mary MALT lymphoma of the gallbladder are usually negative for CD5 and CD10
Primary lymphoma of the gallbladder is resembles that seen elsewhere in the but there may be expression of CD43.
extremely rare, with only about 13 cases digestive tract. Lymphoid follicles are
P. DeMatos
Secondary tumours and melanoma P.P. Anthony
Incidence and origins Hodgkin lymphoma (e.g. mantle cell lym- titis {1433, 1013, 427}. Patients with bile
Although rare in clinical practice, gall- phoma) may also involve the common duct metastases may present with
bladder and extrahepatic bile duct bile duct. obstructive jaundice {180}.
metastases were encountered in 15% Ultrasound may be used to evaluate
and 6% of cases respectively in an Malignant melanoma metastatic lesions within the gallbladder.
autopsy study of melanoma patients Primary malignant melanoma is exceed- Computed tomography is also helpful
{373}. Indeed, malignant melanoma ingly rare in the gallbladder. Junctional especially for assessing the extent of
accounts for more than 50% of all report- activity in the epithelium adjacent to the tumour when therapeutic intervention is
ed cases of gallbladder and intrabiliary tumour, absence of a primary melanoma contemplated {1013}. The common bile
metastases {100}. Other metastatic elsewhere in the body and long term sur- duct is best imaged through the use of
lesions include carcinomas of the kidney, vival are important features to distinguish ultrasound, endoscopic retrograde
lung, breast, ovary and oesophagus {35, primary from the more commonly occur- cholangiography, and percutaneous
1674, 2085}; some examples result from ring metastatic melanoma. However, transhepatic cholangiography.
transcoelomic spread in the setting of junctional activity has been reported in
peritoneal carcinomatosis. The gallblad- metastatic melanoma in the gallbladder. Macroscopy
der and extrahepatic bile ducts may also Intraluminal metastases of melanoma
be involved by direct extension from car- Clinical features tend to be polypoid whilst metastatic car-
cinomas of the pancreas, stomach, colon Involvement of the gallbladder by cinoma of the breast and lymphoma pro-
and liver. metastatic tumour rarely produces symp- duce diffuse infiltrates and strictures.
Metastatic infiltration of the common bile toms, which could explain the paucity of
duct by carcinoma of the breast, giving clinical reports published in the literature Histopathology
rise to obstructive jaundice, has been {373, 427}. When symptoms are present, The features are similar to those
reported {471}. Certain types of non- they are usually those of acute cholecys- observed in other organs.
CHAPTER 10
Benign
Serous cystadenoma 8441/01 Serous cystadenocarcinoma 8441/3
Mucinous cystadenoma 8470/0 Mucinous cystadenocarcinoma 8470/3
Intraductal papillary-mucinous adenoma 8453/0 – non-invasive 8470/2
Mature teratoma 9080/0 – invasive 8470/3
Intraductal papillary-mucinous carcinoma 8453/3
Borderline (uncertain malignant potential) – non-invasive 8453/2
Mucinous cystic neoplasm with moderate dysplasia 8470/1 – invasive (papillary-mucinous carcinoma) 8453/3
Intraductal papillary-mucinous neoplasm with moderate dysplasia 8453/1 Acinar cell carcinoma 8550/3
Solid-pseudopapillary neoplasm 8452/1 Acinar cell cystadenocarcinoma 8551/3
Mixed acinar-endocrine carcinoma 8154/3
Malignant Pancreatoblastoma 8971/3
Ductal adenocarcinoma 8500/3 Solid-pseudopapillary carcinoma 8452/3
Mucinous noncystic carcinoma 8480/3 Others
Signet ring cell carcinoma 8490/3
Adenosquamous carcinoma 8560/3 Non-epithelial tumours
Undifferentiated (anaplastic) carcinoma 8020/3
Undifferentiated carcinoma with osteoclast-like giant cells 8035/3 Secondary tumours
Mixed ductal-endocrine carcinoma 8154/3
_________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded
/0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, (/2 for in situ carcinomas) and /3 for malignant tumours.
_________
1
{1, 66}. This classification applies only to carcinomas of the exocrine pancreas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
Peripancreatic tissues include the surrounding retroperitoneal fat (retroperitoneal soft tissue or retroperitoneal space), including mesentery (mesenteric fat), mesocolon, greater and
lesser omentum, and peritoneum. Direct invasion to bile ducts and duodenum includes involvement of ampulla of Vater.
4
Adjacent large vessels are the portal vein, coeliac artery, and superior mesenteric and common hepatic arteries and veins (not splenic vessels).
G. Klöppel G. Adler
Ductal adenocarcinoma of the pancreas R.H. Hruban S.E. Kern
D.S. Longnecker T.J. Partanen
Definition adjusted incidence rates (world standard with a male/female ratio of 1.6 in devel-
A carcinoma occurring almost exclusive- population) range from 3.1 (Herault, oped nations and 1.1 in developing coun-
ly in adults that probably arises from and France) to 20.8 (central Louisiana, USA, tries. Blacks have distinctly higher rates
is phenotypically similar to, pancreatic blacks) per 100,000 males and from 2.0 than whites {593}.
duct epithelia, with mucin production (Herault, France) to 11.0 (San Francisco,
and expression of a characteristic cyto- CA, USA, blacks) per 100,000 females Aetiology
keratin pattern. {1471}. Rates from most developing The development of pancreatic carcino-
countries range from 1.0 to close to 10 ma is strongly related to cigarette smok-
ICD-O codes per 100,000. Incidence and mortality ing, which carries a 2-3 fold relative risk
Ductal adenocarcinoma 8500/3 rates are almost identical, since survival (RR) that increases with the number of
Mucinous noncystic carcinoma 8480/3 rates for pancreatic carcinoma are very pack-years of smoking {21}. Although the
Signet ring cell carcinoma 8490/3 low. association between cigarette smoking
Adenosquamous carcinoma 8560/3 and pancreatic carcinoma is not as strong
Undifferentiated (anaplastic) Time trends as that between cigarette smoking and
carcinoma 8020/3 After a steady increase between 1930 lung cancer (RR > 20), it has been esti-
Undifferentiated carcinoma and 1980, the incidence rates have mated that a substantial reduction of the
with osteoclast-like giant cells 8035/3 levelled off {593}. It is currently the fifth number of smokers in the European Union
Mixed ductal-endocrine leading cause of cancer death in could save as many as 68,000 lives that
carcinoma 8154/3 Western countries, second only to colon would otherwise be lost to pancreatic
cancer among malignancies of the cancer during the next 20 years {1293}.
digestive tract. Chronic pancreatitis, past gastric sur-
Epidemiology gery, occupational exposure to chemi-
Incidence and geographical distribution Age and sex distribution cals such as chlorinated hydrocarbon
Ductal adenocarcinoma and its variants Approximately 80% of cases manifest solvents, radiation exposure, and dia-
are the most common neoplasms in the clinically in patients 60-80 years; cases betes mellitus have also been associated
pancreas, representing 85-90% of all below the age of 40 years are rare {1781}. with the development of pancreatic car-
pancreatic neoplasms {359, 941, 1781}. The incidence of pancreatic carcinoma is cinoma {593, 1100, 2080}. A markedly
In developed countries, the annual age- slightly higher among men than women, increased risk has been observed in
hereditary pancreatitis {1101}.
A number of dietary factors have been
putatively connected with pancreatic can-
cer, including a diet low in fibre and high
in meat and fat {593}. Coffee consumption
was once thought to be a risk factor for
8.9 pancreatic carcinoma, but recent studies
7.8
7.0 showed no significant associations {593}.
2.8
Localization
60-70% of pancreatic ductal adenocarci-
1.5 nomas are found in the head of the
gland, the remainder occur in the body
5.7 and/or tail. Pancreatic head tumours are
mainly localized in the upper half, rarely
6.1 in the uncinate process {1781}. Rarely,
heterotopic pancreatic tissue gives rise
to a carcinoma {596, 1898}.
Clinical features
< 1.8 < 2.9 < 11.7
Symptoms and signs
< 5.4 < 7.7
Clinical features include abdominal pain,
Fig. 10.01 Global distribution of pancreatic cancer (2000). Note the high incidence areas in North America, unexplained weight loss, jaundice and
Europe, and the Russian Federation. pruritus. Diabetes mellitus is present in
A B
Fig. 10.03 Ductal adenocarcinoma. A Well differentiated tumour with desmoplasia and irregular gland formation. B Well differentiated neoplasm involving a normal
duct (right part).
A B
Fig. 10.06 Undifferentiated carcinoma with osteoclast-like giant cells. A The carcinoma is in the uncinate process and shows haemorrhagic necrosis. B There is
marked cellular pleomorphism with scattered osteoclast-like giant cells and a well-differentiated ductal carcinoma component (left upper corner).
Histological variants
Adenosquamous carcinoma and undif-
ferentiated (anaplastic) carcinoma
(including osteoclast-like giant cell
tumours), mucinous noncystic adenocar-
cinoma and signet-ring cell carcinoma
are considered variants of ductal adeno-
carcinoma because most of these carci-
nomas, even if poorly differentiated, con-
tain some foci showing neoplastic glands
with ductal differentiation {288, 359, 941,
947, 1781}.
Fig. 10.07 Adenosquamous carcinoma. Note the glandular component on the left and the squamous differ-
Adenosquamous carcinoma
entiation on the right (arrowheads).
This rare neoplasm, relative frequency
3-4% {941, 359, 813, 1415}, is character-
ized by the presence of variable propor-
tions of mucin-producing glandular ele- Undifferentiated carcinoma with osteo- Mucinous noncystic carcinoma
ments and squamous components. The clast-like giant cells This uncommon carcinoma (relative fre-
squamous component should account This rare neoplasm is composed of pleo- quency: 1-3%) {941} has also been
for at least 30% of the tumour tissue. In morphic to spindle-shaped cells and called ‘colloid’ or gelatinous carcinoma.
addition, there may be anaplastic and scattered non-neoplastic osteoclast-like Mucin accounts for > 50% of the tumour.
spindle cell foci. Pure squamous carci- giant cells with usually more than 20 uni- The large pools of mucin are partially
nomas are very rare. formly small nuclei. In many cases there lined by well-differentiated cuboidal cells
is an associated in situ or invasive ade- and contain clumps or strands of tumour
Undifferentiated (anaplastic) carcinoma nocarcinoma {359}. The osteoclast-like cells. Some floating cells may be of the
Also called giant cell carcinoma, pleo- giant cells are often concentrated near signet-ring cell type.
morphic large cell carcinoma, and sarco- areas of haemorrhage and may contain Sex and age distribution are similar to
matoid carcinoma, these tumours have a haemosiderin and, occasionally, phago- those of ductal adenocarcinoma. The
relative frequency of 2-7%. They are cytosed mononuclear cells. Osteoid for- tumours may be very large and are usu-
composed of large eosinophilic pleomor- mation may also be found. ally well demarcated. The development
phic cells and/or ovoid to spindle- Immunohistochemically, at least some of of pseudomyxoma peritonei has been
shaped cells that grow in poorly cohe- the neoplastic cells express cytokeratin, described {285}. It is of interest that the
sive formations supported by scanty vimentin and p53 {740, 2095}. The osteo- invasive component of some of the intra-
fibrous stroma. Commonly the carcino- clast-like giant cells, in contrast, are neg- ductal papillary-mucinous tumours re-
mas contain small foci of atypical glan- ative for cytokeratin and p53, but positive sembles mucinous noncystic carcinoma.
