Yasser Gaber Final MD Thesis

Definition of Risk Groups in Oral Cavity Squamous Cell
Carcinoma Patients and Prediction of Their Outcomes

by Using 18F-FDG PET/CT
Thesis
Submitted for the partial fulfillment of M.D. degree
in nuclear medicine
By
Yasser Gaber Ali

Assistant Lecturer
South Egypt Cancer Institute Assiut University
Under Supervision of
Professor Dr. Hosna Moustafa

Professor of Nuclear Medicine
Faculty of Medicine - Cairo University
Professor Dr. Tzu-Chen Yen

Professor and Chairperson of Nuclear Medicine Department
Chang Gung Medical College and University - Taiwan
Dr. Haitham Fouad Abdel-Hameed

Lecturer of Nuclear Medicine
Faculty of Medicine - Cairo University
Faculty of Medicine
Cairo University
2011
Acknowledgement
Acknowledgement
I would like to express my deepest and sincere gratitude to my
professor Dr. Hosna Moustafa, professor of nuclear medicine, Cairo
University. I am greatly indebted to her and no words in my humble
dictionary can express my appreciation to her kind supervision, meticulous
but targeted revision, continuous support, and enormous educational
potential.
I am very grateful to Prof. Dr. Tzu-Chen Yen, professor and chairperson
of nuclear medicine in Chang Gung Memorial Hospital, Taiwan. She gave me
a great opportunity to be among her research team in such amazing and
friendly environment in Taiwan. Indeed, I have learnt a lot from her,
especially how to think, conduct and analyze a research work.
Also, I would like to thank Dr. Haytham Fouad for his uninterrupted
encouragement and fruitful exchange of ideas.
Many thanks to Dr. Liao Chun-Ta, professor of otolaryngology & head
and neck surgery in Chang Gung Memorial Hospital, for providing the
clinical and follow-up data, in addition to his supportive corrections and
advices, and to all my colleagues and friends in Taiwan who helped me
throughout the 2 years I have spent there and to my family who are always
trying their best to make my life easier.
Table of Contents
Table of Contents
Acknowledgement .............................................................................................................................i
Table of Contents .................................................................................................................................ii
List of Figures .....................................................................................................................................iv
List of Tables ......................................................................................................................................vi
List of Abbreviations .........................................................................................................................vii
Introduction..........................................................................................................................................1
Aim of the Work ..................................................................................................................................3
Anatomy of the Oral Cavity.................................................................................................................4
I. Lips ............................................................................................................................................4
II. Oral Cavity Proper....................................................................................................................5
Regional Lymph Nodes .....................................................................................................................12
I. Anatomical Considerations......................................................................................................12
II. AJCC Nodal Classification ....................................................................................................13
Overview of Oral Cavity Carcinoma .................................................................................................16
Epidemiology of OSCC .....................................................................................................................16
Incidence ........................................................................................................................................16
Risk Factors....................................................................................................................................17
Pathology of Oral Cavity Carcinoma.................................................................................................22
I. Precancerous Lesions of oral cavity ........................................................................................22
II. Squamous Cell Carcinoma (SCC)..........................................................................................26
III. Verrucous Carcinoma (VC) ..................................................................................................30
Staging of the Lip and Oral Cavity Cancer........................................................................................31
Diagnosis of OSCC............................................................................................................................35
Treatment Outlines for OSCC............................................................................................................36
1. Lip ...........................................................................................................................................37
2. Floor of the mouth...................................................................................................................38
3. Oral Tongue ............................................................................................................................38
4. Buccal Mucosa........................................................................................................................39
5. Lower Gum .............................................................................................................................39
6. Retromolar Trigone.................................................................................................................39
7. Upper Gum and Hard Palate ...................................................................................................39
Prognostic Factors in Oral Cavity Carcinoma ...................................................................................40
I. Patient-Related Prognostic Factors:.........................................................................................40
II. Tumor-Related Prognostic Factors:........................................................................................41
III. Treatment-Related Prognostic Factors:.................................................................................45
PET Imaging ......................................................................................................................................47
PET Radiopharmaceuticals ................................................................................................................47
Normal PET Imaging .........................................................................................................................48
1. Oral Cavity and Lymphoid Tissues ........................................................................................49
2. Brown Fat and Skeletal Muscles.............................................................................................51
3. Laryngeal Uptake....................................................................................................................53
4. Osseous Uptake.......................................................................................................................53
5. Orbits.......................................................................................................................................54
6. Thyroid gland..........................................................................................................................54
7. Thymus....................................................................................................................................55
8. Salivary Glands .......................................................................................................................55
Limitations of FDG PET in Head and Neck Cancer..........................................................................55
ii
Table of Contents
1. Physiologic FDG Uptake ........................................................................................................55
2. Inadequate Scanner Resolution...............................................................................................55
3. Recent Surgery and Inflammatory Response..........................................................................56
4. Effect of Radiation and Chemotherapy...................................................................................56
5. Low FDG Avidity ...................................................................................................................57
6. PET/CT Artifacts ....................................................................................................................57
Qualitative and Quantitative Parameters from PET...........................................................................60
I. Qualitative Assessment............................................................................................................60
II. Quantitative Assessment ........................................................................................................61
III. Semi-quantitative Assessment ..............................................................................................61
Clinical Role of FDG-PET in Oral Cavity Carcinoma ......................................................................66
I. Staging .....................................................................................................................................66
II. Restaging and Therapy Monitoring........................................................................................70
III. Prognosis and Risk Stratification..........................................................................................72
The Role of Non-FDG Radiopharmaceuticals...................................................................................76
Patients and Methods .........................................................................................................................78
Patients ...........................................................................................................................................78
PET/CT Imaging Protocol .............................................................................................................78
Data Reading & Analysis...............................................................................................................79
Calculation of Total Lesion Glycloysis (TLG) ..............................................................................81
Surgery and Adjuvant Therapy ......................................................................................................81
Follow-up Protocol ........................................................................................................................82
Statistical Analysis.........................................................................................................................82
Results................................................................................................................................................84
1. Patients ....................................................................................................................................84
2. PET/CT Scores and SUV........................................................................................................88
3. Choice of the Best Contouring Method ..................................................................................89
4. Total Lesion Glycolysis (TLG)...............................................................................................90
5. Association between SUV & TLG and Different Pathological Characteristics .....................90
6. Univariate Analyses ................................................................................................................93
7. Multivariate Analyses ...........................................................................................................112
8. Risk Score .............................................................................................................................115
9. Risk Groups Based on ECS & NSUV ...................................................................................118
Case Presentation .............................................................................................................................119
Case 1: Score 0-patient ................................................................................................................119
Case 2: Score 1-patient (pN+)......................................................................................................120
Case 3: Score 2-patient (high NSUV & pN+) .............................................................................121
Case 4: Score 3-patient with a survival of 34 months..................................................................122
Case 7: Patient with positive ECS and low nodal SUV...............................................................125
Case 8: Patient with positive ECS and high nodal SUV..............................................................126
Discussion ........................................................................................................................................127
Conclusion and Recommendations..................................................................................................136
Summary ..........................................................................................................................................137
References........................................................................................................................................141
Arabic Summary ..............................................................................................................................171
iii
List of Figures
List of Figures
Figure 1: Anatomical sites and sub-sites of the oral cavity (20).........................................................4
Figure 2: Lateral view of the tongue showing extrinsic muscles and its nerves(24) ..........................6
Figure 3: Diagram of lymph drainage of the tongue(24)....................................................................7
Figure 4: Coronal section in the floor of the mouth (24)....................................................................8
Figure 5: Schematic diagram showing the deep spaces of the face on the right and some of their
contents on the left (25)................................................................................................................8
Figure 6: A coronal image through the cheek showing the mucosa, muscle, fat pad, masseter, and a
cross-section of the tongue and floor of mouth (21). .................................................................10
Figure 7: Trans-oral view of the alveolar ridge, retromolar region, and mandible of the left side of
the oral cavity (21).....................................................................................................................10
Figure 8: Vestibule and gingivae of the mandible (27).....................................................................11
Figure 9: Lymph vessels and nodes of the head and neck(29)..........................................................13
Figure 10: Schematic diagram indicating the location of the lymph node levels in the neck (20). ..15
Figure 11: Palatal lesion associated with reverse smoking. Note the crate-like ulcerated areas
covered with fibrin (45)..............................................................................................................19
Figure 12: Oral leukoplakia: (A) Gross picture showing numerous lesions that have become
virtually confluent. (B) Microscopic picture showing marked epithelial thickening and
hyperkeratosis ............................................................................................................................23
Figure 13: Proliferative verrucous leukoplakia involving the buccal gingiva (4)............................24
Figure 14: Nicotine Stomatitis: Rough, white, fissured appearance of the hard and soft palate in a
heavy pipe smoker......................................................................................................................25
Figure 15: Squamous cell carcinoma of the lateral tongue ..............................................................26
Figure 16: Verrucous carcinoma. White, exophytic, warty mass of the maxillary alveolar ridge
(22). ............................................................................................................................................31
Figure 17: Methods of measuring tumor thickness. ..........................................................................43
Figure 18: Mechanism of FDG uptake..............................................................................................48
Figure 19: Normal PET/CT scan (121). ............................................................................................49
Figure 20: Midline sagittal view with different H. & N. structures (122).........................................50
Figure 21: Most prominent uptake in the sublingual glands and mylhyoid muscle insertions (122).
....................................................................................................................................................50
Figure 22: Uptake in the soft palate (122). .......................................................................................50
Figure 23: Left: Palatine tonsils uptake, Right: uptake in the pharyngeal tonsil (adenoids) (122)..51
Figure 24: Focal uptake at insertion of muscles into the occipital bone. Uptake is also seen in the
sternocleidomastoid muscles (SCM) and parotid glands (124).................................................51
Figure 25: Asymmetric sternocleidomastoid muscle uptake. (A) Axial CT right sternocleidomastoid
muscle (arrow). (B) Fused PET-CT scan localizes the FDG uptake to the right
sternocleidomastoid muscle (arrow). Note also the symmetric FDG uptake within the
prevertebral strap muscles (arrowheads) (126). .......................................................................52
Figure 26: Asymmetric increased uptake in the muscles of mastication...........................................52
Figure 27: Physiologic uptake in the vocalis muscle, arytenoid muscles and symmetric vocal cord
uptake (122, 126). ......................................................................................................................53
Figure 28: Axial view of FDG-PET showing periodontal/dental (127). ...........................................54
Figure 29: (A) Hypermetabolic thyroid adenoma at the left lobe; (B) Hrthle cell carcinoma at the
right lobe (126). .........................................................................................................................54
Figure 30: Physiologic uptake in the parotid (A) and submandibular glands (B) (126)..................55
Figure 31: Inflammatory FDG uptake at the site of tracheostomy....................................................56
iv
List of Figures
Figure 32: Dental abscess in a patient with history of squamous cell carcinoma of the left side of
the tongue base. (A) CT scan shows no abnormality in the alveolar ridge of maxilla (B) PETCT scan shows a focal area of intense FDG uptake in the site of infected tooth (arrow) (130).
....................................................................................................................................................56
Figure 33: CT attenuation artifact from an implantable catheter port. .........................................58
Figure 34: Truncation artifact...........................................................................................................59
Figure 35: The tumor subsites seen .................................................................................................84
Figure 36: The pattern of recurrence in the 45 patients who experienced treatment failure
(percentages are given among the 45 patients). ........................................................................87
Figure 37: A 65-year-old male with left buccal cancer. (A) Axial T1 post-contrast image showed
enhancement in a small area (2.7 cm) of irregular mucosal thickening in the left buccal area.
(B) Fused PET/CT images revealed low FDG uptake in that site (SUVmax 4.34) and
accordingly was scored 0...........................................................................................................88
Figure 38: Scatter plots for (A) the relation between maximum pathologic axial diameter of the
fixed primary tumor and the diameter derived from tumor delineation using absolute SUV
value of 3, and (B) the relation between maximum diameter of the pathologic lymph nodes and
the diameter derived from lymph node delineation using absolute SUV value of 2.5. ..............89
Figure 39: ROC analyses of TTLG (A) and NTLG (B) in relation to presence of ECS. The best cutoff values identified were 92.19 and 18.51, respectively. NTLG was significantly more accurate
than TTLG for predicting ECS (P < 0.001)................................................................................90
Figure 40: Local control rate according to the primary tumor TLG ..............................................93
Figure 41: Local control rate according to the presence or absence of bone marrow invasion ....93
Figure 42: Neck control rate according to the neck lymph nodal TLG . ..........................................96
Figure 43: Neck control rate according to the histopathological differentiation.............................96
Figure 44: Distant metastases free survival rate according to the primary tumor TLG. .................99
Figure 45: Distant metastases free survival according to the presence or absence of extra-capsular
spread in the neck lymph nodes of 126 patients with oral cavity cancer...................................99
Figure 46: Disease free survival rate according to the primary tumor TLG..................................102
Figure 47: Disease free survival rate according to the pathologic status of neck lymph nodes.....102
Figure 48: Disease specific survival rate according to the primary tumor TLG............................105
Figure 49: Disease specific survival according to the pathologic status of neck lymph nodes. .....105
Figure 50: Overall survival rate according to the neck lymph nodal SUV.....................................108
Figure 51: Overall survival rate according to the pathologic status of neck lymph nodes. ...........108
Figure 52: Disease free survival rate according to the proposed risk score. .................................116
Figure 53: Disease specific survival rate according to the proposed risk score. ...........................116
Figure 54: Distant metastases free survival rate according to nodal SUV in 40 patients with
positive ECS. ............................................................................................................................118
Figure 55: Disease specific survival rate according to nodal SUV in 40 patients with positive ECS.
..................................................................................................................................................118
List of Tables
List of Tables
Table 1: Common + emitters of clinical importance (118). ............................................................47
Table 2: General Clinical Characteristics of the Study Participants..........................................85
Table 3: General Pathological Characteristics of the Study Participants ..................................86
Table 4: Relation of primary tumor TSUV and TTLG to different pathological characteristics
....................................................................................................................................................91
Table 5: Relation of nodal NSUV and NTLG to different pathological characteristics .............92
Table 6: Univariate analysis of 3-year local control (LC) according to clinical characteristics,
SUV and TLG...........................................................................................................................94
Table 7: Univariate analysis of 3-year local control (LC) according to pathological
characteristics...........................................................................................................................95
Table 8: Univariate analysis of 3-year neck control (NC) according to clinical characteristics,
SUV and TLG...........................................................................................................................97
Table 9: Univariate analysis of 3-year neck control (NC) according to pathological
characteristics...........................................................................................................................98
Table 10: Univariate analysis of 3-year distant metastases free survival (DMFS) according to
clinical characteristics, SUV and TLG.................................................................................100
Table 11: Univariate analysis of 3-year distant metastases free survival (DMFS) according to
pathological characteristics...................................................................................................101
Table 12: Univariate analysis of 3-year disease free survival (DFS) according to clinical
characteristics, SUV and TLG..............................................................................................103
Table 13: Univariate analysis of 3-year disease free survival (DFS) according to pathological
characteristics.........................................................................................................................104
Table 14: Univariate analysis of 3-year disease specific survival (DSS) according to clinical
Table 15: Univariate analysis of 3-year disease specific survival (DSS) according to
pathological characteristics...................................................................................................107
Table 16: Univariate analysis of 3-year overall survival (OS) according to clinical
Table 17: Univariate analysis of 3-year overall survival (OS) according to pathological
Table 18: Univariate analyses of 3-year local control (LC), neck control (NC), distant
metastases free survival (DMFS), disease free survival (DFS), disease specific survival
(DSS) and overall survival (OS) according to clinical data, SUV, TLG, and pathological
Table 19: Multivariate analysis of 3-year local primary tumor control (LC)..........................112
Table 20: Multivariate analysis of 3-year neck control (NC).....................................................112
Table 21: Multivariate analysis of 3-year distant metastases free survival (DMFS)...............113
Table 22: Multivariate analysis of 3-year disease free survival (DFS)......................................113
Table 23: Multivariate analysis of 3-year disease specific survival (DSS) ..............................114
Table 24: Multivariate analysis of 3-year overall survival (OS)................................................114
Table 25: Multivariate analysis of 3-year disease free (DFS) and disease specific survival
(DSS), according to the proposed risk score........................................................................115
Table 26: Some of the characteristics of patients with score 3 ..................................................117
vi
List of Abbreviations
AJCC
AUC
CCRT
CGMH
CI
COX
CRT
CT
CWU
DFS
DICOM
DMFS
DOD
DSS
ECS
EORTC
FDG
FLT
FMISO
FWHM
HIF
HNC
HNSCC
HPV
HR
JD
JD
JO
LC
LGI
LN
LND
MD
MIC
MRI
MS
MTV
MVA
NC
American Joint Committee on Cancer

Area Under Curve
Concomitant ChemoRadioTherapy
Chang Gung Memorial Hospital
Confidence Interval
Cycolooxygenase
ChemoRadioTherapy
Computed Tomography
Conventional Work-Up
Disease Free Survival
Digital Imaging and Communications in Medicine
Distant Metastases Free Survival
Died Of Disease cancer death
Disease Specific Survival
Extra-capsular Spread
European Organisation for Research and Treatment of Cancer
Fluodeoxyglucose
Fluoromisonidazole
Fluoromisonidazole
Full Width at Half Maximum
Hypoxia Inducible Factor
Head and Neck Cancer
Head and Neck Squamous Cell Carcinoma
Human Papilloma Virus
Hazards Ratio
Jugulodigastric
Jugulo-Digastric
Jugulo-omohyoid
Local Control
Larson Ginsberg Index
Lymph Node
Lymph Node Dissection
Moderately-Differentiated
Molecular Imaging Center
Magnetic Resonance Imaging
Masticator Space
Metabolic Tumor Volume
Multivariate Analyses
Neck Control
vii
NCCN
NER
ns
NSUV
NTLG
OL
OS
OSCC
PD
PET/CT
PVE
RMT
ROC
ROI
RT
RTOG
S/B Ratio
SCC
SCM
SD
SIL
SOHND
SUV
SUVavg
SUVlean
SUVmax
SUVpeak
TLG
TNM
TSUV
TTLG
UADT
US
UVA
VC
VEGF
VEGF
VOI
WD
WHO
National Comprehensive Cancer Network

No Evidence of Recurrence
Not significant
Standardized Uptake Value of the Lymph Nodes
Total Lesion Glycolysis of Lymph Nodes
Oral Leukoplakia
Overall Survival
Oral Squamous Cell Carcinoma
Poorly-Differentiated
Positron Emission Tomography/Computed Tomography
Partial Volume Effect
Retromolar Trigone
Receiver Operating Characteristics
Region Of Interest
Radiotherapy
Radiation Therapy Oncology Group
Signal to Background Ratio
Squamous Cell Carcinoma
Sternocleidomastoid
Standard Deviation
Squamous Intraepithelial Lesion
Supra-Omohyoid Neck Dissection
Standardized Uptake Value
Average Standardized Uptake Value
Standardized Uptake Value normalized to Lean Body Mass
Maximum Standardized Uptake Value
Peak Standardized Uptake Value
Total Lesion Glycolysis
Tumor, Node and Metastasis
Standardized Uptake Value of the Primary Tumor
Total Lesion Glycolysis of the Primary Tumor
Upper Aerodigestive Tract
Ultrasound
Univariate Analyses
Verrucous Carcinoma
Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor
Volume Of Interest
Well-Differentiated
World Health Organization
viii
Introduction
Introduction
Oral cancer is the eighth most common cancer worldwide, with epidemiologic
variations between different geographic regions (1). The World Health Organization
(WHO) expects a worldwide rising incidence in the next decades (2).
Surgery is the main stay for resectable oral squamous cell carcinoma (OSCC).
Post-operative radiotherapy (RT) or chemoradiotherapy (CRT) is indicated in the
presence of specific adverse features (3).
Numerous prognostic factors have been identified including clinical,
anatomical and pathological risk factors; however, and in spite of the ready
accessibility of the oral cavity to direct examination, these malignancies still often not
detected until a late stage, and the survival rate for oral cancer has remained
essentially unchanged over the past three decades (4).
The possibility of identifying novel prognostic factors in oral cancer may help
in stratifying different risk groups and personalizing the cancer management process.
Recently, standardized uptake value (SUV), a simplified index of glucose
uptake of the tumor measured from
18
F-fluorodeoxyglucose positron emission
tomography/computed tomography (18F-FDG PET/CT), has been strongly introduced

as a possible prognostic factor in many cancers, including head and neck cancer (510). However, some drawbacks are inherent to the use of SUV, one of these
drawbacks is being a single pixel value not reflecting the real tumor heterogeneity
(11).
The concept of total lesion glycolysis (TLG) has been introduced by Larson et
al. to study the change of glucose metabolism pre- and post-therapy (12). It was
calculated as the product of tumor volume from PET/CT and the average SUV within
this volume.
1
Introduction
Their results set the stage for other groups at Memorial Sloan-Kettering Cancer
Center to study TLG among other parameters in evaluation of lung cancer after
radiation treatment (13) and to predict long-term outcomes in patients with rectal
cancer (14). They found good correlation between TLG with treatment response and
outcomes. TLG also was investigated in patients with esophageal cancer (15, 16), soft
tissue sarcoma (17), osteosarcoma (18) and melanoma (19), with encouraging results.
The potential prognostic role of baseline SUV and TLG measured at the
primary tumor and neck lymph nodes has not been studied in patients with OSCC.
Aim of the Work
Aim of the Work

To evaluate the potential prognostic role of presurgical standardized uptake
value (SUV) and total lesion glycolysis (TLG), measured from FDG PET/CT at the
primary tumor and neck lymph nodes, in identifying different risk groups of oral
cavity squamous cell carcinoma (OSCC) and predicting their outcomes.
Review of literature
Chapter 1: Anatomy of the Oral Cavity
Anatomy of the Oral Cavity

Oral cancer can be divided into two main categories: one arising in the
oropharynx and one arising in the oral cavity. The latter, which is the focus of this
review, is subdivided into oral cavity proper and lip vermilion (Figure 1) (4).
Figure 1: Anatomical sites and sub-sites of the oral cavity (20)

I.
Lips
The lip begins at the junction of the vermillion border, which marks the
beginning of the red transitional zone between the skin and the mucous membrane of
the lip, and includes only the vermillion surface (that portion of the lip that comes
into contact with the opposing lip). It is well defined into an upper and lower lip
joined at the commissures of the mouth (20).
Beneath the lip skin is a layer of subcutaneous tissue with many muscles,
nerves, and vessels. This subcutaneous tissue lies just superficial to the orbicularis
oris muscle, which forms the main bulk of the lips. Deep to that muscle are numerous
labial salivary glands, each with a small duct penetrating the mucosal membrane. The
mucosal membrane forms a superior and inferior midline fold connecting to the
alveolar gingiva, forming the superior and inferior labial frenulum (21).
Cancer of the lip carries a low metastatic risk and initially involves adjacent
submental and submandibular nodes, then jugular nodes.(20)
II.
Oral Cavity Proper

The oral cavity proper extends from the skin-vermillion junction of the lips to
the junction of the hard and soft palate above and to the line of circumvallate papillae
below; hence, the intraoral subsites include the buccal mucosa, tongue, floor of
mouth, upper and lower gingivae and alveolar processes, the hard palate and
retromolar trigone (RMT) (22).
1.
The Oral Tongue

The oral (buccal) tongue is the freely mobile anterior two-thirds portion of the
tongue that extends from the line of circumvallate papillae to the undersurface of the
tongue at the junction of the floor of the mouth. It is composed of four areas: the tip,
the lateral borders, the dorsum, and the undersurface (non-villous ventral surface of
the tongue) (20).
The tongue is formed of complex mixture of various intrinsic and extrinsic
muscles. Intrinsic muscles are made up by longitudinal, transverse, vertical, and
oblique fibers, which are not connected with any structure outside the tongue. The
tongue is sagittally divided in two halves by the fatty midline lingual septum. The
extrinsic muscles have their origin external to the tongue and include the
genioglossus (chin), hyoglossus (hyoid bone), and styloglossus (styloid process)
muscles. Both intrinsic and extrinsic muscles of the tongue receive their innervation
from the (XII) hypoglossus nerve except palatoglossus muscle, which is innervated
by the pharyngeal branch of vagus nerve (X). Sensory fibers are carried by the lingual
nerve, a branch of the (V) mandibular nerve (Figure 2) (23).
5
Figure 2: Lateral view

of the tongue showing
extrinsic muscles and
its nerves(24)
The lymphatic drainage of the tongue can be grouped into three groups:
l The tip drains to the submental then jugulo-digastric (JD) nodes
l The anterior two-thirds and lateral borders drain to the submental and
submandibular nodes and thence again to the JD and other lower nodes of the
deep cervical chain along the carotid sheath
l The posterior one-third drains to the upper nodes of the deep cervical chain.
There is a little anastomosis across the midline between the lymphatics of the
anterior two-thirds of the tongue, in contrast to the posterior one third (Figure 3).
2.
The Floor of the Mouth

This is a semilunar space extending from the inner surface of the lower
alveolar ridge to the undersurface of the tongue. Its posterior boundary is the base of
anterior pillar of the tonsil (20).
It is composed of the extrinsic muscles of the tongue along with the mylohyoid
and geniohyoid muscles. The mylohyoid muscle forms a sling that serves as the main
supporting structure. The posterior free edge of the mylohyoid muscle provides a
pathway for both neoplastic and infectious processes to extend from the sublingual
space (situated above the mylohyoid muscle) to the submandibular space (situated
6
below the mylohyoid muscle) and vice versa (Figures 4, 5, 6). No fascial margin
separates the posterior submandibular space and sublingual space from the inferior
parapharyngeal space. The major lymphatic drainage of the floor of the mouth is to
the submental, submandibular, and/or internal jugular nodes (levels 1 and 2).
Figure 3: Diagram of lymph

drainage of the tongue(24)
3.
Buccal Mucosa and Cheek

This includes all the membrane lining of the inner surface of the cheeks and
lips from the line of contact of the opposing lips to the line of attachment of mucosa
to the alveolar ridge (upper and lower) and pterygomandibular raphe (20).
Figure 4: Coronal
section in the floor of
the mouth (24).
Figure 5: Schematic
diagram showing the
deep spaces of the face
on the right and some
of their contents on the
left (25).
The main structural component of the cheek is provided by the buccinator

muscle (Figure 6). This muscle arises from the alveoli of the maxilla and mandible,
as well as from the pterygomandibular raphe. Anteriorly, the buccinator muscle
extends to contribute to the orbicularis oris. It is pierced by the parotid duct that
enters the oral cavity opposite the second maxillary molar. Lateral to the buccinator is
the buccal fat pad, which extends between the masseter and temporalis muscles
(muscles of mastication) (21).
Both masseter and lower part of temporalis muscles are contained in clinicallyimportant space called the masticator space (MS) (Figure 5), which is a fascial
8
compartment, bounded by the superficial layer of deep cervical fascia, and contains,
in addition, the pterygoid muscles and posterior body and ramus of the mandible. The
temporo-mandibular joint (TMJ) lies in the upper part of the masticator space (26).
4.
Retromolar Trigone (RMT)

RMT (or retromolar gingiva) is a triangular region bordered anteriorly by the
posterior surface of the last mandibular molar tooth postero-medially by the anterior
tonsillar pillar, and laterally by the buccal mucosa. Its apex superiorly is attached to
the pterygoid hamulus. The mucosa of the retromolar trigone is separated from the
adjacent ascending mandibular ramus by the buccal fat pad (Figure 7) (26). Hence;
tumors should be carefully assessed for bone involvement as there is minimal tissue
between the overlying mucosa and eriostemon of the mandible (21).
5.
Alveolar Ridges and Gingivae

The alveolar ridges represent bony extensions from the maxilla, superiorly and
mandible inferiorly. The upper alveolar ridge refers to the mucosa overlying the
alveolar process of the maxilla while the lower alveolar ridge refers to the mucosa
overlying the alveolar process of the mandible (20).