dular elements {359, 941, 1786, 1962}. for vimentin, leukocyte common antigen Mucinous noncystic carcinoma should
Carcinomas consisting predominantly of (CD56) and macrophage markers such not be confused with mucinous cystic
spindle cells may also contain areas of as KP1 {740, 1258, 2095}. tumour because of the much better prog-
squamoid differentiation. High mitotic The mean age of patients with osteo- nosis of the latter (see chapter on muci-
activity as well as perineural, lymphatic, clast-like giant cell tumours is 60 years nous cystic neoplasms).
and blood vessel invasion is found in but there is a wide age range from 32 to
almost all cases. Immunohistochemical- 82 years {1370}. Some tumours are Signet-ring cell carcinoma
ly, some or most tumour cells express found in association with mucinous cys- The extremely rare signet-ring cell carci-
cytokeratins and usually also vimentin tic neoplasms {1258, 2095, 2198}. In the noma is an adenocarcinoma composed
{740}. Electron microscopy reveals early reports on this tumour it was sug- almost exclusively of cells filled with
microvilli and mucin granules in some gested that they may have a more mucin {1781, 1951}. The prognosis is
cases {359}. Undifferentiated carcino- favourable prognosis than the usual duc- extremely poor; a gastric primary should
mas with a neoplastic mesenchymal tal adenocarcinoma {359}. More recently always be excluded before making this
component (carcinosarcoma) have so far a mean survival of 12 months has been diagnosis.
not been described. reported.
Precursor lesions
Pancreatic neoplasms
Mucinous cystic neoplasms and intra-
ductal papillary mucinous neoplasms
may progress to invasive cancer. In the
case of mucinous cystic neoplasms, the
invasive component usually resembles
ductal adenocarcinoma {1781}. In the
Fig. 10.09 Pancreatic duct showing high-grade intraepithelial neoplasia (PanIN III). case of intraductal papillary-mucinous
Table 10.01
List of recommended terms with synonyms for focal hyperplastic and metaplastic duct lesions in the human exocrine pancreas.
Recommended WHO term Previous WHO classification {947} Other synonyms
PanIN-IB Ductal papillary hyperplasia Papillary ductal hyperplasia, ductal hyperplasia grade 2
Adenomatoid ductal hyperplasia Adenomatous hyperplasia, ductular cell hyperplasia
carcinoma, the invasive component changes, which both represent high- trating ductal adenocarcinomas are still ill-
either corresponds to a usual ductal ade- grade intraepithelial neoplasia. The defined. Putative precursor lesions (Table
nocarcinoma or to mucinous noncystic lesion corresponds to PanIN III in the 10.01) include mucinous cell hypertrophy,
carcinoma {1781}. proposed terminology of pancreatic ductal papillary hyperplasia with muci-
intraepithelial neoplasia (Table 10.01). nous cell hypertrophy (papillary duct
Severe ductal dysplasia – carcinoma High-grade intraepithelial neoplasia is lesion without atypia), adenomatoid (ade-
in situ commonly found in association with an nomatous) ductal hyperplasia, and squa-
This change of the ductal epithelium is invasive ductal adenocarcinoma {358, mous metaplasia {1781, 947}. All these
characterized by irregular epithelial bud- 555, 943}, and may represent either a lesions may show mild nuclear atypia.
ding and bridging, small papillae lacking precursor to invasive carcinoma or con- The evidence that some of these duct
fibrovascular stalks, and severe nuclear tinuous intraductal extensions of the lesions (i.e. mucinous cell hypertrophy
abnormalities such as loss of polarity, invasive tumour. Similar duct changes and papillary hyperplasia) may be pre-
pleomorphism, coarse chromatin, dense have also been described remote from cursors to invasive carcinoma comes
nucleoli and mitotic figures. The lesion is the macroscopic tumour {1781} or years from three areas: morphological studies,
often surrounded by one or two layers of before the development of an invasive clinical reports, and genetic analyses. At
fibrosclerotic tissue. Here, no attempt is ductal carcinoma {185, 191}. the light microscopic level, ductal papil-
made to distinguish between severe dys- lary hyperplasia was found adjacent to
plasia and carcinoma in situ, since it is Duct changes invasive carcinomas more frequently
very difficult, if not impossible, to draw a With the exception of high-grade intraepi- than it was in pancreases without cancer
clear distinction between these two thelial neoplasia, the precursors to infil- {290, 358, 943, 965}. It was also noted
Table 10.02
Histopathological grading of pancreatic ductal adenocarcinoma {1119}.
Tumour grade Glandular differentiation Mucin production Mitoses (per 10 HPF) Nuclear features
Grade 3 Poorly differentiated glands, Abortive > 10 Marked polymorphism and increased size
mucoepidermoid and
pleomorphic structures
cancer {1514, 1934, 591, 479} identified Recurrent losses of genetic material at match repair gene has been identified in
germline mutations in BRCA2 in about specific loci in a carcinoma suggest that 4% of pancreatic carcinomas {590}. They
7% of patients with pancreatic carcino- these loci harbour tumour suppressor had wild-type KRAS genes and a char-
ma. Remarkably, most pancreatic ductal genes which are inactivated in the carci- acteristic ‘medullary’ histological appear-
carcinoma patients with such mutations noma, and, indeed, the p16 gene on 9p, ance, forming a distinct subset of pan-
do not have a strong family history of the Tp53 gene on 17p, and the DPC4 creatic adenocarcinomas (see section
breast or pancreatic carcinoma. A num- gene on 18q are all frequently inactivat- on other rare carcinomas).
ber of them are, however, of Ashkenazi ed in pancreatic carcinoma {1716}. The
Jewish ancestry {591, 1442}. p16 tumour suppressor gene is inacti- Prognosis and predictive factors
vated in 40% of pancreatic carcinomas Ductal adenocarcinoma is fatal in most
Peutz-Jeghers syndrome by homozygous deletion, in 40% by loss cases {639}. The mean survival time of
Patients with the Peutz-Jeghers syndrome of one allele coupled with an intragenic the untreated patient is 3 months, while
have an increased risk of developing pan- mutation in the second, and by hyperme- the mean survival after radical resection
creatic carcinoma, and recently the bi- thylation of the p16 promoter in an addi- varies from 10-20 months {560, 692, 814,
allelic inactivation of the LKB1/STK11 tional 15% {223, 1698, 2104}. The Tp53 1955}. The overall 5-year survival rate of
gene has been demonstrated in a pan- is inactivated in 75% of pancreatic carci- patients treated by resection is 3-4%
creatic carcinoma which arose in a nomas by loss of one allele coupled with {639}, although in selected and stage-
patient with the Peutz-Jeghers syndrome an intragenic mutation in the second stratified series survival figures approach-
{579, 1851}. allele {1570, 1624}. The DPC4 tumour ing 25 or even 46% have been reported
suppressor gene is inactivated in 55% of {560, 1955, 1966, 1976}. Unresectable
Hereditary nonpolyposis colon cancer pancreatic carcinomas {651}, in 35% of carcinomas are treated with palliative
(HNPCC) the carcinomas by homozygous deletion bypass operations. Response to chemo-
This syndrome is associated with an and in 20% by loss of one allele coupled therapy with 5-fluorouracil or gemcitabine
increased risk of developing carcinoma with an intragenic mutation in the second may be seen in up to approximately 10%
of the colon, endometrium, stomach, and allele. The BRCA2 tumour suppressor of patients. Radiotherapy alone is largely
ovary {2071}. It can be caused by gene on 13q is inactivated in about 7% of ineffective {2061}.
germline mutations in any one of a num- pancreatic carcinomas {591, 1442,
ber of DNA mismatch repair genes, 1697}. Remarkably, in almost all of these Site, size, and stage
including MSH2 on 2p and MLH1 on 3p cases one allele of BRCA2 is inactivated The survival time is longer in patients with
{1029, 1078, 2071}. Lynch et al. have by a germline (inherited) mutation in the carcinomas confined to the pancreas
reported pancreatic carcinomas in some gene {591}. Other tumour suppressor and less than 3 cm in diameter (17-29
kindred with HNPCC, and Goggins et al. genes which have been shown to be months) than in patients with tumours of
have recently reported microsatellite occasionally inactivated in pancreatic greater size or retroperitoneal invasion
instability, a genetic change associated carcinoma include the genes MKK4, (6-15 months) {2172}. Carcinomas of the
with defects in DNA mismatch repair RB1, LKB1/STK11, and the transforming body or the tail of the pancreas tend to
genes, in about 4% of pancreatic carci- growth factor β receptors I and II {592, present at a more advanced stage than
nomas {590, 1130, 1487}. 761, 1850, 1851}. those of the head {560, 1955, 1966,
Several oncogenes have been shown to 1976}. Some have found that lymph node
Genetics be activated in ductal adenocarcinomas metastases significantly worsen progno-
Genetic alterations are listed in Table of the pancreas. These include the KRAS sis, while others have not {710, 1955,
10.03. At the chromosome level, they gene on chromosome 12p, which is acti- 2172}.
include losses and gains of genetic vated by point mutations in over 90% of
material as well as generalised chromo- the carcinomas, overexpression of the Residual tumour tissue
some instability {608, 625, 626}. The HER2-neu gene on 17q in 70% of the car- Patients with no residual tumour following
most frequent gains identified cytogenet- cinomas, and amplification of the AKT2 resection (R0) have the most favourable
ically include those of chromosomes 12 gene on chromosome 19q in 10–20% of prognosis of all patients undergoing sur-
and 7; the most common recurrent struc- the carcinomas, the nuclear receptor gical resection {2108}. This implies that
tural abnormalities involve chromosome coactivator gene AIB1 on chromosome local spread to peripancreatic tissues,
arms 1p, 6q, 7q, 17p, 1q, 3p, 11p, and 20q, and the MYB gene on chromosome i.e. the retroperitoneal resection margin,
19q, and the most frequent losses 6q {47, 292, 380, 576, 761, 1242, 2039}. is of utmost importance in terms of prog-
involve chromosomes 18, 13, 12, 17, and Compared to normal pancreas, Smad2 nosis {1122}.
6 {626, 625}. Similar patterns of loss have mRNA levels are increased in pancreatic
been identified at the molecular level carcinoma, which might lead to the Recurrence
{184, 1716}, using highly polymorphic over-expression of components of the Local recurrence seems to be the major
microsatellite markers. These include TGF-beta signalling pathway that is factor determining survival after resection
very high rates of loss at chromosomes observed in these lesions {931}. of pancreatic ductal carcinoma. The most
18q (90%), 17p (90%), 1p (60%), and 9p DNA mismatch repair genes, such as common sites of recurrences are the tis-
(85%) and moderately frequent losses at MLH1 and MSH2, can also play a role. sues surrounding the large mesenteric
3p, 6p, 8p, 10q, 12q, 13q, 18p, 21q, and Microsatellite instability resulting from the vessels {646}. Clear retroperitoneal resec-
22q (25-50% of cases). inactivation of both alleles of a DNA mis- tion margin or margins are therefore
Table 10.04
Genetic syndromes with an increased risk of pancreatic cancer.