Figure 6: A coronal image through the cheek showing the mucosa, muscle, fat pad,
masseter, and a cross-section of the tongue and floor of mouth (21).
Figure 7: Trans-oral view of the alveolar ridge, retromolar region, and mandible of
the left side of the oral cavity (21).
10
Figure 8: Vestibule and gingivae

of the mandible (27).
The gingiva is composed of fibrous tissue covered with a mucous membrane. It

overlies both the medial lingual and lateral buccal or labial aspects of the
alveolar processes of the mandible and maxilla. Two distinct parts have been
described for the gingiva (Figure 8). The gingiva proper or attached gingiva is the
part firmly attached to the alveolar processes as well as the necks of the teeth. It is
formed of keratinized epithelium. In contrast, the loose gingiva is the less attached
part of the alveolar mucosa that continues into the maxillary and mandibular sulci. It
appears shiny red and formed of non-keratinized epithelium. As the alveolar mucosa
approaches the necks of the teeth, it changes in texture and color to become the
gingiva proper (27).
The junction of the gingiva with the buccal mucosa is termed the
gingivobuccal sulcus and is a common location for squamous cell carcinoma (SCC)
of the oral cavity (28).
6.
Hard Palate
This is the semilunar area between the upper alveolar ridge and mucous
membrane covering the palatine process of the maxillary palatine bones. It extends
11
from the inner surface of the superior alveolar ridge to the posterior edge of the
palatine bone (20).
The bony structure of the hard palate, which consists of the horizontal portions
of the palatine bones and the palatine processes of the maxillae, is covered with
periosteum that is tightly adherent to the overlying mucosa (21).
Cancers of the hard palate and alveolar ridge have a low metastatic potential
and involve buccinator, submandibular, jugular, and occasionally retropharyngeal
nodes (20).
Regional Lymph Nodes

I. Anatomical Considerations
Lymphatics of the head and neck are organized into two circles or cylinders: an
outer one that contains the superficial nodes extending from the chin to the occiput
(Figure 9) (the submental, submandibular, buccal, mandibular, pre-auricular, and
occipital nodes) and an inner one that lies within the outer one and surrounds the
upper aerodigestive tract. Specifically, the nodal groups included in the inner circle
are the retropharyngeal, pretracheal, and paratracheal nodes (28).
Lying vertically between these two circles and accompanying the internal
jugular veins are the deep cervical (jugular chain) nodes, into which virtually all of
the lymph from both the inner and outer circles of nodes drains (Figure 9) (28).
Two nodes are of special importance. The first is the jugulo-digastric (JD)
node, which receives lymph from the tonsils, pharynx, mouth, and facial region. As a
result of numerous infections in its drainage area, this node tends to be hyperplastic
and larger than most other lymph nodes. The second node is the jugulo-omohyoid
(JO) node, which receives all of the lymph from the tongue, and if enlarged, it may be
12
the first physical finding to suggest an otherwise clinically silent tongue tumor
(Figure 9) (28).
Figure 9: Lymph vessels and nodes of the head and neck(29)
II. AJCC Nodal Classification

The Head and Neck Service at Memorial Sloan-Kettering Cancer Center has
described a leveling system of cervical lymph nodes (Figure 10), which was adopted
by the American Joint Committee on Cancer (AJCC). This system divides the lymph
13
nodes in the lateral aspect of the neck into five nodal groups or levels. In addition,
lymph nodes in the central compartment of the neck are assigned levels VI and VII:
Level I: Contains the submental and submandibular triangles bounded by the
posterior belly of the digastric muscle, the hyoid bone inferiorly, and the body of the
mandible superiorly.
Level II: Contains the upper jugular lymph nodes and extends from the level
of the skull base superiorly to the hyoid bone inferiorly.
Level III: Contains the middle jugular lymph nodes from the hyoid bone
superiorly to the cricothyroid membrane inferiorly.
Level IV: Contains the lower jugular lymph nodes from the cricothyroid
membrane superiorly to the clavicle inferiorly.
Level V: Contains the lymph nodes in the posterior triangle bounded by the
anterior border of the sternocleidomastoid (SCM) muscle anteriorly and the clavicle
inferiorly. For descriptive purposes, level V may be further subdivided into upper,
middle, and lower levels corresponding to the superior and inferior planes that define
levels II, III, and IV.
Level VI: Contains the lymph nodes of the anterior compartment from the
hyoid bone superiorly to the suprasternal notch inferiorly. They lie between the
medial borders of the carotid sheaths.
Level VII: Contains the lymph nodes inferior to the suprasternal notch in the
upper mediastinum (28).
14
Figure 10: Schematic diagram

indicating the location of the lymph
node levels in the neck (20).
15
Chapter 2: Overview of Oral Cavity Carcinoma
Overview of Oral Cavity Carcinoma

The oral cavity is a common site for squamous cell cancers of the upper
aerodigestive tract (UADT), probably because it is the first entry point for many
carcinogens; therefore, the incidence may vary according to cultural habits. OSCC
tends to spread regionally to lymph nodes of the submandibular region (Level I) and
to the upper and middle jugular chain lymph nodes (Levels II and III). OSCC may be
less sensitive to chemotherapy and radiation relative to oropharyngeal or laryngeal
cancers, moreover it can be readily accessible to surrounding bony structures. Thus,
primary treatment for most tumors is surgical. Adjuvant treatment by radiotherapy
(RT) or chemoradiotherapy (CRT) is given in advanced and high risk patients.
Follow-up for detection of residual or recurrent tumor is mandatory in view of the
limitations of current anatomical modalities following combined treatment modalities
(30).
Epidemiology of OSCC
Incidence
Oral cancer holds the eighth position in the cancer incidence ranking
worldwide, with epidemiologic variations between different geographic regions (1).
The World Health Organization expects a worldwide rising OSCC incidence in the
next decades (2). In the US, OSCC represents 2-4% of the annually diagnosed
malignancies, being responsible for 8,000 deaths every year (31). In some western
European countries, such as Belgium, Denmark, Greece, Portugal, and Scotland,
there has been an upward trend in the incidence of OSCC. Increasing mortality rates
have been observed for at least two decades in Eastern Europe, where OSCC
comprises a real public health issue (32).
16
According to the National Cancer Institute in Egypt, oral cavity cancer (and
pharynx) represented 5.5% of the newly diagnosed cancer cases in 2002-2003 (704
male and 311 female cases) (33).
In Taiwan, OSCC is currently ranked fourth in cancer incidence and fifth in
cancer mortality among Taiwanese men (34).
Mortality rate from oral cancer has increased significantly, from 4.25 per 100
000 in 1995 to 9.6 per 100 000 in 2006, a 2.26-fold increase in the past decade (35).
Endemic use of betel quid chewing in Taiwan may account for the different
subsite distribution of oral cancer observed in this study. Approximately 40-50% of
oral cavity cancers in our series originated from buccal and retromolar areas (34).
Risk Factors
The development of oral squamous cell cancer (OSCC) is a multistep process
involving the accumulation of multiple genetic alterations modulated by genetic predisposition and environmental influences such as tobacco and alcohol use, chronic
inflammation, and viral infections. The alterations mostly affect two large groups of
genes: oncogenes and tumor suppressor genes, which can be either inactivated or
over-expressed through mutations, loss of heterozygosity, deletions, or epigenetic
modifications such as methylation (36).
Most published reports indicate that age, gender, race, tobacco use, alcohol use
(especially tobacco and alcohol in combination), presence of a synchronous cancer of
the upper aerodigestive track, poor nutritional status, and infection with certain
viruses, all increase the relative risk for developing an oral cancer. Exposure to some
of these extrinsic risk factors varies significantly between ethnic groups and
geographic locations globally and regionally.
1.
Age
More than half of all oral cancer is diagnosed in individuals over the age of 65;
however, several investigators have reported an increase in oral cancers diagnosed in

17
younger patients (37-39). In Taiwan, the peak incident rate in the period from 1989 to
1993 was for people aged 5059 years, but this shifted to 4049 years between 1993
and 2000. A similar trend was also found in the mortality rate (35).
2.
Gender
Incidence rate for oral cancer is between two and four times higher for men
than women for all racial/ethnic groups except for Filipinos where the rates are
similar for the two genders (40).
A study analyzing 703 OSCC patients between 1985 and 1996 in southern
Taiwan found a 51:1 male-to-female ratio (41). This gender difference may be
explained by the lower proportion of betel quid chewing habits in females. Concerns
about the disfiguring effects of areca quid chewing (including red staining of lips and
teeth and foul-smelling breath) are frequently reported by females, which may
account for sex differences in HNC prevalence (35).
3.
Race
When compared with the United States, higher rates of oral cancer have been
reported in India, Southeast Asia, Hungary, and northern France. Lower OSCC
incidence rates are reportedly found in Mexico and Japan 3.
HNC is highly prevalent in South-east Asia, comprising 3540% of all
malignancies in India, compared with approximately 9% in Taiwan and 24% in
Western countries 5.
Before age 55, oral cancer is the sixth most common cancer in white men but is
the fourth most common cancer in black men (40).
4.
Presence of Other Upper Aerodigestive Track Cancers

When a cancer of the upper aerodigestive track is found, it is important to
assess the patient for the presence of another primary malignancy of the associated
structures. Several researchers have reported that patients with an OSCC have a
greater risk for a synchronous or metachronous malignancy of the upper
aerodigestive track (42, 43).
18
5.
Tobacco
Depending on the product, tobacco contains more than 50 established or
potential carcinogens that may increase relative risks for cancers by differing
mechanisms (e.g. causing mutations that disrupt cell cycle regulation or through an
effect on the immune system).
The risk of developing OSCC is five to nine times greater for smokers than for
nonsmokers, and this risk may increase to as much as 17 times greater for extremely
heavy smokers of 80 or more cigarettes per day. In addition, treated oral cancer
patients who continue to smoke have a two to six times greater risk of developing a
second malignancy of the upper aerodigestive tract than those who stop smoking (4).
Beginning smoking at a younger age increases the risk for developing an oral
mucosal squamous cell carcinoma.
Smoking bidis, which are small hand-rolled cigarettes very famous in India and
other Asian countries, is another significant risk factor (28).
The greatest risk for several forms of OSCC is found with reverse smoking,
which is to keep the lit end of the cigar or cigarette in the mouth. This form of
smoking is frequently found in India, southeastern Asia, some parts of Africa, and
central and South America. It creates a more severe heat-related alteration of the
palatal mucosa known as reverse smokers palate (Figure 16), which has been
associated with a significant risk of malignant transformation (44).
Figure
11:
Palatal
lesion
associated with reverse smoking.
Note the crate-like ulcerated areas
covered with fibrin (45).
19
Spit (smokeless) tobacco is another type of tobacco that is usually placed

inside the mouth for chewing or can be snuffed; however, it is associated with
minimal risk for oral cancer (46).
Qat (khat or gat), which is evergreen plant originating from plant Catha edulis,
is very famous tradition in Yemen, Kenya, Madagascar, and Sudan. It might increase
the risk for oral cancer although most studies were confounded by the use of tobacco
(47-49).
6.
Alcohol
Alcohol abuse seems to be the second largest risk factor (after smoking
tobacco) for developing OSCC. A strong correlation exists between excessive alcohol
consumption, cirrhosis of the liver, and oral/pharyngeal cancers. Nutritional
deficiencies associated with heavy alcohol consumption also increase the relative risk
for developing OSCC. In studies controlled for smoking, moderate-to-heavy drinkers
have been shown to have a three to nine times greater risk of developing oral cancer
(50).
The relationship between oral cancer and alcohol consumption seems to be
independent of the type of alcohol consumed and is associated more directly with the
amount of ethanol consumed and the length of time that alcohol has been used.
Patients who are both heavy smokers and heavy drinkers can have over one hundred
times greater risk for developing a malignancy (51).
A cumulative effect from chewing betel quid (which is a traditional habit in
some parts of Asia, and consists of betel leaf wrapped around a mixture of areca nut
and slaked lime usually with tobacco), alcohol drinking and tobacco smoking has
been observed, with a 123-fold increased risk of oral cancer when the three risk
factors are present (52).
20
7.
Viruses
Although great progress has been seen over the last few decades, the
complexity of the viral role in carcinogenesis is not understood completely. However,

viruses do act, at least as cofactors, in several different malignancies.
Evidence suggests that human papillomavirus (HPV) may be associated with
some oral and oropharyngeal cancers (53). HPV-16 and HPV-18 have been detected
in up to 22% of oral cancers (54).
Epidemiological survey in Taiwan has shown that HPV16, HPV18, betel quid
chewing and tobacco smoking were statistically significant risk factors for OSCC.
Multivariate analysis identified HPV16 and betel quid chewing as independent
predictors of oral cancer (55).
Some studies have shown that also EBV may be related to oral cancers,
including SCC (56).
8.
Miscellaneous
Dietary factors, such as a low intake of fruits and vegetables, may also be
related to an increased cancer risk (57, 58).Iron deficiency anemia in combination

with dysphagia and esophageal webs (known as Plummer-Vinson or Paterson-Kelly
syndrome) is associated with an elevated risk for development of carcinoma of the
oral cavity, oropharynx, and esophagus (59).
21
Chapter 3: Pathology of Oral Cavity Carcinoma
Pathology of Oral Cavity Carcinoma

Both keratinized and non-keratinized epithelium share in the formation of oral
mucosa. It is stratified keratinized squamous epithelium over the attached gingiva,
hard palatal mucosa, and specialized keratinized gustatory mucosa of the dorsum of
the tongue, while it is non-keratinized type over mucosal surfaces of the inner lips
and cheeks, loose gingiva, ventral tongue, floor of the mouth, and soft palate (60).
The epithelium is three to four times the thickness of skin epidermis. Beneath
the epithelium is the lamina propria of fibrous tissue and blood vessels, underneath
which, in turn, is the densely fibrous periosteum of the hard palate or the alveolus of
the maxilla and mandible. The term submucosa is sometimes loosely applied to the
deep connective tissue just above the muscle layer, in which the minor salivary
glands are often embedded (60).
The transition from normal squamous epithelium to invasive SCC is a
comprehensive and multistage process that involves distinct histological changes
called squamous intraepithelial lesions (SILs) which are causally related to
progressive accumulation of genetic changes. Particular interest should be focused on
potentially malignant or precancerous SILs. These lesions have been defined as
histomorphological disorders of the squamous epithelium which changes to invasive
cancer in significantly higher percentage than from other epithelial lesions (61).
I.
Precancerous Lesions of oral cavity