Syndrome (MIM No)1 Mode of inheritance Gene (chromosomal location) Lifetime risk of pancreatic cancer
Early onset familial pancreatic Autosomal dominant Unknown About 30%; 100-fold increased risk
adenocarcinoma associated with diabetes of pancreatic cancer;
(Seattle family) {479} high risk of diabetes and pancreatitis
Hereditary pancreatitis (167800) Autosomal dominant Cationic trypsinogen (7q35) 30%; 50-fold increased risk of
pancreatic cancer {1101, 499}
FAMMM: familial atypical multiple Autosomal dominant p16/CMM2 (9p21) 10% {601, 1127, 2097}
mole melanoma (155600)
Familial breast cancer (600185) Autosomal dominant BRCA2 (13q12-q13) 5-10%; 6174delT in Ashkenazi Jews
{1442}, 999del5 in Iceland {1934}
Ataxia-telangiectasia (208900) Autosomal recessive ATM, ATB, others (11q22-q23) Unknown; somewhat increased
(heterozygote state)
HNPCC: hereditary non-polyposis Autosomal dominant MSH2 (2p), MLH1 (3p), others Unknown; somewhat increased
colorectal cancer (120435) {1130, 2071}
Familial pancreatic cancer Possibly autosomal dominant Unknown Unknown; 5-10fold increased risk
if a first-degree relative has
________ pancreatic cancer {499, 1128, 755}
1
Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/omim
required, if a ‘curative’ resection (R0) is to found that median postoperative survival is associated with advanced tumour stage
be achieved {1122}. Second in frequency correlated significantly with tumour and shorter survival {46, 105, 476, 2079}.
are recurrences arising from lymph node grade {944}, mitotic index, and severity Tumours with low argyrophylic nucleolar
or liver metastases that were too small to of cellular atypia. As grading systems organizer region (AgNOR) counts per
be detected during surgery. The peri- are, however, to a great extent subjec- cell (< 3.25) have been reported to have
toneum and the bone marrow are rare tive, reproducibility may be low {1119}. a better prognosis than tumours with a
sites of recurrence, although malignant Other studies found no relationship high AgNOR count {1413}. High Ki-67
cells are detected cytologically in one between grade and survival {2079}. labeling index is an indicator of poor
quarter of the patients during laparoscopy Nuclear parameters such as median prognosis, but does not seem to be an
and one half of the patients when bone nuclear size, nuclear area, and nuclear independent prognostic parameter
marrow trepanation is performed during a perimeter have been shown to be of {1111, 1119}
Whipple procedure {870}. prognostic value for ductal adenocarci- The immunohistochemical expression of
noma {477, 944}. a number of growth factors has shown
Grading weak association with survival {21, 535}.
Based on the criteria of the grading sys- DNA content and proliferation
tem summarised in Table 10.02, it was Nondiploid and/or aneuploid DNA content
C. Capella
Serous cystic neoplasms E. Solcia
of the pancreas G. Klöppel
R.H. Hruban
Serous cystic pancreatic tumours are Serous microcystic adenoma stellate scar and a sunburst type calcifi-
cystic epithelial neoplasms composed of cation {532, 817, 1544}. On angiography,
glycogen-rich, ductular-type epithelial Definition the tumours are usually hypervascular.
cells that produce a watery fluid similar to A benign neoplasm composed of numer-
serum. Most are benign (serous cystade- ous small cysts lined by uniform glyco- Macroscopy
nomas), either serous microcystic adeno- gen-rich cuboidal epithelial cells, dis- Serous microcystic adenomas are sin-
ma or serous oligocystic adenoma. Only posed around a central stellate scar. gle, well-circumscribed, slightly bosse-
very rare cases exhibit signs of malig- lated, round lesions, with diameters
nancy (serous cystadenocarcinoma). Epidemiology ranging from 1-25 cm in greatest dimen-
A solid variant of serous cystadenoma This is a rare neoplasm, accounting for 1 sion (average, 6-10 cm). On section, the
(solid serous cystadenoma) has been to 2% of all exocrine pancreatic tumours neoplasms are sponge-like and are
described {1499} but remains to be {1280}. The mean age at presentation is made up of numerous tiny cysts filled
established as a separate disease entity. 66 years (range, 34-91 years), with a pre- with serous (clear watery) fluid. The
dominance in women (70%) {1781}. It cysts range from 0.01-0.5 cm, with a few
ICD-O codes has been reported in patients with differ- larger cysts of up to 2 cm in diameter.
Serous cystadenoma 8441/0 ent ethnicity {327, 2151}. Often, the cysts are arranged around a
Serous cystdenocarcinoma 8441/3 more or less centrally located, dense
Aetiology fibronodular core from which thin fibrous
The aetiology and pathogenesis of the septa radiate to the periphery (central
neoplasm are unknown. The striking stellate scar).
predilection for women suggests that sex
hormones or genetic factors may play a Histopathology
role. An association with Von Hippel- At low magnification, the pattern of the
Lindau disease has been reported {327, cysts is similar to a sponge. The cysts
2026} and confirmed by recent genetic contain proteinaceous fluid and are lined
molecular investigations {2026}. by a single layer of cuboidal or flattened
epithelial cells. Their cytoplasm is clear
Localization and only rarely eosinophilic and granular.
The neoplasms occur most frequently The nuclei are centrally located, round to
(50-75%) in the body or tail; the remain- oval in shape, uniform, and have an
ing tumours involve the head of the pan- inconspicuous nucleolus. Due to the
creas {49, 327}. presence of abundant intracytoplasmic
glycogen, the periodic acid-Schiff (PAS)
Clinical features stain without diastase digestion is posi-
About one third of the neoplasms pres- tive, whereas PAS-diastase and Alcian
ent as an incidental finding at routine blue stains are negative {160}. Mitoses
A physical examination or at autopsy {445}. are practically absent and there is no
Approximately two thirds of patients cytological atypia. Occasionally, the neo-
exhibit symptoms related to local mass plastic cells form intracystic papillary
effects, including abdominal pain, palpa- projections, usually without a fibrovascu-
ble mass, nausea and vomiting, and lar stalk. The central fibrous stellate core
weight loss {1544}. Jaundice due to is formed of hyalinized tissue with a few
obstruction of the common bile duct is clusters of tiny cysts.
unusual, even in neoplasms originating
from the head of the pancreas. Immunohistochemistry
Pancreatic serum tumour markers are The epithelial nature of these neoplasms
B generally normal. Calcifications are is reflected in their immunoreactivity for
found in a few patients on plain abdomi- epithelial membrane antigen and cytok-
Fig. 10.10 Microcystic serous cystadenoma. A CT
scan showing a well demarcated, spongy lesion in nal roentgenograms. Ultrasonography eratins 7, 8, 18, and 19. In addition, the
the head of the pancreas. B Cut surface showing a (US) and computed tomography (CT) neoplastic cells may focally express
typical honeycomb appearance and a (para-)cen- reveal a well circumscribed, multilocular CA19-9 and B72.3 {815, 1752}. They are
tral stellate scar (arrowhead). cyst, occasionally with an evident central uniformly negative for carcinoembryonic
Genetics
Loss of heterozygosity at the von Hippel-
Lindau (VHL) gene locus, mapped to
chromosome 3p25, was found in 2/2
serous microcystic adenomas associat-
ed with VHL disease and in 7/10 spo-
radic cases {2026}. In contrast to ductal
adenocarcinomas, serous microcystic
adenomas have wild-type KRAS and
lack immunoreactivity for TP53 {815}.
Fig. 10.13 Serous cystadenoma. A cystic neoplasm
Prognosis replaces the head of the pancreas; a portion of duo-
The prognosis of patients with this neo- denum is on the right.
plasm is excellent, since there is only a
minimal risk of malignant transformation
{1159}. Aetiology
The aetiology of this neoplasm is not
known. In children, it has been suggest-
ed that the lesions may be of malforma-
Serous oligocystic adenoma tive origin and not true neoplasms since
in two cases there was a cytomegalo-
Definition virus infection in the adjacent pancreas
A benign neoplasm composed of few, {52, 273}.
Fig. 10.11 Serous oligocystic adenoma. This CT
scan shows a macrocystic neoplasm in the head of
relatively large cysts, lined by uniform
the pancreas. glycogen-rich cuboidal epithelial cells. Localization
Most serous oligocystic adenomas are
Synonyms located in the head and body of the pan-
antigen (CEA), trypsin, chromogranin A, This tumour category includes macro- creas {1781}. In the head, they may
synaptophysin, S-100 protein, desmin, cystic serous cystadenoma {257, 1062}, obstruct the periampullary portion of the
vimentin, factor VIII-related antigen and serous oligocystic and ill-demarcated common bile duct.
actin {49, 119, 445, 689, 815, 1752, adenoma {445}, and some cystade-
1781, 2151}. nomas observed in children {2057}. Clinical features
Whether these neoplasms form a homo- In most cases reported in adult patients,
Ultrastructure geneous group remains to be estab- the neoplasms caused symptoms that
Electron microscopy shows a single row lished. led to their discovery and removal. The
of uniform epithelial cells lining the cysts most common symptom was upper
and resting on a basal lamina {49, 160, Epidemiology abdominal discomfort or pain {1781}.
915}. The apical surfaces have poorly Serous oligocystic adenomas are much Other symptoms included jaundice and
developed or no microvilli. The cyto- less common than serous microcystic steatorrhoea. In infants, the tumours pre-
plasm contains numerous glycogen adenomas {445, 1062}. There is no sex sented as a palpable abdominal mass
granules but only a few mitochondria, predilection. Adults are usually 60 years {52, 273}.
short profiles of endoplasmic reticulum, and over (age range, 30-69 years; mean,
lipid droplets, and multivesicular bodies. 65 years); the tumour has been Macroscopy
Golgi complexes are rarely identified. described in two male and two female These neoplasms typically appear as a
Zymogen granules and neurosecretory infants, aged between 2 and 16 months cystic mass with a diameter of 4-10 cm
granules are absent. {1781}. (mean, 6 cm) {1781}. On cut surface,
A B C
Fig. 10.12 Serous microcystic cystadenoma. A The lesion is well demarcated from the adjacent pancreas. B Cysts of varying size. C The epithelium is cuboidal and
focally PAS-positive.
Histopathology
Serous oligocystic adenoma has gener-
ally the same histological features as
serous microcystic adenoma. Occasion-
ally, however, the lining epithelium may
be more cuboidal and less flattened, and
the nuclei are generally larger. The cyto-
plasm is either clear, due to the presence Fig. 10.14 Serous cystadenoma. Characteristic cuboidal epithelium forms intracystic papillary structures in
this field.
of glycogen, or eosinophilic. The stromal
framework is well developed and often
hyalinized. The tumour border is not well between 63 and 72 years of age; there Invasion of the spleen and metastasis to
defined and small cysts often extend into were four women and four men. Three the gastric wall were found in one case.
the adjoining pancreatic tissue. The patients were Caucasian and four were
immunohistochemical and ultrastructural from Japan {8, 815, 1781}. Histopathology
features are the same as for serous The histological features in the primary
microcystic adenoma {445, 2057}. Clinical features tumour as well as in the metastases are
Clinical symptoms reported in the cases remarkably similar to those of serous
Prognosis so far observed include bleeding from microcystic adenoma, although focal
There is no evidence of malignant poten- gastric varices due to tumour invasion of mild nuclear pleomorphism can be found
tial {445}. the wall of the stomach and the splenic {573, 2182}. One carcinoma reported
vein, a palpable upper abdominal mass, showed neural invasion and aneuploid
and jaundice. Ultrasonography and CT nuclear DNA content {879}, while other
Serous cystadenocarcinoma revealed a hyperechoic mass. CEA and cases showed vascular and perivascular
CA19-9 were normal or slightly increased. invasion {1412} or involvement of a
Definition lymph node and adipose tissue {8}.
A malignant cystic epithelial neoplasm Macroscopy
composed of glycogen-rich cells. These neoplasms have a spongy appear- Prognosis
ance {573, 879, 2182}. Their reported Serous cystadenocarcinomas are slowly
Epidemiology size has varied between 2.5 and 12 cm. growing neoplasms and palliative resec-
So far, only eight cases have been report- Liver and lymph node metastases have tion may be helpful even in advanced
ed {573, 815, 1781}. These patients were been reported {573, 815, 1781, 2182}. stages {2182}.
Stroma
The ovarian-type stroma consists of
densely packed spindle-shaped cells
with round or elongated nuclei and
sparse cytoplasm. It frequently displays
a variable degree of luteinization, char-
acterized by the presence of single or
clusters of epithelioid cells with round to
oval nuclei and abundant clear or
eosinophilic cytoplasm. Occasionally,
these cells, resembling ovarian hilar
cells, can be found associated with (or
present in) nerve trunks. Stromal luteini-
zation is found in decreasing order of fre- Fig. 10.19 Mucinous cystadenocarcinoma. The neoplasm exhibits well differentiated and poorly differenti-
quency from adenomatous to carcinoma- ated mucinoius epithelium.
tous cases {2194}. The stroma of large
MCNs may become fibrotic and hypocel-
lular. Rare MCNs show mural nodules tric type mucin marker M1 and PGII, the Genetics
with a sarcomatous stroma or an associ- intestinal mucin markers CAR-5 and Activating point mutations in codon 12 of
ated sarcoma {1932, 2088, 2198}. M3SI, and the pancreatic type mucin KRAS were found in invasive mucinous
marker DUPAN-2 and CA19-9 {119, cystic neoplasms (MCNs) {117} and
Immunohistochemistry 1714, 2151, 2190}. Furthermore, pancre- mucinous cystic neoplasms associated
The epithelial component is immunoreac- atic, hepatobiliary, and retroperitoneal with osteoclast-like giant cells {1485}.
tive with epithelial markers including MCNs share the same types of intraep- Mutations of KRAS and allelic losses of
EMA, CEA, cytokeratins 7, 8, 18 and 19 ithelial endocrine cells {613, 1911, 1910}. 6q, 9p, 8p have been reported in MCNs
{2151}, and it may show gastroen- p-53 nuclear positivity in more than 10% with sarcomatous stroma {1998}.
teropancreatic differentiation, as is also of neoplastic cells, found in 20% of MCN, Prognosis and predictive factors
observed in ovarian and retroperitoneal strongly correlates with mucinous cys- The prognosis of MCN, regardless of the
MCN {1714, 1910}. With increasing tadenocarcinoma {2198}. degree of cellular atypia, is excellent if
degrees of epithelial atypia the character The stromal component expresses the tumour is completely removed {328,
of mucin production changes from sul- vimentin, alpha smooth muscle actin, 410, 2060, 2198}. The prognosis of inva-
phated to sialated or neutral mucin desmin and, in a high proportion, prog- sive mucinous cystadenocarcinoma
{1932}. The neoplastic cells express gas- esterone and estrogen receptors {2198}. depends on the extent of tumour inva-
The luteinized cells are labeled with anti- sion. Tumour recurrence and poor out-
bodies against tyrosine hydroxylase, cal- come correlate with invasion of the
retinin, which have been shown to recog- tumour wall and peritumoural tissues
nize testicular Leydig cells and hilar {2198}. Patients older than 50 years
ovarian cells, and the sex cord-stromal appear to have a lower survival rate
differentiation marker inhibin {2198, {2198}. Other variables such as site,
2206}. tumour size, macroscopic appearance,
grade of differentiation, luteinization of
Ultrastructure the stroma and p53 positivity have no
Electron microscopy of tumours with only prognostic significance.
mild to moderate dysplasia demon- Aneuploidy is a rare event in MCNs, is
strates columnar epithelial cells resting largely restricted to mucinous cystade-
Fig. 10.20 Mucinous cystadenocarcinoma. The on a thin basement membrane. The cells nocarcinomas and carries a worse prog-
thick wall of this cystic neoplasm is invaded by may have well-developed microvilli and nosis {1792, 1932, 512}.
mucinous carcinoma at upper left. mucin granules {33}.
Histopathology
IPMN tumour cells are usually tall colum-
nar mucin-containing epithelial cells that
line dilated ducts or cystic spaces aris-
ing from dilated branch ducts. The
epithelium typically forms papillary or
pseudopapillary structures, but portions
Fig. 10.22 Intraductal papillary mucinous neoplasm of the neoplasm may be lined by non-
in the main pancreatic duct (arrowhead). papillary epithelium or be denuded of
epithelium. The amount of mucin produc-
tion varies widely, as does the degree of
papillary growths are large, the dilated duct dilatation {97, 872}. Goblet or
ducts may show localized excrescences Paneth cells may be present as a mani- Fig. 10.24 Intraductal papillary-mucinous neoplasm
or be filled with soft papillary masses of festation of intestinal metaplasia in the within the dilated main pancreatic duct and branch
ducts.
tissue. neoplastic epithelium, and neuroen-
The pancreatic parenchyma surrounding docrine cells have also been demon-
and retrograde to the tumour is often strated.
pale and firm, reflecting changes of The recently described intraductal onco- Histochemistry and immunohistochemistry
chronic obstructive pancreatitis. When cytic papillary neoplasm probably repre- A variety of abnormalities have been
there is invasion, gelatinous areas may sents a rare related phenotype that is demonstrated in IPMNs using mucin and
be identified in fibrotic tissue. similar macroscopically {1244, 1860}. immunohistochemical stains.
Oncocytic IPMNs are composed of strat- Most IPMNs express epithelial mem-
Tumour spread and staging ified oncocytic cells with pale pink cyto- brane antigen (EMA) as well as several
Adenomas, borderline tumours and non- plasmic granules that are much finer cytokeratins {1917}. A variety of
invasive carcinomas may extend intra- than those seen in Paneth cells. Goblet endocrine cell types occur in most
ductally into adjacent portions of the duct cells may be interspersed among the tumours but account for fewer than 5 per
system, and evidence of such extension oncocytic cells. A characteristic feature cent of the tumour cells {1676}.
is often encountered adjacent to IPMNs. of the oncocytic papillary neoplasms is A change in type of mucin has been sug-
Recurrence following surgical resection the formation of ‘intraepithelial lumina’, gested as a marker of progression since
has been reported in patients that had which are spaces in the epithelium about normal duct cells characteristically
IPMNs extending into the margin of one quarter the size of the cells. secrete sulfated mucin, intraductal papil-
lary-mucinous adenomas characteristi-
cally secrete neutral mucin, and dysplas-
tic epithelium secretes predominantly
sialomucin {1138, 1916, 1186}. Nearly all
IPMNs express MUC2 {2179}.
Overexpression of c-erbB-2 protein
occurs in a high fraction of IPMNs {1939,
1675, 1877, 380}.
A study of cell proliferation, as shown by
PCNA and Ki67 labelling indices,
demonstrated a progressive increase in
cell proliferation from normal duct epithe-
lium, to adenomas, to borderline
tumours, to carcinomas {1917}. The
labeling index in IPM carcinomas was
lower than in ductal adenocarcinomas.
Although immunostaining of p53 protein
was detected in a lower fraction of IPMN
(31%) than is usually seen in solid ductal
adenocarcinomas, it was found only in
borderline and malignant IPMN and
therefore may be a marker of progression
{1939}.
A B Failure of IPMN to elicit the production of
Fig. 10.23 Intraductal papillary mucinous neoplasms with (A) columnar epithelium and (B) oncocytic epithe- a collagenase that mediates invasion
lium. was reported {2193}.
D.S. Klimstra
Acinar cell carcinoma D. Longnecker
Definition eosinophilia may also be noted. In some vessels may occur. Multicystic examples
A carcinoma occurring mainly in adults, patients, the lipase hypersecretion syn- of acinar cell carcinoma have been
composed of relatively uniform neoplas- drome is the first presenting sign of the reported as acinar cell cystadenocarci-
tic cells that are arranged in solid and tumour, while in others it develops follow- noma {229, 739, 1815}.
acinar patterns and produce pancreatic ing tumour recurrence. Successful surgi-
enzymes. cal removal of the neoplasm may result in Tumour spread and staging
the normalization of the serum lipase Metastases most commonly affect
ICD-O codes levels and resolution of the symptoms. regional lymph nodes and the liver,
Acinar cell carcinoma 8550/3 although distant spread to other organs
Acinar cell cystadenocarcinoma 8551/3 Laboratory analyses occurs occasionally. Acinar cell carcino-
Mixed acinar-endocrine carcinoma 8154/3 Other than an elevation of serum lipase mas are staged using the same protocol
levels associated with the lipase hyper- as ductal adenocarcinomas.