1.
Oral Leukoplakia (OL)

As defined by the World Health Organization (WHO), leukoplakia is a white
patch or plaque that cannot be scraped off or characterized clinically or

pathologically as any other disease(62).
22
OL is seen most frequently in middle-aged and older men, with an increasing

prevalence with age. Less than one percent of men below the age of 30 have OL, but
the prevalence increases to an alarming eight percent in men over the age of 70. The
prevalence in women past the age of 70 is approximately two percent (63).
The most common sites are the buccal mucosa, alveolar mucosa, and lower lip;
however, lesions in the floor of mouth, lateral tongue, and lower lip are most likely to
show dysplastic or malignant changes. The frequency of dysplastic or malignant
alterations in OL has ranged from 15.6 to 39.2 percent in several studies (4).
OL is divided clinically into homogenous and non-homogenous types. The
former type is characterized as a uniform, flat, thin lesion with a smooth or wrinkled
surface showing shallow cracks, but a constant texture throughout. The latter type is
defined as a predominantly white or white and red lesion that may be irregularly flat,
nodular or exophytic (Figure 11) (61).
(A)
(B)
Figure 12: Oral leukoplakia: (A) Gross picture showing numerous lesions that have
become virtually confluent. (B) Microscopic picture showing marked epithelial
thickening and hyperkeratosis
Sometimes OL occurs in combination with adjacent red patches or
erythroplakia. If the red and white areas are intermixed, the lesion is called a
speckled leukoplakia or speckled erythroplakia or erythroleukoplakia which is
23
believed to carry relatively increased risk for dysplasia and malignant transformation
(14-52%) (4).
Proliferative verrucous hyperplasia (PVL) is a special type of OL with a
proven high risk of becoming malignant. The diagnosis is made retrospectively after
evidence of a progressive clinical course, accompanied by a particular deterioration
in histological changes. It appears most frequently in the buccal mucosa, followed by
the gingiva (Figure 12), tongue, and floor of the mouth. A mean time of 7.7 years
was found from the diagnosis of PVL to cancer development in 70.3% of patients
(64). The treatment of PVL continues to be an unsolved problem with high rates of
recurrence, since total excision is rarely possible because of the widespread growth
(61).
Figure
13:
Proliferative
verrucous
leukoplakia involving the buccal gingiva (4).
Another disturbing finding is that OL is more likely to undergo malignant

transformation in non-smokers more than in smokers. This should not be interpreted
to detract from the well-established role of tobacco in oral carcinogenesis, but may
indicate that nonsmokers who develop leukoplakia do so as a result of other more
potent carcinogenic factors (4).
2.
Erythroplakia (Dysplastic Leukoplakia)

Erythroplakia is a clinical term that refers to a red patch that cannot be defined
clinically or pathologically as any other condition (62). It occurs most frequently in

24
older men. The floor of mouth, lateral tongue, retromolar area, and soft palate are the
most common sites of involvement.
It represents a red, velvety, possibly eroded area within the oral cavity that
usually remains level with or may be slightly depressed in relation to the surrounding
mucosa. The epithelial changes in such lesions tend to be markedly atypical,
incurring a up to 50% risk of malignant transformation (65).
3.
Nicotine Stomatitis
Nicotine stomatitis is a thickened, hyperkeratotic alteration of the palatal
mucosa, sometimes developing a fissured surface (Figure 13); the changes are
caused by the intense heat generated from pipe and cigar smoking (4).
Figure 14: Nicotine Stomatitis:

Rough, white, fissured appearance
of the hard and soft palate in a
heavy pipe smoker.
The red, punctate areas represent
the inflamed openings of the minor
salivary gland ducts (4).
It is not considered to be premalignant and it is readily reversible with

discontinuation of the tobacco habit. However, a more severe form can happen with
reverse smoking habit and known as reverse smokers palate. This is associated with
a significant risk of malignant transformation (4).
4.
Oral Submucous Fibrosis

Submucous fibrosis is a disease that produces progressive, scarring and
changes similar to those of scleroderma but is limited to oral tissue. It presents as a

whitish yellow discoloration with readily palpable fibrous bands especially in the
25
buccal mucosa (35). The development of squamous cell carcinoma has been noted in
as many as one third of patients with submucous fibrosis (66).
5.
Tobacco Pouch Keratosis

It typically occurs in the buccal or labial vestibule where the tobacco is held in
people who practice snuffing or chewing smokeless tobacco. True epithelial dysplasia
is uncommon (4).
II.
Squamous Cell Carcinoma (SCC)

In the early stages, cancers of the oral cavity appear either as raised, firm,
pearly plaques or as irregular, roughened, or verrucous areas of mucosal thickening,
possibly mistaken for leukoplakia. Either pattern may be superimposed on a
background of apparent leukoplakia or erythroplakia. As these lesions enlarge, they
create protruding masses or undergo central necrosis, forming an irregular, shaggy
ulcer rimmed by elevated, firm, rolled borders (Figure 14) (65).
Figure 15: Squamous cell carcinoma of the lateral tongue

(Gross & microscopic view) (66).
On histologic examination (Figure 14), these cancers begin as in situ lesions,
sometimes with surrounding areas of epithelial atypicality or dysplasia. They range
from well-differentiated keratinizing neoplasms to anaplastic, sometimes sarcomatoid
tumors. Four grades are described:
G1: well-differentiated
G2: moderately well-differentiated.

26
G3: poorly-differentiated
G4: undifferentiated
As a group, they tend to infiltrate locally before they metastasize to other sites,
and the tumor depth considered one of the most important prognosticators. The routes
of extension depend on the primary site. Favored sites of metastasis are mediastinal
lymph nodes, lungs, liver, and bones. Unfortunately, such distant metastases are often
occult at the time of discovery of the primary lesion (65).
Any part of the oral mucosa can be the site of development of squamous cell
carcinomas. The common oral locations can show wide variations in different
geographical areas depending on the prevalent risk factors (22).
1.
Lip
Lip carcinomas account for 25% to 30% of all oral cancers. They appear most
commonly in patients between 50 and 70 years of age and affect men much more
often than women. Some components of lipstick may have sunscreen properties and
account, in part, for this finding. Lesions arise on the vermilion and typically appear
as a chronic non-healing ulcer or as an exophytic lesion that is occasionally verrucous
in nature. Deep invasion generally appears later in the course of the disease.
Metastasis to local submental or submandibular lymph nodes is uncommon but is
more likely with larger, more poorly differentiated lesions (66).
From a biologic viewpoint, carcinomas of the lower lip are far more common
than upper lip lesions. UV light and pipe smoking are much more important in the
cause of lower lip cancer than in the cause of upper lip cancer. The growth rate is
slower for lower lip cancers than for upper lip cancers. The prognosis for lower lip
lesions is generally very favorable, with over 90% of patients alive after 5 years. By
contrast, the prognosis for upper lip lesions is considerably worse (66).
27
2.
Tongue
Globally, the tongue is the most common oral location of SCC and can account
for 25% to 40% of OSCC. It has a definite predilection for men in their sixth,
seventh, and eighth decades (66). The majority affects the middle third of the lateral
border and adjacent ventral surface. Lingual tumors are often exophytic and
ulceration is common. Even clinically small tumors can infiltrate deeply into the
underlying muscle. With progressive growth, tumors become indurated and
frequently develop characteristic rolled, raised, everted margins. Infiltration of the
lingual musculature may cause pain, dysphagia and dysphonia (22).
Half of patients have regional lymph node metastases at presentation. Tumors
towards the tip of the tongue drain to the submental and thence to the jugulo-digastric
lymph node, and those located on the dorsum and lateral borders tend to involve the
submandibular and jugulo-digastric nodes (22) Contralateral or bilateral spread is
relatively common; however, growths more than 12mm from the midline usually do
not metastasize to the opposite side of the neck till late in the disease (24).
3.
Floor of the Mouth

Floor of the mouth is the second most common intraoral location of SCC,
accounting for 15% to 20% of cases. It occurs predominantly in older men, especially
those who are chronic alcoholics and smokers. The usual presenting appearance is
that of a painless, non-healing, indurated ulcer (66); however, this site shows the
highest frequency of small and symptomless tumors (22). It is more frequent in the
anterior segment and tends to spread superficially rather than deeply; occasionally the
lesion may infiltrate deeply in the soft tissues, causing decreased mobility of the
tongue. Involvement of the submandibular duct can cause obstructive sialadenitis
(22). It tends to metastasize early to submandibular lymph nodes (66).
28
4.
Buccal Mucosa
Although buccal cancer is not common in Western Countries, it forms the
second most common intra-oral cancer in India and Taiwan (35).

The majority of carcinomas arise from the posterior area, soon spread into the
underlying buccinator muscle and though insidious initially they may eventually
cause trismus. Bone, however, is generally involved only in advanced tumors.
Tumors at this site often extend posteriorly into the palatoglossal fold and tonsillar
fossa. Metastases are most common in the submandibular, submental, parotid and
lateral pharyngeal lymph nodes (22).
5.
Gingiva and Alveolar Ridge

Tumors at this site can be exophytic resembling dental abscesses or epulides,
or ulcerated and fixed to the underlying bone. They account for about 20% of oral
tumors. In parts of the USA there is a very high frequency in women who practice
snuff dipping. Related teeth are often loosened and there is extension along the
periodontal ligament. On the alveolus tumors can resemble simple lesions like
denture-induced hyperplasia or denture-related ulceration. The underlying bone may
be eroded or invaded in 50% of patients and regional metastases are seen in over half
the patients at presentation (22).
6.
Retromolar Trigone (RMT)

Tumors from this site spread to the buccal mucosa laterally and distally involve
the tonsillar area. They can penetrate into the para-pharyngeal area and may show
extensive spread along the lingual and inferior alveolar nerves. In addition, tumors
frequently erode or invade the adjacent mandible (22).
29
7.
Hard Palate
This is a relatively uncommon site of involvement except in areas where
reverse smoking is common. Tumors at this site can be exophytic or ulcerative, but
tend to spread superficially rather than deeply (22).
III.
Verrucous Carcinoma (VC)

Verrucous carcinoma is a low-grade variant of OSCC and comprises
approximately 3-5 percent of all primary invasive carcinomas of the oral mucosa. The
buccal mucosa is the location for more than half of all cases, and the gingiva is the
location for nearly one third of cases. There is a distinct male predominance, and
most individuals are over 50 years of age (66).
It is closely associated with the use of tobacco in various forms, especially
smokeless tobacco. A role for HPV in either a primary or an ancillary relationship is
suspected. Identification of intra-tumor HPV DNA adds support for a possible role of
this virus in tumor development (66).
The tumor presents as a diffuse, thickened plaque or mass with a warty or
papillary surface (Figure 15). The lesion is usually white, although some examples
with less keratinization may appear pink. In tobacco users, tobacco pouch keratosis
may be seen on the adjacent mucosal surfaces; in non-users of tobacco may arise
from lesions of PVL (4).
30
Figure 16: Verrucous carcinoma.

White, exophytic, warty mass of the
maxillary alveolar ridge (22).
Microscopically, it shows markedly acanthotic and highly keratinized

epithelial surface with well-differentiated epithelial masses extending into the
submucosa. Occasionally, there are lymphocytic infiltrates and focal areas of acute
inflammation surrounding foci of well-formed keratin (66).
Because VC is slowly-growing, exophytic, and well differentiated, it is
associated with a much better prognosis than conventional SCC. Treatment usually
consists of surgical excision without the need for neck dissection because metastasis
is rare. However, local recurrences may develop and require re-excision. Also,
lesions that arise from PVL may recur and undergo dedifferentiation into a more
aggressive conventional SCC (4).
Staging of the Lip and Oral Cavity Cancer

(T) Classification
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ.
T1 Tumor 2cm or less in greatest dimension.
T2 Tumor more than 2cm but not more than 4 cm in greatest dimension.
31
T3 Tumor more than 4 cm in greatest dimension.

T4a (Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of
mouth, or skin of face, i.e., chin or nose.
T4a (Oral Cavity) Tumor invades adjacent structures e.g. through cortical bone,
into extrinsic muscles of tongue (genioglossus, hyoglossus, palatoglossus, and
styloglossus), maxillary sinus, or skin of face. It worth noting that superficial erosion
alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as
T4.
T4b Tumor involves masticator space (MS), pterygoid plates, or skull base
and/or encases internal carotid artery. It is considered inoperable.
(N) Classification of the Neck Lymph Nodes
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest
dimension.
N2 Metastasis in a single ipsilateral lymph node more than 3 cm but not more
than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more
than 6cm in greatest dimension; or in bilateral or contralateral lymph nodes, none
more than 6cm in greatest dimension.
N2a Metastasis in single ipsilateral lymph node more than 3 cm but not more
than 6 cm in greatest dimension.
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in
greatest dimension.
32
N2c Metastasis in bilateral or contra-lateral lymph nodes, none more than 6 cm

in greatest dimension.
N3 Metastasis in a lymph node more than 6 cm in greatest dimension.
It should be kept in mind that most masses larger than 3 cm in diameter are not
single nodes but are confluent nodes or tumors in soft tissues of the neck and that the
three stages of clinically positive nodes are N1, N2, and N3. The use of subgroups a,
b, and c is not required but is recommended.
The main routes of lymph node drainage are into the first station nodes (i.e.,
buccinator, jugulo-digastric, submandibular, and submental). Second station nodes
include the parotid, jugular, and the upper and lower posterior cervical nodes.
Midline nodes are considered ipsilateral.
Regional lymph nodes should also be described according to the level of the
neck that is involved. It is recognized that the level of involved nodes in the neck is
prognostically significant (lower is worse) (20).
Once tumor penetrates the nodal capsule, it extends into the adjacent soft
tissues. This tumor growth has been referred to as extracapsular spread (ECS), and it
is associated with poor prognosis and decrease in survival. Histologically, such
disease was found in 23 percent of lymph nodes less than 1 cm in greatest length
(67).
Metastatic Sites:
The risk of distant metastasis is more dependent on the N than on the T status
of the head and neck cancer. The lungs are the commonest site of distant metastases;
skeletal and hepatic metastases occur less often. Mediastinal lymph node metastases
are considered distant metastases (20).
33
Stage Grouping
Stage 0 : Tis, N0, M0
Stage I :
T1, N 0, M 0
Stage II :
T2, N 0, M 0
Stage III : T3, N0, M0 or T1-2 , N1, M0