Epidemiology secretion syndrome, there are no specif-
Acinar cell carcinomas represent 1-2% of ic laboratory abnormalities in patients Histopathology
all exocrine pancreatic neoplasms in with acinar cell carcinoma. A few cases Large nodules of cells are separated by
adults {739, 936}. Most occur in late show increased serum alpha-fetoprotein hypocellular fibrous bands. The desmo-
adulthood, with a mean age of 62 years {819, 1426, 1369, 1747}. plastic stroma characteristic of ductal
{825, 979, 2073}. The tumour is rare in adenocarcinomas is generally absent.
adults under the age of 40. Pediatric Imaging Tumour necrosis may occur and is gen-
cases do occur, usually manifesting in Acinar cell carcinomas are generally erally infarct-like in appearance. Within
patients 8 to 15 years of age {979, 1282}. bulky with a mean size of 11 cm {979}. the tumour cell islands, there is an abun-
Males are affected more frequently than On abdominal CT scans, they are cir- dant fine microvasculature.
females, with an M:F ratio of 2:1 {739, cumscribed and have a similar density to Several architectural patterns have been
936}. the surrounding pancreas. Because of described. The most characteristic is the
their larger size and relatively sharp cir- acinar pattern, with neoplastic cells
Aetiology cumscription, acinar cell carcinomas can arranged in small glandular units; there
The aetiology is unknown. generally be distinguished from ductal are numerous small lumina within each
adenocarcinomas radiographically. island of cells giving a cribriform appear-
Localization ance. In some instances, the lumina are
Acinar cell carcinomas may arise in any Fine needle aspiration cytology more dilated, resulting in a glandular pat-
portion of the pancreas but are some- There is usually a high cellular yield from tern, although separate glandular struc-
what more common in the head. fine needle aspiration {1446, 1978, 2015}. tures surrounded by stroma are usually
The cytological appearances of acinar not encountered. A number of the micro-
Clinical features cell carcinomas closely mimic of pancre-
Symptoms and signs atic endocrine neoplasms, although the
Most acinar cell carcinomas present clin- latter are more likely to exhibit a plasma-
ically with relatively non-specific symp- cytoid appearance to the cells and a
toms including abdominal pain, weight speckled chromatin pattern. Immuno-
loss, nausea, or diarrhoea {739, 936, histochemistry may be used on cytologi-
979, 2073}. Because they generally push cal specimens to confirm the diagnosis of
rather than infiltrate into adjacent struc- acinar cell carcinoma {1446, 1978}.
tures, biliary obstruction and jaundice
are infrequent presenting complaints. Macroscopy
A well-described syndrome occurring in Acinar cell carcinomas are generally cir-
10-15% of patients is the lipase hyper- cumscribed and may be multinodular
secretion syndrome {1781, 213, 936, {739, 936}. Individual nodules are soft
975}. It is most commonly encountered in and vary from yellow to brown. Areas of
patients with hepatic metastases, and is necrosis and cystic degeneration may
characterized by excessive secretion of be present. Occasionally, the neoplasm
lipase into the serum, with clinical symp- is found attached to the pancreatic sur-
toms including subcutaneous fat necro- face. Extension into adjacent structures, Fig. 10.27 Acinar cell carcinoma. The hypodense
sis and polyarthralgia. Peripheral blood such as duodenum, spleen, or major lobulated tumour occupies the tail of the pancreas.
D.S. Klimstra
Pancreatoblastoma D. Longnecker
Definition many patients present with an incidental- tumours are grossly cystic, a phenome-
A malignant epithelial tumour, generally ly detected abdominal mass {782, 939}. non reported in all cases associated with
affecting young children, composed of Related symptoms include pain, weight the Beckwith-Wiedeman syndrome {432}.
well-defined solid nests of cells with aci- loss, and diarrhoea. The paraneoplastic
nar formations and squamoid corpus- syndromes associated with acinar cell Histopathology
cles, separated by stromal bands. Acinar carcinoma (lipase hypersecretion syn- The epithelial elements of pancreato-
differentiation prevails, often associated drome) and pancreatic endocrine neo- blastomas are highly cellular and
with lesser degrees of endocrine or duc- plasms have not been described, but arranged in well-defined islands separat-
tal differentiation. one patient developed Cushing syn- ed by stromal bands, producing a ‘geo-
drome {1478}. graphic’ low power appearance. Solid,
ICD-O code 8971/3 Radiologically, pancreatoblastomas are hypercellular areas composed of nests
large, well-defined, lobulated tumours of polygonal cells alternate with regions
Epidemiology which may show calcifications on CT showing more obvious acinar differentia-
Incidence scan {1833, 2027, 2117}. tion, with polarized cells surrounding
Pancreatoblastoma is an exceedingly There is no consistent elevation of serum small luminal spaces. In rare tumours,
rare tumour, less than 75 cases having tumour markers, but some cases have larger glandular spaces lined by mucin-
been reported {782, 939, 2117}. exhibited increased alpha-fetoprotein containing cells may be seen {939}.
However, it is among the most frequent levels {802, 939}. Nuclear atypia is generally minimal.
pancreatic tumours in childhood, proba- Squamoid corpuscles. One of the most
bly accounting for 30-50% of pancreatic Macroscopy characteristic features of pancreatoblas-
neoplasms occurring in young children The size of pancreatoblastomas varies toma is the ‘squamoid corpuscle’. These
{631}. from 1.5-20 cm. Most tumours are soli- enigmatic structures vary from large
tary, solid neoplasms composed of well- islands of plump, epithelioid cells to
Age and sex distribution defined lobules of soft, fleshy tissue sep- whorled nests of spindled cells to frankly
The majority of pancreatoblastomas arated by fibrous bands. Areas of necro- keratinizing squamous islands. The
occur in children, most being under the sis may be prominent. Uncommonly the nuclei of the squamoid corpuscles are
age of 10. The median age of pediatric larger and more oval than those of the
patients is approximately 4 years {742, surrounding cells; nuclear clearing due
939}, and only a few cases have been to the accumulation of biotin may be
described in the second decade of life seen {1895}. The frequency and compo-
{782}. A number of congenital examples sition of the squamoid corpuscles varies
have also been documented {939}. in different regions of the tumour and
Rarely, tumours histologically indistin- between different cases.
guishable from pancreatoblastomas Stroma. Especially in pediatric cases, the
occur in adult patients ranging between PB stroma of pancreatoblastomas is often
19 and 56 years of age {939, 1053, hypercellular, in some instances achiev-
1452}. There is a slight male predomi- ing a neoplastic appearance. Rarely, the
nance, with an M:F ratio of 1.3:1 {939}. A presence of heterologous stromal ele-
ments, including neoplastic bone and
Aetiology cartilage, has been reported {127, 939}.
The aetiology is unknown.
Histochemistry and immunohistochemistry
Localization PB Over 90% of pancreatoblastomas exhibit
The head of the gland is affected in evidence of acinar differentiation in the
about 50% of cases, the remainder form of PAS-positive, diastase resistant
being equally divided between the body cytoplasmic granules as well as immuno-
and the tail. histochemical staining for pancreatic
B enzymes, including trypsin, chymo-
Clinical features Fig. 10.32 Pancreatoblastoma. A CT image showing trypsin, and lipase {939, 1282, 1400}. The
The presenting features of pancreato- a large tumour (PB) in the head of the pancreas, staining may be focal, often limited to the
blastoma are generally non-specific. with hypodense areas. B The cut surface of the apical cytoplasm in areas of the tumour
Especially in the pediatric age group, neoplasm demonstrates a lobulated structure. with acinar formations. At least focal
Ultrastructure
By electron microscopy, pancreatoblas-
tomas generally exhibit evidence of aci-
nar differentiation {939, 1758}, with rela-
tively abundant rough endoplasmic retic-
ulum and mitochondria, and apically
located dense zymogen granules. The
zymogen granules may be round and
uniform, resembling those of non-neo-
plastic cells. In addition, irregular fibril-
lary granules similar to those described
in acinar cell carcinomas may be found
{936, 939}. In rare cases, dense-core
neurosecretory-type granules and muci-
gen granules have also been observed
{939}. Examination of the squamoid cor-
Fig. 10.33 Pancreatoblastoma with squamoid corpuscule (arrowhead), surrounded by solid (left) and tubular puscles has revealed tonofilaments but
(right) structures. no evidence of a specific line of differen-
tiation.
immunoreactivity for markers of endocrine Relationship to acinar cell carcinoma
differentiation (chromogranin or synapto- Both pancreatoblastomas and acinar cell Genetic susceptibility
physin) is found in over two-thirds of carcinomas consistently exhibit acinar In several reported cases (all congenital
cases, and expression of markers of duc- differentiation and may exhibit lesser examples), pancreatoblastomas have
tal differentiation such as CEA, DUPAN-2, degrees of endocrine and ductal differ- been a component of the Beckwith-
or B72.3 is found in more than half of entiation. {936, 939}. Histologically, aci- Wiedeman syndrome {432}.
cases {939}. In most instances, the pro- nar formations are characteristic of pan-
portion of cells expressing acinar markers creatoblastoma, and the solid areas Prognosis
outnumbers the proportion expressing resemble the solid pattern of acinar cell Pancreatoblastomas are malignant
endocrine or ductal markers. In cases carcinoma. Biologically, the two tumours tumours. Nodal or hepatic metastases
associated with elevations in the serum are also similar, with a relatively favorable are present in 35% of patients {782, 939}.
levels of alpha-fetoprotein, immunohisto- prognosis in childhood, but a very poor More widespread dissemination may also
chemical positivity for AFP has been prognosis in adulthood. For these rea- occur. In pediatric patients lacking evi-
detectable {802, 939}. sons, some observers have suggested dence of metastatic disease at first pres-
Immunohistochemical evaluation of the that pancreatoblastoma represents the entation, the prognosis is very good,
squamoid corpuscles has failed to define paediatric counterpart of acinar cell car- most patients being cured by a combina-
a reproducible line of differentiation for cinoma. Although this proposal is attrac- tion of surgery and chemotherapy {894,
this component {939}. tive in many ways, pancreatoblastoma 1299}. In the presence of metastatic dis-
ease or in adult patients with pancreato-
blastomas, the outcome is usually fatal
{312, 939}, the mean survival being 1.5
years {939}. However, a favourable
response to chemotherapy has been
noted in some children {235, 2027}.
Pancreatoblastoma 245
10b 19.7.2006 8:25 Page 246
Definition It occurs predominantly in adolescent solitary masses (average size 8-10 cm;
A usually benign neoplasm with predomi- girls and young women (mean 35 years; range, 3-18 cm), and are often fluctuant.
nant manifestation in young women, com- range 8-67 years) {1781, 1072}. It is rare They are usually encapsulated and well
posed of monomorphic cells forming solid in men (mean, 35 years; range 25-72 demarcated from the surrounding pan-
and pseudopapillary structures, frequent- years) {945, 1193, 1975}. There is no creas. Multiple tumours are exceptional
ly showing haemorrhagic-cystic changes apparent ethnic preference {978, 1395}. {1427}. The cut surfaces reveal lobulat-
and variably expressing epithelial, mes- ed, light brown solid areas, zones of
enchymal and endocrine markers. Aetiology haemorrhage and necrosis, and cystic
The aetiology is unknown. The striking spaces filled with necrotic debris.
ICD-O codes sex and age distribution point to genetic Occasionally, the haemorrhagic-cystic
Solid pseudopapillary neoplasm 8452/1 and hormonal factors, but there are no changes involve almost the entire lesion
Solid pseudopapillary carcinoma 8452/3 reports indicating an association with so that the neoplasm may be mistaken
endocrine disturbances including over- for a pseudocyst. The tumour wall may
Synonyms production of oestrogen or progesterone. contain calcifications {1358}. A few
Solid-cystic tumour {946}, papillary-cys- Moreover, only very few women devel- tumours have been found to be attached
tic tumour {170}, solid and papillary oped a solid pseudopapillary neoplasm to the pancreas or even in extrapancre-
epithelial neoplasm. after long-term use of hormonal contra- atic locations {812, 914, 945}. Invasion of
ceptives {359, 436, 1655}. adjacent organs or the portal vein is rare
Epidemiology {1655, 1684, 1701}.
Solid-pseudopapillary neoplasm is Localization
uncommon but has been recognized There is no preferential localization within
with increasing frequency in recent years the pancreas {1282, 1358}.