Stage IVA: T4a, N0-1, M0 or T1-3, N2, M0
Stage IVB: Any T, N3, M0 or T4b, any N, M0
Stage IVC: Any T, any N, M1
34
Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma
Diagnosis of OSCC
National Comprehensive Cancer Network (NCCN) guidelines recommend the
following procedures for the staging work-up:
History and complete physical examination including a complete head and

neck exam; mirror and fiberoptic examination as clinically indicated
Biopsy
Chest X-ray
CT with contrast and/or MRI with contrast of primary and neck as indicated
Consider PET-CT for stage III-IV disease
Examination under anesthesia, if indicated
Dental evaluation, including panorex as indicated
Nutrition, speech & swallowing evaluation/therapy as indicated
Multidisciplinary consultation as indicated (3).
A general medical evaluation is performed, including a thorough head and

neck examination by one or more physicians. The location and extent of the primary
tumor and any clinically positive cervical lymph nodes is documented. Almost all
patients will undergo contrast-enhanced CT and/or MRI to further delineate the
extent of local and regional disease. There is some preference to use CT and reserve
MRI for situations where further information is required. The scan(s) should be
obtained prior to biopsy so that changes from the biopsy are not confused with tumor.
A chest x-ray is obtained to determine the presence of distant metastases and/or a
synchronous primary lung cancer. Patients with N3 neck disease, as well as those
with N2 adenopathy with adenopathy below the level of the thyroid notch, have a
20% to 30% risk of developing distant metastases and should be considered for a
chest CT or PET (68).
35
For tumors amenable to transoral biopsy, such as those in the oral cavity,
biopsy may be performed using local anesthetics in the clinic. Otherwise direct
laryngoscopy under anesthesia is performed to determine the extent of the tumor and
to obtain a tissue diagnosis (68).
Before initial treatment, the patient should be evaluated by members of the
team who may be involved in the initial management as well as possible salvage
therapy. Head and neck surgeons, radiation oncologists, medical oncologists,
diagnostic radiologists, plastic surgeons, pathologists, dentists, speech and
swallowing therapists, and social workers may all play a role. The treatment options
are discussed and recommendations are presented to the patient who makes the final
decision (68).
Treatment Outlines for OSCC

According to NCCN (3), surgery is the main stay for resectable OSCC. Postoperative RT/CRT is indicated in the presence of adverse features extracapsular
nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease,
selected pT2N0-N1 disease, nodal disease in levels IV or V, perineural invasion,
vascular embolism (69).
With adequate excision, the resection margins should be at least 2 cm clearance
from gross tumor or clear frozen section margins. In general, frozen section
examination of the margins will usually be undertaken intraoperatively if a margin
has less than 2 cm clearance from the gross tumor, a line of resection has uncertain
clearance because of indistinct tumor margins, or there is suspected residual disease
(i.e., soft tissue, cartilage, carotid artery, or mucosal irregularity) (69).
A clear margin is defined as the distance from the invasive tumor front that is 5
mm or more from the resected margin. A close margin is defined as the distance from
the invasive tumor front to the resected margin that is less than 5 mm (69).
36
Either preoperative or postoperative irradiation-based therapy may be used;

there are advocates of each. Analysis of available data suggests there is no difference
in local, regional control or survival rates comparing the two sequences (68).
Preoperative radiation therapy should be considered for the following
situations: (1) fixed neck nodes, (2) if initiation of postoperative radiotherapy will be
delayed by more than 8 weeks due to reconstruction, and (3) open biopsy of a
positive neck node (68).
Postoperative radiation therapy is considered when the risk of recurrence above
the clavicles exceeds 20%. The operative procedure should be one stage and of such
magnitude that irradiation is started no later than 6 to 8 weeks after surgery. The
operation should be undertaken only if it is believed to be highly likely that all gross
disease will be removed and margins will be negative. The currently recommended
approach is to use 60 Gy in 6 weeks to 66 Gy in 6.5 weeks for patients with negative
margins and fewer than three indications for radiation therapy. For patients with close
(less than 5 mm) or positive margins, 70 Gy in 7 weeks or 74.4 Gy at 1.2 Gy twice a
day is recommended (68).
The advantages of postoperative compared with preoperative radiation therapy
include less operative morbidity, more meaningful margin checks at the time of the
operation, a knowledge of tumor spread for radiation treatment planning, safe use of a
higher radiation dose, and no chance the patient will refuse surgery (68).
Chemotherapy has been integrated with surgery or radiation in a variety of
ways
including
induction/neoadjuvant;
concurrent
with
radiation;
and/or
maintenance/adjuvant. There is increasing trend for using concomitant cisplatin

chemotherapy for patients with positive margins and/or extracapsular extension (68).
Outlines for management of OSCC are summarized as follows:
1.
Lip
Early lesions may be cured equally well with surgery or radiation. Surgical
excision is preferred for the majority of lower lip lesions up to 2 cm in diameter that
37
do not involve the commissure; the treatment is simple and the cosmetic result is
satisfactory (68).
Removal of more of the lip with simple closure usually results in a poor
cosmetic and functional result and therefore requires reconstructive procedures.
Irradiation is often preferred for lesions involving the commissure, for lesions over 2
cm in length, and for upper lip carcinomas. Advanced lesions with bone, nerve, or
node involvement frequently require a combined approach (68).
The regional lymphatics are not treated electively for early cases. Advanced
lesions, high-grade lesions, and recurrent lesions should be considered for elective
neck treatment (68).
2.
Floor of the mouth

Operation or radiation therapy is equally effective treatment for T1 or T2
lesions. Most patients are treated surgically because of the risk of soft tissue or bone
necrosis after irradiation (68).
The usual recommendation for moderately advanced anterior midline lesions is
rim resection or segmental mandibulectomy and osteomyocutaneous free flap
reconstruction; postoperative irradiation is added as dictated by the findings in the
specimen. The neck, with clinically negative nodes, is usually managed by bilateral
functional neck dissection for midline lesions (68).
3.
Oral Tongue
A partial glossectomy with primary closure or a skin graft may be done
transorally and is usually the preferred therapy. Depending on the depth of invasion,
an elective neck dissection may be indicated. RT is reserved for cases with adverse
features (68).
The preferred treatment for the majority of patients with T2 or T3 is partial
glossectomy, neck dissection, and postoperative radiotherapy. In contrast, combined
38
treatment with surgery and radiation therapy may cure very few T4 patients. Most
patients in this category will receive palliative therapy (68).
4.
Buccal Mucosa
Small lesions (1 cm or smaller) may be excised with primary closure; small
lesions that involve the lip commissure are sometimes treated by radiation therapy.
Lesions 2 to 3 cm in size can be treated with surgery or by radiation therapy, usually
the former. Larger lesions are usually treated with surgery and postoperative
radiotherapy (68).
5.
Lower Gum
The majority of lesions are managed by operation. Postoperative irradiation
may be indicated depending on pathologic findings (68).
6.
Retromolar Trigone
Surgery is preferred for discrete early lesions. Radiation therapy is
recommended for superficial lesions involving a large surface area. Advanced

carcinomas are treated with surgery and postoperative irradiation (68).
7.
Upper Gum and Hard Palate

Resection is the usual treatment for most lesions; postoperative radiation
therapy is added as needed. However, if the lesion is superficial and extensively

involves the hard palate or involves a significant portion of the soft palate, then
radiation should be considered for the initial therapy. Bone invasion requires a partial
maxillectomy. The defect usually is repaired with a prosthesis (68).
39
Chapter 5: Prognostic Factors in Oral Cavity Carcinoma
Prognostic Factors in Oral Cavity Carcinoma

A lot of factors may modify disease outcome in OSCC. These have been
grouped into three main groups: patient-, tumor- and treatment related (70).
I.
Patient-Related Prognostic Factors:

1.
Gender
Most published data showed no prognostic differences between females and
males (71-74); however, a Brazilian study reported lower survival rates in females,
which might be attributed to delay in seeking medical care and lower acceptance of
treatment (75).
2.
Age
The prognostic role of age is rather controversial. Many studies showed no age
difference in prognosis (71, 73). Old age (> 50 years) was linked to worse prognosis
in some reports (76-78), but that seems to be related to co morbid disease rather than
age itself. Reports showing the bad prognosis in young age (< 40 years) have been
published (37-39, 79, 80).
3.
Smoking and Drinking:

Most authors report higher mortality in smokers and alcohol drinkers. A large
Swedish case-control study identified smoking and alcohol as risk factors for OSCC.
Also they showed that female smokers have a greater risk for recurrence than male
smokers at any level of tobacco consumption (81).
Smokers and alcohol drinkers seem to be at higher risk for the development of
second primary oral cancer than nonsmokers and nondrinkers, thus facing more
onerous outcomes (42).
40
4.
Chewing Betel Quid:

Liao et al (71) found that chewing betel quid is an independent prognostic
factor for poor local control. Lo et al (74) reported about 20% higher relative risk of
death in this category, which is increased up to 5 times with drinking alcohol and
smoking cigarettes.
5.
Miscellaneous Factors:
Poor oral hygiene, depressed host immunity, comorbid chronic conditions and
weight loss have been associated with bad prognosis (82, 83) (84-86). However, there
is no consensus on which comorbidity index should be used and how this data may
complement the current TNM staging system (87-89).
II.
Tumor-Related Prognostic Factors:

1.
Site:
Different tumor subsites carry different implications in prognosis. Lip cancer is
generally readily curable compared with malignancies at other head and neck sites
(90). Tiwari (91) reported poorer prognosis in superior gingivolabial sulcus tumors,
because cancer at this location has high propensity for lymphatic spread especially
with the involvement of the parapharyngeal and retropharyngeal lymph nodes which
makes surgical therapy difficult and prognosis is often poor. Reports on buccal cancer
prognosis were controversial. Sieczka et al (92) suggested the use of definitive and
vigorous treatment, not only for the more advanced buccal squamous cell cancers, but
for early lesions as well. They considered the typical disease markers (T-stage and
histologic margin) not to be wholly reliable indicators of success with surgical
treatment. Comparable results were reported by others (93). However, these results
were challenged by other authors (71, 94). In a series of 276 patients, Liao et al (71)
reported a 5-year local control rate and disease specific survival of 86% & 78%
41
respectively. It worth noting that buccal cancers represent about 10% in Europe and
USA, while it is considered the most common subsite in India and Southern Asia and
regarded as having favorable prognosis. Hence, the interpretation of the prognostic
data is difficult because the effects of differences in staging and treatment approaches
in addition to varying tumor behavior and presentations in different regions of the
world.
2.
Stage:
OSCC staging is based on TNM system. The vast majority of authors accept
that disease staging has a crucial influence on the outcome (95). Lo et al. described 5year survival rates of 75%, 65.6%, 49%, and 30% for disease stages I, II, III, and IV,
respectively (74).
The presence of cervical lymph node metastasis is the single most adverse
independent prognostic factor in HNSCC. Cervical node metastases may be classified
into 2 distinct categories: overt (clinical) or non-overt (occult, subclinical). The latter
may be even subpathological or submicroscopic metastases, which is detectable
only by immunohistochemical and/or molecular analysis of the dissected lymph
nodes. It is yet to be determined what is the clinical impact of detecting these
submicroscopic occult lymph node (96). The incidence of occult metastases varies
according to T-stage and ranges from 13% for T1 to 46% for T4 (97).
3.
Tumor Thickness:
The risk of nodal metastases, ECS and mortality rates vary directly with the
thickness of the primary tumor and may be more important than clinical and
pathological staging (98, 99). However, the cut-off marking decimal prognosis varies
between studies. Huang et al, in their meta-analysis, considered a 4-mm tumor
thickness to be predictive of nodal metastases and recommended prophylactic
management (100). In another meta-analysis (101), a cut-off from 3 up to 10 mm was
linked to poor progression free and overall survivals. This report especially
42
emphasized the importance of standardizing measurement technique for tumor

thickness among studies (Figure 17).
Figure 17: Methods of measuring tumor thickness.

Left: exophytic cancer; right: ulcerative cancer. In all types, tumor thickness is
measured to the deepest point of invasion, the starting point varies according to the
method of measurement, in A & D: from the summit of tumor surface (exophytic
type) or floor of the ulcer (ulcerative type); B & E: from the level of adjacent intact
mucosa; C & F: from the level of basal membrane (101).
In a series of 827 patients, Liao et al. showed that DSS was significantly lower
when the tumor thickness was 10 mm or more (69% vs. 91%). They measured the
tumor from the deepest point to the basal membrane and referred to as tumor depth.
They also suggested that tumor depth, rather than tumor size, should be included in
the pathological tumor staging system (71).
4.
Extracapsular Spread:
Extracapsular spread (ECS) is indicted when irregular nodal boundaries,
infiltration of adjacent fat planes, thickening of adjacent fascia, and apparent invasion
of adjacent structures are present. CT has been shown to be more specific in
determining extracapsular spread and remains the study of choice for evaluating neck
disease (102).
ECS was noted in the majority of the lymph nodes larger than 3 cm and in
about 40% of clinically and up to 16% of clinically N0 patients (103).
43
ECS was significantly higher with large primary tumor size (> 4 cm), poor
differentiation, close and involved surgical margins and positive perineural invasion
(103).
In1971, Bennet et al. showed that aerodigestive tumors with ECS indicate a
poor prognosis (104). Since that time, it has been widely documented that patients
with OSCC & ECS have a high risk of regional recurrence and distant metastasis, and
hence, reduced survival (105). According to NCCN guidelines, the presence of ECS
is an indication for post-operative RT or chemoradiation (69). Some authors try to
stratify the risk within the patients with OSCC and ECS. Liao et al. found that within
all the patients with OSCC and ECS, those with level IV/V metastases appear to have
the worst prognoses (5-year DFS, DSS, and OS rates were 14%, 12%, 10%) (72).
5.
Histologic Differentiation:
Most authors have established significant correlations between lower histologic
differentiation and poorer prognosis (71, 74, 83) but others did not find such
association (75).
6.
Perineural Invasion:
Perineural invasion apparently correlates with higher probability of regional
and distant metastases, higher depth of tumor invasion, lower differentiation, and
lower 5-year survival rates in OSCC (106, 107).
7.
Angiogenesis:
The vascular endothelial growth factor (VEGF) is a key component in tumor
angiogenesis, and 4 subtypes have been described (A, B, C, and D). Recently
Shintani et al. described its expression in OSCC, correlating subtypes A and B with
tumor angiogenesis and subtypes C and D with the risk of nodal metastases (108).
Marked angiogenesis correlated well with the risk of nodal metastases and it is
considered an independent predictor of tumor recurrence (109).
44
8.
Human Papilloma Virus (HPV):

A large study conducted by Gillison et al. has shown that patients with HPV-
positive tumors had a 60% reduction in risk of death from cancer and significantly
improved disease-specific survival when compared patients with HPV-negative
tumors (110). Schwartz et al. also found a strong association between the presence of
HPV-16 DNA in OSCC and prolonged survival (111). These findings support the
theory that HPV-positive OSSC may represent a distinct molecular, biologic, and
clinical identity.
III.
Treatment-Related Prognostic Factors:

1.
Resection Margin:
The surgical resection margin is considered clear or free when the distance
from the invasive tumor front that is 5 mm or more from the resected margin (69).
A strong correlation has been demonstrated between a resection margin free of
disease and higher survival rates (112). It was reported that the 5-year DSS of
patients with a positive margin was poorer by 12% than for those patients with a
negative margin (113). Close margins (45 mm) may represent risk factors for local
tumor control, and that patients with close margins should receive adjuvant therapy
(114).
2.
Post-operative Chemoradiation:
The role of chemotherapy in the postoperative management of the patient with
adverse prognostic risk factors has been clarified by 2 separate multicenter

randomized trials (115, 116) and a combined analysis of data from the 2 trials (117).
The US Intergroup trial -the Radiation Therapy Oncology Group (RTOG) trialrandomly assigned patients with 2 or more involved nodes, positive margins, or ECS
to receive standard postoperative radiotherapy or the same radiotherapy plus cisplatin
45
100 mg/m2 every 3 weeks for 3 doses (115). The European Organisation for
Research and Treatment of Cancer (EORTC) trial was designed using the same
treatment but also included as high-risk factors the presence of perineural or
perivascular disease and nodal involvement at levels 4 and 5 from an oral cavity or
oropharynx cancer (116). The RTOG trial demonstrated statistically significant
improvement in locoregional control and disease-free survival but not overall
survival, whereas the EORTC trial found significant improvement in survival and the
other outcome parameters. Both the RTOG and EORTC trials use high-dose cisplatin
(100 mg/m2 every 3 weeks).
To better define risk, a combined analysis of prognostic factors and outcome
from the 2 trials was performed. This analysis demonstrated that patients in both
trials with ECS of tumor and/or positive resection margins benefited from the
addition of cisplatin to postoperative radiotherapy. For those with multiple involved
regional nodes without extracapsular spread, there was no survival advantage (117).
3.
Cervical Lymph Node Dissection:

This procedure is a source of significant postoperative morbidity, namely
shoulder dysfunction. Furthermore, recently published work asserts that sparing 1 or

both internal jugular veins is associated with a reduction in mortality rates, not
endangering the prognosis (96).
46
Chapter 6: PET Imaging
PET Imaging
Positron emission tomography (PET) is a powerful metabolic imaging
technique utilizing possibly many radiopharmaceuticals; however the mostcommonly used one is
18
F-fluorodeoxyglucose (FDG). It yields excellent quality
images and has an enormous clinical impact, a demonstrated in many well-conducted

studies.
PET Radiopharmaceuticals
There are several positron-emitting radioisotopes that have been used for PET
imaging (Table 1). A medical cyclotron can be used to produce C-11, N-13, O-15,
and F-18, and then various labeling techniques are applied. Fluorine, the fourth entry
in the table, is the most commonly used one (118).
Table 1: Common + emitters of clinical importance (118).

Synthesis of FDG is an automated computer-controlled radiochemical process
that takes approximately 50 minutes to complete.
47
FDG is a radiopharmaceutical analog of glucose that is taken up by

metabolically active tumor cells using facilitated transport similar to that used by
glucose (Figure 18). Like glucose, it undergoes phosphorylation to form FDG-6phosphate; however, unlike glucose, it does not undergo further metabolism, thereby
becoming trapped in metabolically active cells. Uptake of FDG in tumor cells is also
influenced, among other factors, by tumor hypoxia and blood glucose level (119).
Figure 18: Mechanism

of FDG uptake
Normal PET Imaging

Normal physiologic uptake of 18F-FDG can be seen to some extent in every
viable tissue (Figure 19), including the brain, myocardium (where the uptake is
significant in some patients despite prolonged fasting), breast, liver, spleen, stomach,
intestines, kidneys and urinary bladder, muscle, lymphoid tissue (e.g., tonsils and
adenoids), bone marrow, salivary glands, thymus, uterus, ovaries, testes, and brown
adipose tissue (120).
48
Figure 19: Normal PET/CT scan (121).

The head and neck region presents some unique challenges for several reasons,
including the large number of anatomic structures in this region, their small size, and
the prominent yet variable physiological FDG uptake seen within some of these
normal structures. To effectively and accurately interpret PET or fused PET/CT
scans, a comprehensive knowledge of physiologic and altered physiologic FDG
uptake in the head and neck is essential.
1.
Oral Cavity and Lymphoid Tissues

Physiological uptake within the tongue and oropharynx is seen in the shape of
an inverted "U" on the midline sagittal view (Figure 20), within which three more
prominent foci of uptake are seen:
The first is the most prominent and caused by the sublingual glands and hyoid
muscle (mylohoid) insertions on the mandible (Figure 21).
The second is formed by uptake in the soft palate, as well as the opposed
surface of the tongue. This is shown axially in (Figure 22).
49
The third focus of more prominent uptake is a result of uptake within the
lingual tonsil and the base of the tongue (Figure 21) (Burrell and Van den
Abbeele; 2005).
Uptake in the tonsils can be particularly prominent in children and in adults
with some attach of pharyngitis or tonsillitis (Figure 23) (122).

Figure 20: Midline
sagittal
view
with
different H. & N.
structures (122).
Figure
21:
Most
prominent uptake in the
sublingual glands and
mylhyoid
muscle
insertions (122).
Figure 22: Uptake in the

soft palate (122).
50
Figure 23: Left: Palatine tonsils

uptake, Right: uptake in the
pharyngeal
tonsil
(adenoids)
(122).
2.
Brown Fat and Skeletal Muscles

Variable uptake may be demonstrated within the skeletal muscles of the head
and neck; some of this uptake is also within brown fat (123).
Uptake in the sternocleidomastoid muscle and at muscular insertion sites into
the occipital bone is commonly seen (Figure 24). Also, uptake in the trapezius,
intercostal muscles may be seen (124).
Figure 24: Focal uptake at insertion of muscles into the occipital bone. Uptake is
also seen in the sternocleidomastoid muscles (SCM) and parotid glands (124).
Intense
asymmetric
FDG
uptake
can
also
be
seen
within
the
sternocleidomastoid muscle (Figure 25) and can mimic an enlarged lymph node
(125).
51
Figure 25: Asymmetric sternocleidomastoid muscle uptake. (A) Axial CT right

sternocleidomastoid muscle (arrow). (B) Fused PET-CT scan localizes the
FDG uptake to the right sternocleidomastoid muscle (arrow). Note also the
symmetric FDG uptake within the prevertebral strap muscles (arrowheads)
(126).
Muscles of the mastication also can show asymmetry in their uptake (Figure
26).
Figure 26: Asymmetric increased uptake in the muscles of mastication.
52
3.
Laryngeal Uptake
A horizontal band of uptake corresponding to the base of the vocalis muscles
or the transverse arytenoid muscle is frequently seen. Two discrete foci are seen
posteriorly, corresponding with the convergence of the various arytenoid muscles.
The appearance vocal cords is quite variable, however normal uptake should be
relatively symmetric (Figure 27) (122).
Figure 27: Physiologic uptake in the vocalis

muscle, arytenoid muscles and symmetric
vocal cord uptake (122, 126).
4.
Osseous Uptake
In bones composed predominantly of cortical bone, such as the skull, mandible
and maxilla, FDG uptake is virtually absent. In bones containing a large proportion of
marrow, mild-to-moderate FDG uptake is typically seen (e.g. the vertebral bodies)
(122). Discrete foci of uptake within the maxilla and mandible are frequently seen
(Figure 28), almost invariably because of periodontal/dental disease (127).
53
Figure 28: Axial view of FDG-PET showing

periodontal/dental (127).
5.
Orbits
Within the orbits, uptake is frequently seen at the apex as a result of uptake at
the convergence of the extra-ocular muscles. Uptake may also be seen throughout the
length of the extra-ocular muscles (127).
6.
Thyroid gland
Observable uptake in 34% of patients undergoing PET imaging for non-thyroid
malignancies was detected. Diffuse thyroid uptake may indicate Graves disease or
thyroiditis, although it can also be seen in clinically euthyroid patients
Focal thyroid uptake is relatively nonspecific (Figure 29) and has been
reported in benign entities such as toxic thyroid adenoma as well as in thyroid
malignancies (126).
(A)
(B)
Figure 29: (A) Hypermetabolic thyroid adenoma at the left lobe; (B) Hrthle
cell carcinoma at the right lobe (126).
54
7.
Thymus
Benign uptake in the thymus is frequently seen in children and young adults. It
is usually diffuse, homogeneous, and bi-lobed in appearance (128).

8.
Salivary Glands
Mild-to-moderate FDG uptake is usually seen within all salivary glands
(Figure 30).
(A)
(B)
Figure 30:
Physiologic uptake in
the parotid (A) and
submandibular glands
(B) (126).
Limitations of FDG PET in Head and Neck Cancer

1.
Physiologic FDG Uptake

Physiological FDG uptake, as above mentioned, and uptake in muscles that are
contracting or tensed during the uptake phase (e.g., in anxious or talkative patients,
excessive cough.. etc) may lead to false-positive findings and symmetry alone is not a
reliable indicator of physiologic processes (129). However, combined PET/CT allows
direct correlation of FDG uptake with anatomic structures to reduce false positive
results (130).
2.
Inadequate Scanner Resolution

Even with combined PET/CT, the spatial resolution of PET limits the accurate
characterization of lesions to those over approximately 6-8 mm in diameter "2 times

the system resolution" (131).
55
3.
Recent Surgery and Inflammatory Response

Surgery may incite variable inflammatory response in the surrounding tissue.
This inflammation may result in increased glycolysis and therefore be associated with
increased FDG uptake (132).
Figure 31: Inflammatory FDG

uptake at the site of
tracheostomy.
At least one-fifth of false-positive foci of post-surgical FDG uptake occurred at

sites of known infection, inflammation or granuloma (5).
(A)
(B)
Figure 32: Dental abscess in a patient with history of squamous cell carcinoma of the
left side of the tongue base. (A) CT scan shows no abnormality in the alveolar ridge
of maxilla (B) PET-CT scan shows a focal area of intense FDG uptake in the site of
infected tooth (arrow) (130).
4.
Effect of Radiation and Chemotherapy

After radiotherapy, there is typically increased uptake within the soft tissues
most obvious in the region of the hypopharynx, and decreased uptake within the bone
marrow and finally. Increased uptake within the salivary glands is frequently seen
(122).
56
Delaying the PET study to at least 6 weeks post-radiation is necessary for

better discrimination (133).
(A)
(B)
(C)
Figure 29: Residual neoplasm after treating a squamous cell carcinoma of the right
side of the tongue base and neck.
(A) PET-CT scan obtained 3 12 weeks after radiation therapy shows linear, intensely
increased FDG uptake in the right side of the neck (arrow), and interpreted as
treatment-related changes. (B&C) PET-CT scans obtained 4 months later show
globular increased FDG uptake in the same location (arrow), as well as increased
FDG uptake anteriorly (C) (130).
5.
Low FDG Avidity

Salivary gland and spindle cell neoplasms inherently show low FDG uptake.
Also necrotic neoplasms and lymph nodes may yield false-negative results (130).
Recent high-dose steroid therapy as well as hyperglycemia and hyper-insulinemia
may affect the tumor avidity for FDG (120).
6.
PET/CT Artifacts
a.
Metal Artifacts
Metallic devices, including dental implants, create areas of photopenia on PET
scans (127). In contrast, with use of current CT-based attenuation correction

algorithms, these areas can demonstrate falsely elevated FDG uptake (134).
57
b.
Contrast Material
Dense contrast material is present in venous structures during CT but not
during the PET portion of the examination. This mismatch causes areas of linear
artifact (mimicking intense FDG accumulation) on the attenuation-corrected PET
scans. Occasionally, this artifact can appear focal and mimic a metastatic lymph node
in the axilla or supraclavicular area (Figure 33). A relatively simple means of
resolving any diagnostic uncertainty regarding the presence of a CT-based
attenuation artifact is inspection of the raw uncorrected emission data (134).
(A)
(B)
(C)
Figure 33: CT attenuation artifact from an implantable catheter port.

(A) Corrected coronal PET scan demonstrates focal intense FDG accumulation in
the right supraclavicular area (arrow). (B) Axial fused PET-CT scan helps localize
the FDG activity to an implanted catheter port (arrow). (C) Axial uncorrected
emission image confirms that the abnormality (arrowhead) is an attenuation
correction artifact (126).
c.
Truncation Artifacts
Truncation artifacts in PET/CT are due to the difference in size of the field of
view between the CT and PET tomographs. These artifacts are frequently seen in
large patients or patients scanned with arms down, such as in the case of head and
neck indications (Figure 61). It results in absence of attenuation correction values for
the truncated region in the PET emission data, hence introducing a bias on the PET
attenuation-corrected images that underestimates the standardized uptake values in
these regions. Truncation also produces streaking artifacts at the edge of the CT
58
image, resulting in an overestimation of the attenuation coefficients and creating a

rim of high activity at the truncation edge (134).
Figure 34: Truncation artifact

Difference (A) in maximum transverse field of view of CT (blue) and
PET (orange) may lead to truncation artifacts as seen in images (B).
(B) CT, uncorrected, and corrected PET. (C) Truncated attenuation
information may be recovered before CT-based attenuation correction
(135).
59
Chapter 7: Qualitative and Quantitative Parameters from PET
Qualitative and Quantitative Parameters from PET

Generally, the parameters derived from FDG PET scan can be divided into
qualitative, quantitative and semiquantitative indices.
I.
Qualitative Assessment
Qualitative assessment involves simple visual analysis of a static scan by the
reporter. Interpretation is based on contrast in uptake between a lesion and

surrounding tissues and is dependent on uptake time, blood glucose and insulin
levels, and also the nature of the surrounding tissues. The reference of uptake is
usually either the non-diseased liver, or mediastinal blood pool activity. Different
scores have been introduced, but all are dependent mainly on physicians experience
and lacking objectivity. Although it may be suitable for some routine clinical work, it
is often insufficient for clinical trials where objective parameters of response are
usually required and recommended (136, 137).
Dual phase scanning may be useful in differentiating inflammatory or normal
tissue uptake which shows decreased or stationary uptake over time, versus
possible malignant tissue which shows increased uptake. The first time is usually
obtained after 50 to 60 minutes and the delayed phase is at 90 or 120 minutes from
injection. This technique has proven useful in single pulmonary nodule (138), pleural
disease (139) and some other clinical situations (140-149).
In head and neck cancers, dual phase imaging may be valuable in post-therapy
setting where it is difficult to distinguish recurrent disease from post-treatment
reactions (150). It is also reported to increase the confidence in differentiating
malignant lesions from inflammation and normal tissues at initial staging (151).
However, in patients with untreated nasopharyngeal carcinoma, it contributes no
further information in the detection of primary tumors or loco-regional metastatic
nodes (152).
60
Although the technique is relatively well cited, it has not been incorporated in
any of the known guidelines for FDG PET tumor imaging (120, 153), also there is
lack of homogeneity in published literature regarding the optimal time of second
phase, and the exact methodology for objective assessment of its results.
II.
Quantitative Assessment
Full quantitative data from PET scans necessitates the use of dynamic scanning
with complex kinetic analysis, which seems more appropriate for drug development
trials rather than clinical work (154).
III.
Semi-quantitative Assessment
Semiquantitative indices include standardized uptake values (SUVs) in
different formats, and recently metabolic tumor volumes have been used. There is
general agreement that semiquantitative techniques are superior to qualitative
assessment alone in -at least- monitoring treatment response and are probably
sufficient for routine clinical work (136, 137, 155).
1.
Standardized Uptake Value