{946, 1192, 1358}. It accounts for
approximately 1-2% of all exocrine pan- Clinical features
creatic tumours {359, 941, 1280}. Usually, the neoplasms are found inci-
dentally on routine physical examination
or they cause abdominal discomfort and
pain {1358}, occasionally after abdomi-
nal trauma {945}. Jaundice is rare {1427},
even in tumours that originate from the
head of the pancreas, and there is no Fig. 10.35 Solid-pseudopapillary neoplasm. The
T associated functional endocrine syn- pseudopapillary structures are lined by small
drome. All known tumour markers are monomorphic cells.
normal.
Ultrasonography (US) and computed
tomography (CT) reveal a sharply demar- Tumour spread
A cated, variably solid and cystic mass Only few metastasizing solid-pseudo-
without any internal septation {300}. The papillary neoplasms have been reported
tumour margin may contain calcifications. {359, 1358}. Common metastatic sites
Administration of contrast medium results include regional lymph nodes, the liver,
in enhancement of the solid tumour parts. peritoneum, and greater omentum {300,
On angiography, the neoplasms are usu- 2209, 1358}.
ally hypovascular or mildly hypervascular
lesions with displacement of surrounding Histopathology
vessels {2153}. Fine needle aspiration In large neoplasms, extensive necrosis is
cytology performed under radiological typical and the preserved tissue is usual-
B control shows monomorphic cells with ly found in the tumour periphery under
round nuclei and eosinophilic or foamy the fibrous capsule. This tissue exhibits a
Fig. 10.34 Solid-pseudopapillary neoplasm. A The
round hypodense tumour (T) replaces the tail of the cytoplasm {234, 2119, 2140}. solid monomorphic pattern with variable
pancreas. B The pseudocystic neoplasm is sclerosis. More centrally there is a
attached to the spleen, and shows haemorrhagic Macroscopy pseudopapillary pattern, and these com-
necrosis. The neoplasms present as large, round, ponents often gradually merge into each
Criteria of malignancy
Although criteria of malignancy have not
yet been clearly established, it appears
that unequivocal perineural invasion,
angioinvasion, or deep invasion into the
surrounding tissue indicate malignant
behaviour, and such lesions should be
classified as solid-pseudopapillary carci- Fig. 10.37 Solid pseudopapillary tumour. In this solid area, the uniform tumour cells are separated by vas-
noma. Nishihara et al. {1358} compared cular hyalinized stroma.
the histological features of three metasta-
sizing and 19 nonmetastasizing solid-
pseudopapillary neoplasms, and found Histochemistry and immunohistochemistry for NSE and vimentin, in contrast, is usu-
that venous invasion, degree of nuclear The most consistently positive markers ally diffuse.
atypia, mitotic count and prominence of for solid-pseudopapillary neoplasms are Inconsistent results have been reported
necrobiotic cell nests (cells with pyknotic alpha-1-antitrypsin, alpha-1-antichymo- for epithelial markers, synaptophysin,
nuclei and eosinophilic cytoplasm) were trypsin, neuron specific enolase (NSE), pancreatic enzymes, islet cell hormones
associated with malignancy. However, vimentin and progesterone receptors and other antigens such as CEA or CA
neoplasms in which the above-mentioned {306, 945, 963, 1226}. The cellular reac- 19.9. Most authors report negative results
histological criteria of malignancy are not tion for alpha-1-antitrypsin and alpha-1- for chromogranin A, CEA, CA 19.9 and
detected may also give rise to metas- antichymotrypsin is always intense, but AFP. A few neoplasms have been found
tases. Consequently, benign appearing only involves small cell clusters or single to express S-100 {945, 1226, 1358}.
solid-pseudopapillary neoplasms must be cells, a finding that is characteristic of Cytokeratin is detected in 30% {946} to
classified as lesions of uncertain malig- this neoplasm. Alpha-1-antitrypsin also 70% {963, 2195}, depending on the
nant potential. stains the PAS-positive globules. Staining method of antigen retrieval applied.
Usually, the staining for keratin is focal integrate, forming multilamellated vesi- nal trauma and rupture of the tumour
and faint. The keratin profile (CK 7, 8, 18 cles and lipid droplets {946, 1031, 1226, {1060}. Even in patients who had local
and 19) is that of the ductal cell {740, 2154}. Neurosecretory-like granules have spread, recurrences {359, 999}, or
1844}. Positive immunoreactivity for been described in a few tumours {867, metastases {234, 1192, 1642}, long dis-
trypsin, chymotrypsin, amylase and/or 880, 1684, 2119, 2147}. Intermediate cell ease-free periods have been recorded
phospholipase A2 has been reported junctions are rarely observed and micro- after initial diagnosis and resection. Only
{166, 1072, 1192, 1226, 1844}, but has villi are lacking, but small intercellular a few patients have died of a metastasiz-
not been confirmed by most other spaces are frequent. ing solid-pseudopapillary neoplasm
authors {812, 945, 1282}. Similarly, focal {1192, 1395}.
positivity for glucagon, somatostatin Genetics Histological criteria. Perineural invasion,
and/or insulin has been described in In contrast to infiltrating ductal carcino- angioinvasion, or deep invasion into the
some tumours {1226, 2021, 2147}, but mas, solid-pseudopapillary neoplasms surrounding tissue indicate malignant
was not detected in most other cases appear to have wild-type KRAS genes behaviour, and such lesions are classi-
{1072, 1282, 1844}. and do not immunoexpress p53 {512, fied as solid-pseudopapillary carcinoma.
1007, 1039}. An unbalanced transloca- Venous invasion, a high degree of
Ultrastructure tion between chromosomes 13 and 17 nuclear atypia, mitotic activity and promi-
The neoplastic cells have round or resulting in a loss of 13q14→qter and nence of necrobiotic cell nests (cells with
markedly indented nuclei containing a 17p11→pter has been described in one pyknotic nuclei and eosinophilic cyto-
small single nucleolus and a narrow rim of solid-pseudopapillary neoplasm {616}. plasm) were reported to be associated
marginated heterochromatin. The cells with malignancy {1358}.
show abundant cytoplasm, which is rich Prognosis and predictive factors DNA content. There is evidence that an
in mitochondria. Zymogen-like granules In general, the prognosis is good. After aneuploid DNA content assessed by flow
of variable sizes (500-3000 nm) are complete removal more than 95% of the cytometry is associated with malignant
conspicuous, probably representing patients are cured. Local spread or dis- behaviour, although the number of cases
deposits of alpha-1-antitrypsin. The semination to the peritoneal cavity has studied is small {867, 1358, 234}.
contents of these granules commonly dis- been reported in the context of abdomi-
G. Zamboni
Miscellaneous carcinomas G. Klöppel
of the pancreas
M. Miettinen
Mesenchymal tumours of the pancreas J.Y. Blay
L.H. Sobin
Primary mesenchymal tumours of the Recently, solitary fibrous tumours, similar cells in a collagenous background. The
pancreas are exceedingly rare. Leio- to those more commonly seen on the lesional cells are positive for CD34 but
myosarcomas and malignant gastroin- serosal surfaces of the pleura and peri- negative for KIT and desmin; focal actin
testinal stromal tumours appear to be the toneum, have been described (1118). positivity may occur.
least uncommon. Histologically they show bland spindle
H.K. Müller-Hermelink
Lymphoma of the pancreas A. Chott
R.D. Gascoyne
A. Wotherspoon
Definition lowing solid organ transplantation {240}. MALT lymphoma {1925}, and large B-cell
Primary lymphoma of the pancreas is Familial pancreatic lymphoma has been lymphoma {1529, 830}. Only extremely
defined as an extranodal lymphoma aris- reported in a sibling pair (brother and rare cases of pancreatic T-cell lymphoma
ing in the pancreas with the bulk of the sister) who each presented with a high- have been reported, including a single
disease localized to this site. Contiguous grade B-cell lymphoma in their seventh case of anaplastic large cell lymphoma
lymph node involvement and distant decade {830}. Pancreatic lymphoma has (CD30 positive) of T-cell type {1179} and
spread may be seen but the primary clin- also been described in a patient with a case of pancreatic involvement by
ical presentation is in the pancreas with short bowel syndrome {903}. adult T-cell leukaemia/lymphoma {1408}.
therapy directed to this site. The histology of these cases varies little
Clinical features from that seen where these lymphoma
Epidemiology The presentation of primary pancreatic types are encountered more frequently.
Primary lymphoma of the pancreas is lymphoma may mimic that of carcinoma
very rare accounting for less than 0.5% or pancreatitis {240}. Pain free jaundice Prognosis
of pancreatic tumours. As with primary can occur {1330}. Ultrasonography may The distinction between lymphoma and
lymphomas occurring elsewhere in the show an echo-poor lesion {1330}. carcinoma is important, as pancreatic
digestive tract, patients are more fre- lymphomas are associated with better
quently elderly {796}. Histopathology prognosis and may be curable even in
Primary pancreatic lymphomas are usu- advanced stages. Occasional cases of
Aetiology ally of B phenotype. Lymphomas of vari- relapse following prolonged remission
Immunodeficiency predisposes to pan- ous types have been described, includ- have been reported in cases treated by
creatic lymphoma, both in the setting of ing low-grade lymphomas of diffuse chemotherapy {1529}.
HIV infection {866} and as post-trans- small cell type {903, 1480}, follicle centre
plant lymphoproliferative disorders fol- cell lymphoma {1330, 1238}, low-grade
E. Paál
Secondary tumours of the pancreas A. Kádár
A B
C D
Fig. 10.38 Secondary tumours in the pancreas. A Metastatic small cell lung carcinoma. B Metastatic melanoma. C Metastatic renal cell carcinoma.
D Metastatic gastric signet ring cell carcinoma.
unique as a primary site since it might mas, small cell carcinoma, and lym- Prognosis
give rise to late solitary metastases phomas {240, 645, 1781}. Apart from the Since in most cases pancreatic metas-
{1644, 218}. clinical and radiological signs {934}, mul- tases indicate an advanced neoplastic
tiple tumour foci with an abrupt transition disease, the prognosis is generally poor.
Histopathology from normal pancreas to the neoplastic In cases of solitary metastases, com-
The main differential diagnostic problem tissue without signs of chronic pancreati- bined adjuvant therapy and surgical
is to distinguish metastases from primary tis in the surrounding parenchyma sup- resection might be beneficial {360, 674,
pancreatic neoplasms. The most prob- port metastatic origin {2089}. Immunohis- 218, 1597}.
lematic tumours are metastases from the tochemistry specific for certain primary
gastrointestinal tract, renal cell carcino- tumours may also be helpful {1190, 1707}.