The SUV is a unitless ratio that can be understood as the concentration of FDG
within a lesion divided by the concentration of radiotracer distributed throughout the

body. Mathematically, it can be expressed as follows:
SUV = C (T)/(dose injected/body weight)
Where C is the tissue concentration of FDG at time T. An SUV is a simplified
index of FDG uptake and provides a relative indication of the degree of metabolism
within the lesion being evaluated. SUV can be notated as the maximum value within
a lesion (SUVmax), the average value within a region of interest (ROI) drawn around
a lesion (SUVavg), or the highest value within a fixed-sized ROI (SUVpeak) (156).
The SUVmax is more robust because it is more reproducible, being less affected by
61
the size and placement in the ROI (131). However, SUVmax is highly dependent on
the statistical quality of the images and the size of the maximal pixel (157).
However, the SUV is affected by multiple factors that include time interval
between FDG administration and scanning, size of the ROI used to make the SUV
calculation, serum glucose level, extravasation of radiotracer which alters wholebody distribution, and patient obesity (11). Another major problem is the partial
volume effect (PVE), which simply indicates that some portions of a tomographic
image containing part of one anatomic structure and part of another, mixed together,
so that there might be spill-in from a nearby active uptake or spill-out from the
source or target lesion itself and hence part of its activity is seen outside, leading to
mis-identification of tumor border. This effect typically occurs whenever the tumor
size is less than 3 times the system resolution full width at half maximum (FWHM)
of the reconstructed image resolution(158).
The SUV is usually normalized to body weight, but lean body mass and body
surface area are being used as well. It has been advocated that SUV normalized to
body surface area might be more appropriate during longitudinal studies in case of
weight loss during therapy (136, 137, 155, 159, 160). The most accurate method for
SUV normalization is still a matter of debate, but the method should be standardized
for follow-up and multicenter trials.
ROI selection is a key aspect of determining tumor SUV. A wide variety of
SUV ROI selection metrics has been used: manually defined ROIs; irregular
isocontour ROIs based on a fixed percentage of the SUVmax in the tumor (e.g., 41%,
50%, 70%, 75%, or 90% of the maximum); irregular isocontour ROIs based on a
fixed SUV threshold (e.g., SUV 2.5, SUV 3); irregular isocontour ROIs based on a
background-level threshold (e.g., relevant background + 23 standard deviations
[SDs]) (156).
62
2.
Total Lesion Glycolysis

The concept of total lesion glycolysis (TLG) was first introduced by Larson
and Ginsberg in their published work in 1999, and they named it Larson Ginsberg
Index (LGI) (12). It was defined as Average SUV of the lesion times the metabolic
tumor volume (MTV). The main objectives of measuring the uptake within the
whole volume, rather than a single pixel value in case of SUVmax, is to overcome
tumor heterogeneity and better assess the gross tumor.
The major obstacle to the wide implementation of TLG is the method used to
measure the MTV. PET images are fuzzy and the exact tumor border is hard to
delineate (161). Broadly, two main approaches were employed for segmenting the
PET images that is to identify tumor border from non-tumor; visual segmentation
method and automatic and semi-automatic segmentation methods.
A.
Visual Assessment Method

This is the most commonly employed method for target delineation (162).
Nuclear medicine physicians determine the nature and margins of lesions after
adjusting the window level, often with reference to the FDG uptake within the normal
organs, such as the liver. Although this method may be reliable in excluding
physiological and inflammatory uptake of FDG, it is largely operator dependent and
is prone for inter-observer as well as intraobserver variations. The use of a standard
contouring protocol with predefined window and color settings can help to reduce the
variations in the target definition (163, 164).
B.
Automated or Semi-Automated Methods

The idea behind these techniques is an algorithm that identifies what is tumor
from what is background based on certain criteria. Two major problems with this
approach: first, there is lack of pathological gold standard and so validation studies
are almost totally based on phantom studies; and second, the segmentation algorithms
63
cannot differentiate physiological and inflammatory uptake from tumor uptake (161,
164).
Although there are many different methods for image segmentation e.g.
thresholding, region growing, clustering, Markov Random Fields modeling, edgedetection methods, and statistical classification methods, but generally four different
approaches were implemented: SUV-based methods, thresholding, background cutoff and source-to-background algorithms.
SUV-Based Contouring
Some authors employ an absolute SUV value to define what is tumor from
what is non-tumor e.g. an SUV of 2.5 (165). However, this method suffers the
problems of SUV itself regarding accuracy and reproducibility.
Thresholding
This method involves outlining the lesion by a regular outline or free
contouring outlines, then applying a given fixed percent intensity level relative to the
maximum activity within the original outline. However, a fixed threshold value in the
commonly reported range of 4050% can lead to significant errors in the volume
estimation and underestimation of large tumors (166, 167).
Background Cut-off
This method involves defining a cut-off with respect to the background and
contouring the region with intensity above the cut-off (e.g. intensity greater than
three standard deviations above the background level). This approach is independent
of heterogeneity of lesional tracer uptake, which could hamper the application of
threshold methods. However, the assessment of activity in the lesion and in the
background and the robustness of the contour definition are strongly affected by
statistical fluctuations and image noise (156).
Source/Background Algorithms
64
It was found that optimum thresholds varied according to the contrast of the
lesion i.e. signal-to-background (S/B) ratios rather than SUV of the lesion (168).
The difference between S/B ratio and SUV is that the S/B reflects the background
specific activity of the local normal tissue, rather than assuming that the activity is
uniformly distributed over the whole body in case of SUV (169). Gradient-based
methods rely on a model that determines the appropriate threshold of activity on the
basis of S/B ratio (170). The determined volumes according to this method were by
far the closest to the reference volume assessed from few surgical laryngectomy
specimens using non-retraction fixation methods (171).
Originally, the volume calculation method adopted by Larson et al (12) was
based on the algorithm developed by Erdi et al (169) to determine the volumes of
metastases to the lung from PET images, under conditions of variable background
activity. In clinical application, the optimum threshold obtained from this method
requires a priori estimation of the lesion volume from anatomic images such as CT
(169).
Although this method seems to be the most encouraging, it is markedly
affected by image noise and reconstruction and a consistent algorithm should be
strictly applied.
65
Chapter 8: Clinical Role of PET in Oral Cavity Carcinoma
Clinical Role of FDG-PET in Oral Cavity Carcinoma

Both qualitative and quantitative indices from PET scanning are used together
in different clinical scenarios starting from staging, therapy monitoring, restaging,
risk stratification and follow-up. There is a progressive shift from the use of PET to
the combined PET/CT, which is especially advantageous for the complex anatomy in
this area (172). The possible clinical role of FDG-PET scan in oral cavity cancer
patients is discussed in the following section.
I.
Staging
1.
Primary Tumor
The precise identification, localization, and delineation of size and anatomic
extent of a primary lesion is very important to correctly plan surgical interventions

and radiation treatment. The recommendation of NCCN is to do CT with contrast
and/or MRI with contrast of the primary tumor and neck. PET/CT should be
considered for stage III-IV disease (69). It is also reported that PET/CT might
increase confidence in determining the extent of the primary lesion (130, 173).
Several studies have addressed the ability of FDGPET to image primary
tumor sites in the head and neck. FDGPET has detection rates that range from 88 to
98% (174, 175). Hannah and coworkers performed PET and CT for 40 patients with
HNSCC (32 of them were in the oral cavity), FDGPET detected 35 of 40 primary
tumors (88%) compared with CT, which only detected 18 of the 35 primary tumors
imaged (51%). Of the 17 primaries that were not detected by CT scan, 11 were
visualized by FDG PET (174). Differences between FDGPET and anatomic
imaging (CT or MRI) may be related to the fact that smaller or submucosal
malignancies may be difficult to distinguish from adjacent normal tissues with
anatomic imaging studies alone.
Although it is known that PET/CT has little to provide for staging the primary
tumor in the presence of optimized CT/MRI studies, it may be valuable in two
66
clinical situations: the detection of bone invasion and the presence of metal artifacts.
Pentenero et al. studied 23 patients and found that PET/CT scan was able to correctly
exclude bone involvement in 3 cases reported by CT and MR to be positive (173).
Goerres et al. studied 34 patients by CE-CT, SPECT/CT and PET/CT. They reported
a negative predictive value (NPV) of 100% for detecting bone invasion by PET/CT in
OSCC (176). Similar results obtained by Babin et al. (177). In a recent study with
larger series of 114 patients, PET/CT was more specific, though less sensitive, than
MRI in detecting bone marrow invasion. It was suggested that PET/CT could be used
to rule out disease (178).
Patients with OSCC frequently have some metal artifacts from dental filling or
prosthesis. It is established that such artifacts can degrade the image quality and
hamper the accurate estimation of tumor extension (179). Baek et al. studied 69
patients with OSCC and dental artifacts by PET/CT, CE-CT and MRI. They found
that PET/CT detected significantly more primary tumors than did CE-CT, but no
difference was noted when compared to MRI (180). Ng et al. prospectively studied
124 patients with OSCC and found that PET could successfully identify the primary
tumor in 122 patients compared to 108 for CT/MRI. Metal artifacts obscured the site
of primary tumors in 7 out of these 16 false negative CT/MRI results (181). Also
Superior contrast resolution of FDG uptake in PET/CT images may be especially
valuable in this subgroup of patients, but large-scale prospective studies are needed to
further establish its exact role and the possible clinical impact.
2.
Neck Lymph Nodes

For diagnosis of possible neck LN metastases, CT and MRI depend primarily
on descriptive criteria such as size, central necrosis and peripheral contrast

enhancement. They frequently have false negative rates between 10 and 30%. Many
borderline-sized nodes without necrosis, therefore, remain indeterminate and larger
reactive nodes may be read as positive (182-184).
67
The role of PET/CT in assessing the cervical N-status is still debatable.

Nakasone et al performed PET and CT/MRI for 25 patients with oral cancer. They
found no difference between PET and CT/MRI for nodal staging (179). Seitz et al
found similar diagnostic accuracy parameters between PET/CT and MRI in their
prospective analysis of 90 patients (185) and so was seen by Yoon et al. in a
retrospective comparison of PET/CT, US, CT and MRI for 67 patients. On the other
hand, Piao et al. reported a sensitivity and specificity of 84% and 91%, respectively,
in a prospective report of 56 patients OSCC (186). Other studies reported comparable
diagnostic indices, but they included patients from different head and neck subsites
(174, 187-189).
In a large recent study by Liao et al (190), they prospectively enrolled 473
patients with OSCC who were treated surgically. 18F-FDG PET correctly diagnosed
164 of 211 patients with neck metastases and 152 of 262 patients without pathologic
neck metastases, resulting in a modest sensitivity and specificity of 77.7% and
58.0%, respectively. Pathological LN size was less than 1 cm in 41 out of 47 false
negative PET results.
It was reported that PET has little to provide in clinically N0 oral cancer and
sentinel lymph node should be the investigation of choice (190-193). Schoder et al.
reported more encouraging results in 31 patients who were diagnosed as N0
according to clinical examination and CT/MRI. The prevalence of occult metastases
was 25% (9/31 patients). PET/CT demonstrated lymph node metastases in more than
one half of the instances (6/9). On the basis of lymph node levels, the sensitivity for
disease detection was 67%, with a specificity of 95%. The low sensitivity is attributed
to the low disease prevalence and heavy prescreening by examination and CT/MRI
(194).
Wensing et al (195) studied 28 OSCC patients with clinically negative neck.
Occult metastatic disease was found in 30% of supra-omohyoid neck dissection
(SOHND) specimens. Average diameter of metastatic deposits was 4.3 mm.
68
Sensitivity, specificity, and accuracy of FDG-PET was 33%, 76%, and 63%,
respectively.
Ng et al also studied 134 patients prospectively by PET and CT/MRI and
found that PET was twice as sensitive as CT/MRI for detecting cervical nodal
metastasis in OSCC patients with palpably negative neck. The probability of still
having occult metastases after PET was reported to be 6.7% for T1, 10.8% in T2
13.3% in T3 and 25% in T4 (97).
Studies comparing the diagnostic accuracy of PET/CT to the conventional
modalities lack consistency in methodology, starting from the PET machines used,
imaging and reconstruction protocols, data interpretation, selecting patients for neck
dissection and also the method of pathological examination and sectioning. PET/CT
seems to have some potential disadvantages. First, PET still has resolution limitations
and is not likely to be able to detect small metastatic nodes. It worth noting that more
than 50% of neck metastases from OSCC is less than 1 cm in diameter. Even with the
newer machines with better resolution, the problem of partial volume effect may still
underestimate SUV value in small lesions and subsequently falsely reported to be
negative. Second, nodal necrosis may cause false-negative findings on PET because
of the low glycolytic activity of the necrotic material. Third, false-positive PET
results may be caused by inflammatory processes in benign lymph nodes (196).
3.
Distant Metastases
The clinical impact of PET as a staging tool partly lies in detecting
unsuspected metastases or second primary tumor, consequently changing the

management. Yen et al. reported a 2% reduction in futile surgery when they
prospectively randomized 102 patients with buccal cancer to either PET and
conventional work-up (CWU) or CWU alone (197). In a study by Goerres et al,
distant lesions were seen in 6% with PET imaging in bone, lung, mediastinum, liver
and colon. A secondary cancer was detected in 12% of patients (198). Schmid and
69
coworkers studied patients with advanced HNSCC and found that the addition of
PET to initial staging evaluation resulted in a change in management in
approximately 8% of patients (199).
It has been suggested that routine work-up to detect distant metastases in
patients with HNSCC may not be feasible; however, in advanced stage (III-IV)
disease the probability of distant metastases is relatively high (200) and PET/CT may
be considered (69).
II.
Restaging and Therapy Monitoring