Contributors
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Subject Index
Biliary microhamartoma, 178 CD11c, 85, 140 Clear cell carcinoma, 226, 249
Biliary papillomatosis, 158, 175, 178 CD16, 190 Cleft palate, 185
Bilroth II operation, 39 CD19, 85, 86, 140 Clonorchis sinensis, 173
Blastemal cells, 185 CD20, 27, 59, 85, 86, 140, 190, 217 c-met, 50, 188
Blood group A, 49 CD21, 59 c-myc, 18, 61, 86, 116, 123, 151
Borrmann classification, 42 CD22, 86 c-neu, 74
Bowen disease, 150, 151 CD23, 59, 85, 86, 190 Coeliac disease, 12, 58, 72, 73, 84, 87-89
Bowenoid papulosis, 151 CD30, 88, 250 Collagen type IV, 29, 65, 142
Brain tumours, 115, 126 CD31, 29, 90, 142, 195, 196, 198 Collision tumour, 35, 45, 181, 226
BRCA 1, 116 CD34, 28, 29, 63, 65, 90, 142, 143, 164, 169, 185, Colonic EC-cell carcinoids, 138
BRCA 2, 49, 116, 228-230 192, 194-196, 198, 202, 249 Colonoscopy, 107
Breast cancer, 66, 67, 115, 133, 134, 228 CD35, 59 Colorectal carcinoma, 106, 109, 110, 112, 115,
Budd-Chiari syndrome, 185, 191, 196 CD43, 27, 59, 85, 140, 217 125, 126, 132, 136, 153, 155, 199, 200, 201
Burkitt lymphoma, 61, 70, 83, 85, 86, 104, CD44, 118 Columnar cells, 21, 33, 36, 47, 73, 133, 202,
139, 140, 190 CD56, 88, 190, 225 208, 210-213, 215, 224, 226, 235
Burkitt-like/atypical Burkitt-lymphoma, CD68, 164, 209 Columnar metaplasia, 21
70, 86, 104 CD79a, 27, 59, 86, 190, 217 Combined fetal and embryonal epithelial
Buschke-Lowenstein tumour, 149 CD95, 25 hepatoblastoma, 185
Bussey-Gardner polyposis, 120 CD103, 61, 88 Combined hepatocellular and cholangiocar-
Byler syndrome, 170 CD117, 28, 63, 65, 90 cinoma, 158, 181
CD138 (syndecan-1), 141 Comparative genomic hybridization (CGH), 13,
CDH1, 49 29, 34, 36, 49, 63, 90, 151, 171
C CDK4, 171 Condyloma, 149, 150
CDKN2, 18, 36, 115 Condyloma acuminatum, 150
C. sinensis, 173, 207 CDKN2A, 17, 25, 213 Congenital hepatic fibrosis, 170, 174
CA 19-9, 182, 212, 222, 224, 231, 233, 235-237, CEA, see Carcinoembryonic antigen Congenital hypertrophy of the retinal pigment
240, 247 Cell cycle control, 18 epithelium (CHRPE), 121
CA 15-3, 235 Centrocyte-like (CCL) cell, 59 Consumption coagulopathy, 191, 192
CA 125, 224 Cellular leiomyoma, 62 Cornelia de Lange syndrome, 192
CagA, 40, 41, 58 c-erbB-2, 19, 25, 36, 51, 151, 180, 213, 224, Cowden polyps, 48
Cajal cells, 62 238, 240 Cowden syndrome, 132
Calcitonin, 27, 78 Cerebellar dysplastic gangliocytoma, 133 CpG islands, 17
cAMP-dependent protein kinase (PKA), 76 Children's Cancer Study Group (CCSG) CpG sites, 36
CAR-5, 236 classification, 187 Crohn disease, 71-73, 83, 87, 106, 114, 137,
Carbohydrate metabolism disorders, 169 Cholangiocarcinoma, 159, 164, 170, 173-175, 148, 152, 155
Carcinoembryonic antigen, 163, 187, 209, 232 177, 179-181, 183, 196, 201, 202 Crypt cell carcinoma, 110
Carcinoembryonic antigen (CEA), 95, 100, 153, Cholangiography, 175 CTRB, 171
155, 176, 178, 181, 200-202, 212, 215, 222, Cholangiolocellular carcinoma, 177 Cushing syndrome, 54, 214, 244
224, 226, 232, 233, 235-237, 240, 242, 245, Cholangitis, 174, 175, 178, 206, 207 Cyclin A, 118
247 Cholate stasis, 169 Cyclin D, 151, 171
Carcinoid (well differentiated endocrine Choledocholithiasis, 207 Cyclin D1, 17, 18, 61, 85, 123, 124, 140, 171,
neoplasm), 10, 26, 27, 38, 45, 53-57, 70, 71, Chondrosarcoma, 209 188, 190
77-82, 90, 92, 94-97, 99-102, 104, 137-139, Choriocarcinoma, 45, 110, 201, 249 Cyclin E, 240
146, 200-202, 204, 206, 214-216, 226 Chorionic gonadotrophin, 78, 184, 249 Cyclin-dependent kinase, 116, 171
Carcinoid syndrome, 82, 137 Chromoendoscopy, 12, 107 Cyclo-oxygenase 2, 118
Carcinoma in situ, 10, 14, 15, 22, 38, 70, 94, Chromogranin A, 54, 55, 78, 81, 100, 101, 155, Cystadenocarcinoma, 95, 98, 182, 183, 204,
97, 104, 146, 150, 158, 167, 202, 204, 205, 187, 215, 232, 247 208, 211, 220, 234-236, 241
211-214, 220, 227, 228 Chromosomal instability, 116, 117, 128, 171 Cystadenoma, 97, 98, 158, 182, 183, 204, 208,
Carcinomas with ‘medullary’ histology, 226 Chronic alpha-irradiation, 174 211, 220, 231-234
Carcinomatous cirrhosis, 200, 201 Chronic atrophic gastritis, 46, 53 Cystic disease fluid protein, 153, 157, 202
Carcinosarcoma, 14, 110, 158, 198, 209, 225 Chronic cholestasis, 169 Cystothioninuria, 185
Cardiac tumour syndrome, 191 Chronic cholestatic syndromes, 170 Cytochrome P-450, 106, 161
Caroli disease, 174 Chronic gastritis, 33, 40, 60 Cytokeratin, 44, 92, 149, 163, 176, 181, 202, 209,
Caspase 5, 128 Chronic pancreatitis, 221 224, 225, 231, 236, 238, 240, 247, 249
Catenins, 25 Chronic ulcerative colitis, 95 Cytokeratin 7, 20, 92, 178
Cathepsin D, 151 CHRPE, see Congenital hypertrophy of the
Cathepsin-L, 118 retinal pigment epithelium, 125
Cavernous haemangioma, 191, 192 Chymotrypsin, 224, 242, 244, 248 D
CCL, 27, 59, 217 Ciliated cell carcinoma, 226, 249
CD2, 88, 190 CIP1, 116, 119, 171 DALM, 114
CD3, 88, 127, 190 Cirrhosis, 160-163, 167-170, 174, 180, 190, DCC (deleted in colon cancer), 36, 49, 114, 118
CD4, 88, 190 200, 202 D-cell, 77, 78
CD5, 27, 59, 61, 85, 86, 88, 140, 190, 217 c-kit, 29, 62, 63, 90, 142, 143, 202 DCIS, 133
CD7, 88, 190 c-kit mutations, 29, 63 Des-gamma-carboxyprothrombin (DCP), 162
CD8, 88, 127, 190 c-KRAS, 114, 171 Desmoid tumour, 120-122, 124
CD10, 27, 59, 61, 85, 86, 140, 190, 217 Clear cell adenocarcinoma, 204, 208 Desmoplasia, 45
Diabetes mellitus, 78, 194, 221, 235 Epidermoid metaplasia, 227 Gallstones, 78, 206
Diffuse carcinoma, 39, 44 Epithelial membrane antigen (EMA), 153, 163, Gamma-glutamyl-transpeptidase (GGT), 162
Diffuse hyperplasia, 97, 112 215, 236, 238, 240 Gangliocytic paraganglioma, 70, 77-80
Diffuse large B-cell lymphoma (DLBCL), Epithelioid granulomas, 152 Ganglioneuromas, 142
24, 38, 39, 42, 60, 61, 70, 83, 84, 86, 104, Epithelioid haemangioendothelioma, Ganglioneuromatosis, 216
140, 141, 215 158, 191, 195 Ganglioneuromatous proliferation, 131
DLC1 gene, 17, 18 Epstein Barr virus, 61, 85, 87, 141, 174, 177, GANT, see Gastrointestinal autonomic nerve
DNA methylation, 172 190, 194 tumour
DNA methyltransferase, 172 Erythrocytosis, 162 Gardner syndrome, 120, 185, 210
DNA mismatch repair, 117, 129, 228, 229 Exploratory laparotomy, 201 Gastric adenocarcinomas, 42
DNA replication errors (RER), 116 Extrahepatic bile duct adenocarcinomas, 208 Gastric adenomas, 47, 122
DNMT1, 172 Extrahepatic bile duct carcinoma, 175, 206, Gastric mucin MUC5AC, 136
Down syndrome, 185 214 Gastrin, 53-56, 77-82, 202, 210, 215, 226
DPC4, 132, 228, 229, 240 Extramedullary haematopoiesis (EMH), 185, Gastrin cell tumour (gastrinoma), 53-57, 70,
Ductal adenocarcinoma, 221, 223-227, 230, 192, 193 77-79, 214
235, 243 Extramucosal (perianal) adenocarcinoma, 152 Gastrin-cell (G-cell) tumours, 77
Ductal papillary hyperplasia, 227 Gastritis, 40, 46
Ductular cell hyperplasia, 227 Gastrointestinal autonomic nerve tumour
Dukes classification, 109 F (GANT), 64, 79
Duodenal gastrin-cell tumours, 78 Gastrointestinal hamartomas, 132, 134
DUPAN-2, 222, 224, 236, 240, 245 Factor VIII-related antigen, 164, 192, 198 Gastrointestinal stromal tumour (GIST),
Dye endoscopy, 47 Familial adenomatous polyposis (FAP), 48, 49, 10, 28, 29, 62, 64, 65, 70, 94, 104, 142
Dyspepsia, 41, 58 71-74, 97, 114, 120-127, 130, 135, 170, 188 Gastrointestional polyposis syndromes, 49
Dysphagia, 12, 23, 26-28, 30, 34 Familial atypical multiple mole melanoma Gastro-oesophageal reflux, 20, 21, 33
Dysplasia associated lesion or mass (DALM), (FAMMM), 228 G-cell (gastrin-producing) tumours, 53, 54,
114 Familial breast cancer, 230 77, 78
Dysplastic gangliocytoma of the cerebellum, Familial multiple polyposis, 120 Gelatinous carcinoma, 225
132 Familial pancreatic cancer, 97, 120, 230 Genetic haemochromatosis, 170
Dysplastic nodules, 158, 167-169 Familial polyposis coli, see Familial adeno- Genetic heterogeneity, 161
matous polyposis Genetic instability, 171
Fanconi anaemia, 170 Genitourinary tumours, 134
E Fas receptor, 25 GERD (high risk group for adenocarcinoma),
Fecal bile acids, 106 33, 34, 36
E2F-4, 50, 128 Fetal epithelial hepatoblastoma, 188 Germline APC mutation, 115
E6-associated protein, 151 Fetal hydrops, 185 Germline CDH1 mutations, 49
E7 protein, 151 FEZ1, 18 Germline mutations, 49, 73, 115, 123, 124,
Early gastric cancer, 41, 45, 51 FGFR4, 79, 82 128, 129, 132, 228, 229
EBV see Epstein-Barr virus FHIT, 17, 25, 36, 50 Giant (malignant) condyloma, 149
E-cadherin, 25, 49, 50, 116, 123, 129, 172, Fibrinogen, 163, 165, 201 Giant cell carcinoma, 225
180, 224 Fibrocystic disease of the breast, 132-134 GIST, see Gastrointestinal stromal tumour
EC-cell, 55, 79-82, 100, 137, 138 Fibroepithelial polyp, 155 Glicentin, 81, 100, 138
EC-cell, serotonin-producing carcinoid, Fibrolamellar HCC, 164, 165 Glioblastoma multiforme, 123
53-56, 70, 77, 78, 80, 81, 94, 100, 104 Fibrosarcoma, 154, 165, 177, 198 Glisson capsule, 194, 196, 198
ECL-cell hyperplasia, 53, 54 Fibrous polyp, 155 Globoid extracellular collagen accumula-
ECL-cell tumours, 54, 56, 82 FldA gene, 58 tions, 90
EGFR, see Epidermal growth factor receptor Fluorescent in situ hybridization (FISH), Globular hyaline bodies, 165
EMA, see Epithelial membrane antigen 86, 141 Glomus tumour, 38, 65
embryonal carcinoma, 45 Focal atypical epithelial hyperplasia, 227 GLP-1, 100, 138
Embryonal rhabdomyosarcoma, 184, 216 Focal epithelial hyperplasia, 227 GLP-2, 100, 138
Embryonal sarcoma, 191, 194, 195 Focal liver cell dysplasia (LCD), 168 Glucagon, 78, 81, 100, 101, 202, 248
Endocrine tumours, 26, 77, 78, 80, 137, 214, Focal nodular hyperplasia, 158, 169, 184, 188 Glucagon-like peptide and PP/PYY-producing
249 Focal non-epidermolytic palmoplantar kera- L-cell carcinoids, 99
Endodermal sinus tumour, 45, 158 toderma, 12, 17 GLUT1 glucose transporter, 118
Endogenous nitrosamine formation, 174 Follicle centre cell lymphoma, 61, 250 Glutathione S-transferase, 25, 106
Endometrial carcinoma, 126, 133 Follicular carcinoma, 133, 134 Gluten sensitive enteropathy, 87
Endoscopic mucosectomy, 108 Follicular lymphoma, 84, 86 Giant haemangioma, 193
Endoscopic ultrasonography (EUS), 12, 23, FRA3B, 25 Glycogen, 12, 123, 165, 168, 169, 183, 185, 186,
34, 222 Free radicals, 41 193, 208, 231-233, 249
Enkephalin, 81, 138 Fundic gland polyps, 48 Glycogen storage disease (GSD), 169
Enteroglucagons, 100 Glycogen synthase kinase 3 ß (GSK3b), 123
Eosinophilic granuloma, 155 Goblet cell carcinoid (mucinous carcinoid),
Ependymoma, 154 G 94, 99-101, 204
Epidermal cysts, 123 Goblet cell metaplasia, 178
Epidermal growth factor receptor (EGFR), G:C>A:T transition mutations, 25 Goblet cell mucin MUC2, 136
17, 18, 25, 36, 79, 213 Galectin 3, 118 Goblet cells, 21, 36, 73, 100, 112, 113, 133, 176,
Epidermoid cysts, 120, 121 Gallbladder carcinoma, 206 208, 212, 215
MUC1, 26, 47, 224, 240 Nodular transformation, 158 Paneth cells, 21, 24, 100, 105, 111, 208,
MUC2, 26, 47, 180, 224, 238, 240 Nodule-in-nodule, 166, 170 210-212, 215, 238
MUC3, 224 Non ECL-cell gastric carcinoids, 54 Papillary adenocarcinoma, 43, 208, 216
MUC5, 224 Non-biliary cirrhosis, 174 Papillary adenoma, biliary type, 211
MUC5AC, 47, 240 Non-Hodgkin lymphoma, 57, 83, 85, 190, 202, Papillary adenoma, intestinal type, 210
MUC6, 47 217 Papillary carcinoma of thyroid, 123
Mucinous adenocarcinoma 24, 42-44, 71, Non-medullary thyroid carcinoma, 132 Papillary ductal hyperplasia, 227
95, 96, 109, 111, 114, 117, 127, 177, 204, 208 Nonmucinous, glycogen-poor cyst-adenocar- Papillary hidradenoma, 153
Mucinous carcinoid tumour, 226 cinoma, 249 Papillary hyperplasia, 178, 224, 227, 239
Mucinous cystadenocarcinoma, 96, 234-236, NRASL3, 36 Papillary pancreatic neoplasms, 237
249 NRH, 169 Papillary-cystic tumour, 246
Mucinous cystadenomas, 235 Nucleotide instability, 116 Papillary-mucinous carcinoma, 220, 239
Mucinous cystic neoplasm (MCN), 220, Nutrition, 11 Papillomatosis (adenomatosis), 204, 211
225, 226, 234-237, 239 Papillomatous papules, 132-134
Mucinous noncystic carcinoma, 220, 221, 225, PAR-4, 76
227, 239 O Paraganglioma, 216
Mucocutaneous melanin pigmentation, 74 Parietal (oxyntic) cells, 32
Mucoepidermoid carcinoma, 10, 24, 27, 35, O. viverrini, see Opisthorchis viverrini Parietal cell carcinoma, 45
177 Obesity, 21 PCNA, 18, 36, 185, 238, 240
Mucosa associated lymphoid tissue (MALT), Octreotide, 81 PDGF, 82
57 Oesophagitis, 11, 16, 33 Pectum excavatum, 185
Mucosal prolapse, 113 Oesophagogastric junction, 20, 21, 32-36, 39 Peliosis hepatis-like change, 164
Muir-Torre syndrome, 126, 129 Oestrogen receptor, 202 Pen A type, 46, 51
Multicentric HCCs, 166 Oligocryptal adenomas, 72, 121 Pen B type, 46, 51
Multilayered metaplasia, 227 Oncocytic carcinoma, 249 Periampullary neoplasms, 79
Multinodular goiter, 134 Opisthorchiasis, 173, 174, 178 Perianal adenocarcinomas, 151
Multiple adenomatosis, 120 Opisthorchis viverrini, 159, 173, 180, 207 Peripheral bile duct carcinoma, 158
Multiple endocrine neoplasia syndrome, type Oral contraceptive, 160, 185, 196 Persistent ductus arteriosus, 185
2b (MEN2b), 123, 216 Ornithine decarboxylase, 118 Peutz-Jeghers syndrome, 48, 49, 70, 73-75, 97,
Multiple hamartoma syndrome, 132 Osteoclast-like giant cell tumours, 225, 236 104, 112, 113, 138, 210, 229, 230
Multiple lymphomatous polyposis, 61, 85, 86, Osteoporosis, 185 Peutz-Jeghers polyps, 48, 74, 75, 113
139, 140 Osteosarcoma, 115, 209 Peyer patches, 58
MYB, 228, 229 Ovarian cancer, 67, 116 Phaeochromocytoma, 79
MYBL2, 36 Oxidative stress, 40 Phospholipase A2, 248
MYC, 17, 36, 123 Oxyntomodulin, 100 Phosphtidylinositol-3,4,5-triphosphate (PIP3),
Myeloma, 155, 190 134
Myoblastoma, 63, 154 PI3 kinase pathway, 134
Myogenic sarcoma, 165 P PiZ type, 170
PLA2G2A, 124
p15, 18, 36 Plasmablastic lymphoma, 61
N p16, 18, 25, 61, 86, 114, 171, 213, 228-230, 240 Platelet-derived growth factor (PDGF), 51, 82
p16INK4, 171 Pleomorphic large cell carcinoma, 225
N-acetyltransferases, 106 p19arf, 25 Plummer-Vinson syndrome, 12
Natural killer (NK) cell lymphomas, 89 p21WAF1/CIP1 cyclin-dependent kinase PMS1 (Postmeiotic segregation 1),
NCAM, 82 inhibitor, 116, 119, 171 128, 129
Negative for intraepithelial neoplasia, 22 p27Kip1, 118, 171, 240 PMS2 (Postmeiotic segregation 2),
Nephroblastomas, 185 p53 (see also TP53), 19, 36, 54, 61, 74, 82, 86, 128, 129
NEPPK, 17 114-116, 118, 119, 136, 151, 170, 180, 212, Polymorphism, 11, 14, 50, 106, 114, 124, 171,
Neural adhesion molecule (NCAM), 82 225, 236, 238, 240, 248 227
Neurilemmoma, 154 Padova classification, 47 Polypoid carcinoma, 14
Neuroblastoma, 185, 186 Paget cells, 150, 153, 155 Polypoid type I carcinoids, 57
Neuroendocrine tumour, 155, 153, 199-201 Paget disease, 152,153 Polyposis syndromes, 48
Neurofibroma, 142, 154 Pale bodies, 165 Poorly differentiated adenocarcinoma, 110,
Neurofibromatosis, 64, 65, 79, 128, 142, 170, Palmoplantar keratoses, 134 127, 176, 178
216 Pancolitis, 95, 106 Poorly differentiated HCC, 166, 170
Neurofibromatosis type I (NF1), 65, 79 Pancreatic carcinoma, 91, 221, 222, Poorly differentiated neuroendocrine carci-
Neurokinin A, 81 228-229 noma, 26, 27, 53, 138, 149, 215
Neuroma, 94, 102 Pancreatic ductal adenocarcinomas, 221 Population-based study, 74
Neuron specific enolase (NSE), 247 Pancreatic gastrinomas, 80 Porcelain gallbladder, 207
Neurotensin, 78, 81, 138 Pancreatic intraepithelial neoplasia (PanIN), Porphyria cutanea tarda (PCT), 170
Nitric oxide (NO), 40, 41 228 Porphyrin metabolism, 170
Nitric oxide synthase, 36, 40 Pancreatic polypeptide, 54, 78, 210, 226 Positron emission tomography (PET), 200
Nitrosamines, 11, 21, 39-41 Pancreatic somatostatin-cell tumours, 78 PP cells, 78
N-nitroso compounds, 40, 174 Pancreatic T-cell lymphoma, 250 PP/PYY immunoreactive cells, 81
Nodular regenerative hyperplasia (NRH), 158, Pancreatoblastoma, 220, 226, 244, 245 PP-cell tumours, 77
169, 184, 188 Paneth cell rich-adenocarcinoma, 45 Prader Willi syndrome, 185, 188
Xanthomas, 44
U
VacA, 40
Vascular endothelial growth factor (VEGF),
172
Vascular leiomyosarcoma, 201
Vasoactive intestinal peptide, 202
Verrucous (squamous) carcinoma, 10, 14, 149
Vesicular monoamine transporter type 2
(VMAT-2), 54
VHL, see Von Hippel-Lindau syndrome
Villiform hyperplasia, 22
Vimentin, 165, 183, 187, 224, 225, 232, 236, 247,
249
Vinyl chloride monomer, 196, 198
Vinyl chloride monomer (VCM), 196
Viral protein E6, 151
Virulent cagA vacA s1a H. pylori, 41
Von Hippel-Lindau syndrome, 114, 216,
231, 232
Von Meyenburg complex (biliary micro-
hamartoma), 174, 178
Von Recklinghausen disease, 79
Von Willebrand factor, 90, 196