Generally, the post-surgical/post-therapy head and neck is a difficult region to
evaluate with conventional imaging. Local therapy results in inflammation with or
without edema and/or hemorrhage, production of granulation tissue and fibrosis, and
soft tissue vasculitis. Enlarged reactive and inflammatory nodes may be present,
normal anatomic landmarks may be absent, contrast-enhancing granulation tissue
may form, and post-therapy fibrotic changes may mimic residual or recurrent tumor.
Anatomic resolution of disease may lag behind the metabolic resolution, resulting in
residual masses and nodes that do not have malignancy and an inability to fully
evaluate therapy response with anatomic imaging alone (131).
Metabolic characterization with glucose utilization is a very sensitive, specific,
and accurate method to determine the presence of viable tumor and to assess the
given therapy; because FDG accumulation is closely related to cellular density,
proliferation indices (e.g. Ki-67 and MIB1), and tumor size, which are supposed to
express biologic tumor characteristics (131, 201).
Even though FDGPET interpretation may also be complicated in this
posttreatment setting, it has been found to be the most sensitive method for detecting
recurrence. The negative predictive value is high enough to rule out the disease,
however a positive study necessitates either close follow-up or biopsy (5, 150, 202204).
70
Klabbers and coworkers compiled a detailed analysis of all FDG-PET studies

for detection of residual and recurrent head and neck tumors after radiation and/or
chemoradiation published between 1994 and early 2003. The weighted average for
sensitivity and specificity for PET was 86% and 73% respectively, compared with
56% and 59% for CT and/or MRI (205).
Most of these studies enrolled patients with head and neck cancer in any of the
subsites and also they were enrolled when there is clinical suspicion for recurrence. It
is known that the advantage of a test lies partly in its ability to detect subclinical
recurrence when it is otherwise unlikely to be demonstrated (206).
Although some authors advocate the routine use of PET study at 12 months
(206), others prefer selection of patients for post-therapy PET/CT, which may result
in better specificity and positive predictive value.
Moeller et al (207) prospectively studied 98 patients with HNSCC by PET/CT
and CT at 8 weeks after finishing their RT. They found that positive and negative
predictive values of FDG-PET/CT scanning were similar to those for CT alone in the
unselected study population. They suggested FDG-PET/CT might be the imaging
modality of choice for patients with highest risk disease (T3-4, N2-3, stage III, IV)
particularly those with HPV-negative tumors.
Few studies limited the inclusion criteria just to oral cancer patients. Kunkel et
al (208) studied 97 patients with resected OSCC. The overall sensitivity of a PET
scan was 90% and its specificity varied from 67% for local disease recurrence/second
primaries to 99% for lymph node metastasis. A significant association was
established for incremental SUV and 3-year patient survival, indicating that intense
glucose metabolism in the tumor is a negative marker of survival in recurrent OSCC.
The same author (209) also studied the role of PET scan after potentially
curative radical surgery for salvage therapy in 41 OSCC patients. PET had an overall
71
sensitivity of 85% (92% for recurrence or second primaries, 88% for lymph node
failure and 73% for distant metastases). Survival was significantly higher in PET
negative group. SUV > 4 suggested poor prognosis.
The interval between end of treatment and FDG PET study varied considerably
among these reports. Although the optimum time for PET imaging after treatment is
still debated, in most practices PET imaging is usually deferred for 3 to 4 months
after radiation (205, 210).
III.
Prognosis and Risk Stratification

Trend to more individualized cancer therapy made the search for more possible
cancer prognosticators mandatory. Biological information derived from PET scan,
either from baseline or post-therapy studies, could be one of these possible new
prognostic factors.
Baseline SUVmax was significantly correlated with pathological features, such
as tumor thickness, depth of invasion and Bcl-2 intensity in patients with OSCC
(211).
Furthermore,
SUVmax
was
found
to
correlate
well
with
the
immunohistochemical staining score of hypoxia-inducible factor-1 (HIF-1) and so

with treatment response in OSCC who underwent neoadjuvant CRT prior to surgery
(212). It could be a non-invasive useful parameter for predicting patients' prognosis.
Many authors suggested that baseline SUV could predict tumor control and/or
survival rates in patients with HNSCC (5-10, 213). However, these studies found
different SUV cut-off values for predicting the worse outcomes, ranging from 5.5 (7),
7 (10), 9 (6, 9) and 10 (8). Some studies used the median SUVmax, while others used
the best cut-off based on the best correlation with the clinical outcome either from
log-rank test or receiver operating characteristics curve [ROC] analysis. Both
methods required a retrospective analysis even if the data might have been collected
prospectively.
72
In a retrospective analysis of 143 patients, Wong et al. found that SUV is an

independent predictor of relapse-free and overall survival. An increase in SUV by
one unit increased the relative risk of relapse by 11% and of death by 14% (5). The
great majority of patients enrolled for this study were suffering of larygeal and
oropharyngeal cancers mainly, with only 8 patients with oral cavity cancer.
Allal et al studied 63 patients with HNSCC who underwent FDG-PET scan
before radical RT. Patients having tumors with high FDG uptake (SUV > 5.5) had a
significantly lower 3-year local control and DFS compared with patients having low
uptake tumors. In the multivariate analysis, the only factor that retained its
significance for DFS was SUV category. They concluded that high FDG uptake
might be a useful parameter for identifying patients requiring more aggressive
treatment approaches (7).
Halfpenny et al studied 73 consecutive patients with newly diagnosed HNSCC.
SUV > 10 predicted for significantly worse outcome independent of the tumor stage
and diameter (8).
Minn et al had prospectively studied 37 patients with HNSCC. They used SUV
normalized to body lean mass (SUVlean). The overall survival of patients with a
SUVlean 9.0 was clearly better (6).
Schwartz et al prospectively enrolled 63 consecutive patients with a
histological diagnosis of HNSCC. Primary tumor SUV > 9 predicted inferior local
recurrence-free survival and disease-free survival. Nodal SUV dichotomized
according to the cohort median of 6.1 did not predict for either disease outcome (9).
Torizuka et al confirmed these results later (10).
Most of these series contains mixture of tumor subsites, which may differ in
their tumor behavior and management. Also, they differ in their inclusion criteria and
73
outcome endpoints, in addition to the differences in PET acquisition protocols and

possible differences in SUV measurement.
Studies that focus on the prognostic role of PET in oral cavity cancer patients
were few. Taiwanese group (214) studied the possible prognostic role of baseline
primary tumor SUV in a homogenous cohort of 109 OSCC patients with
pathologically positive LNs. In multivariate analysis, SUVmax of 19.3 and tumor
depth of 12 mm predict for 5-year LC and survival in OSCC patients with
pathologically positive lymph nodes. They reported a 5-year local control rate of only
55% in patients with high SUVmax, compared to 88% for low SUV group. The
authors explained their high cut-off value by the fact that they included homogenous
group of advanced stage III & IV oral cavity cancer patients only. In addition, they
used the SUV cut-off, which generated the lowest P-value in log-rank test for local
control. It is worth noting that local failure was seen only in 13 out of the enrolled
109 patients.
Hofele et al retrospectively studied 79 patients with OSCC and found that high
baseline primary tumor SUVmax (> 4.75) was independently associated with poor
overall survival while SUVmax > 11 was independently associated with poor disease
free survival (215). The generated cut-off values were based on the best value in
ROC curve generated for disease control and overall survivals.
Kim and coworkers performed PET to 82 patients with oral cavity cancer and
clinically negative necks. They found that SUVmax > 5 was predictive for poor local
control (63% vs. 83%) and disease free survival (52% vs. 88%) only in univariate
analysis. However, in multivariate analysis T category was the only independent
variable on multivariate analysis. These results might be from confounding with other
variables, mainly T category and tumor thickness which both were linked to the
SUVmax(216).
74
The importance of neck lymph nodal FDG uptake did attract a lot of
researchers. Liao et al explored the prognostic role of SUV in the metastatic neck
lymph nodes. They could stratify 77 patients with pathological ECS into two groups
according to nodal SUVmax of 5.7. They found that nodal SUVmax is an
independent prognosticator for 5-year neck cancer control (54% for high nodal
SUVmax group vs. 78% for low SUVmax group) and disease-specific survival rates
(39% vs. 61%; respectively) (217). Neck nodal SUV was itself predictive of ECS in a
study done by Kubicek et al, although this work included mainly oropharyngeal and
laryngeal cancers (218).
In another study of 108 patients, who had either early (before 10 months after
initial treatment) or late relapse (after 10 months), Liao and coworkers found that
baseline nodal SUVmax was the only independent risk factor in patients with late
relapse. They recommended surgical salvage either with or without adjuvant therapy
in patients with nodal SUVmax < 4.2 (219).
In a recent larger study with 473 patients conducted in Taiwan by the same
group (190), Liao and coworkers used a qualitative visual scoring system for nodal
uptake, varying from 0 = no uptake, 1 = faint uptake (likely benign), 2 = mild uptake
(equivocal), 3 = moderate uptake (likely malignant), 4 = intense uptake (definitely
malignant). PET score of 2 or more in the neck lymph nodes was independently
associated with rates of neck control, distant metastasis, disease-free survival,
disease-specific survival and overall survival.
Most of the published studies sought to identify high-risk patients based on
mixture of clinical, pathological or therapy factors, instead of using already known
high-risk groups trying to further stratify according to the possible new biological
prognosticators from FDG PET. Also, the results cannot be generalized. Studies
differ in their design, inclusion criteria, PET imaging and processing protocols and
selection of the cut-off value of SUV. All these points limit the inclusion of
prognostic data from PET into prospective multi-center trials.
75
The Role of Non-FDG Radiopharmaceuticals

18
F-FDG is the main radiotracer used in oncology. Other radiopharmaceuticals
have not been widely studied especially in the head and neck region.
11
C-methionine has high uptake in liver, pancreas, and intestine and is excreted
through the bladder. These characteristics interfere with tumor imaging in the
abdominal region and in the region of the bladder or prostate (220). Although it is
taken by HNSCC, this uptake does not predict neither for outcome (221) nor for
response to radiotherapy (222). However, it might be used to dynamically measure
the salivary gland functions post-irradiation (223).
To date, the most promising radiotracer for imaging cell proliferation is 3 deoxy-30-[18F]fluorothymidine (18F-FLT).
18
F-FLT is taken up by cells and
phosphorylated by thymidine kinase-1, leading to the 5-phosphate, which is

intracellularly trapped. It has been reported promising for imaging tumor cell
proliferation and early response assessment in HNSCC. However, it does not provide
additional visual information in comparison to 18F-FDG (224) and showed uptake in
metastatic as well as in non-metastatic lymph nodes due to reactive B-lymphocyte
proliferation (225).
Choline has been labeled with both 11C and 18F for tumor imaging. 11C-Choline
has higher contrast than 18F-FDG in HNSCC (226) and can be used for imaging skull
base and intracranial lesions in non-squamous cell head and neck malignancies
because the normal brain is not choline avid (227). It does not prove superior in
detecting recurrence from HNSCC (228).
Acetate accumulation in tumor cells seems to be caused by the low oxygen
consumption and enhanced lipid synthesis. Both
been used as tumor imaging agents.
11
11
C- and
18
F-labeled acetate have
C-acetate imaging appears promising for the
staging of HNSCC (229) and may be useful for imaging tumor perfusion and
oxidative metabolism in patients with HNSCC (230).
76
The first PET agent for imaging hypoxia in tumor was 18F-fluoromisonidazole
(18F-FMISO), which has been studied in patients with a variety of tumors. 18F-FMISO
has relatively low uptake in hypoxic cells and slow clearance from normoxic
background cells (220). Pretherapy FMISO uptake shows a strong trend to be an
independent prognostic measure in HNSCC (231). It was reported that neither the
presence nor the absence of hypoxia, as defined by positive 18F-FMISO findings on
the mid-treatment PET scan, correlated with patient outcome (232). However,
18
F-
FMISO might prove useful for guiding dose escalation to hypoxic tissue using IMRT
techniques (233).
60/62
Cu-ATSM is another hypoxia imaging radiopharmaceutical.
62
Cu-ATSM
uptake may be a predictive indicator of tumor response to chemoradiotherapy in

patients with locally advanced HNC (234). 60Cu-ATSM also has been used for dose
escalation purposes (235).
Imaging angiogenesis in HNSCC using
18
F-galacto-RGD PET is promising
with good contrast and feasibility of image fusion and definition of subvolumes
(236).
77
Patients and Methods

Patients
The study was conducted at the Molecular Imaging Center (MIC), Chang Gung
Memorial Hospital (CGMH), Taiwan. The common eligibility criteria were a
histologic diagnosis of OSCC; previously untreated tumor scheduled for radical
surgery; no other suspected distant metastatic lesions detected by imaging (including
magnetic resonance imaging/computed tomography and FDG-PET). The exclusion
criteria included the presence of a fasting blood glucose 200 mg/dL or a previous
diagnosis of another malignant disease and/or refusal or inability to receive definitive
treatment for the disease.
One hundred and thirty four patients underwent an extensive preoperative
evaluation, including FDG-PET, within 2 weeks before surgery. This included
medical
history
and
complete
physical
examination,
flexible
fiberoptic
pharyngoscopy, complete blood count and routine blood biochemistry panel,

computed tomography or magnetic resonance imaging scans of the head and neck,
chest radiography, bone scan, and liver ultrasonography. Primary staging was
performed according to the staging criteria of the American Joint Committee on
Cancer (AJCC), 1997 (5th edition). The main reason for the use of the 1997 criteria
instead of the 2002 staging system was the difficulty of correct pathologic staging of
T4b disease, which may prove troublesome for the analysis of OSCC (237). In
addition, this work was part of a larger prospective project, which started before
2002.
This study was approved by the Institutional Review Board at CGMH, and all
patients provided written informed consent.
PET/CT Imaging Protocol
Patients were asked to fast for at least 6 hours before the start of the PET study.
Serum glucose level was measured and all the patients had glucose concentrations <
78
200 mg/dL. A dose of 370 MBq (10 mCi) of
18
F-FDG was injected intravenously
then all the patients stayed in a well equipped room during the uptake phase and
instructed to remain recumbent, warm and silent, to minimize the non-desired FDG
uptake. PET/CT images were acquired 50 minutes after the injection time using a
combined PET/CT scanner (Discovery ST 16, GE Healthcare). Before PET
acquisition, helical CT images were obtained for anatomical localization/attenuation
correction (AL/AC) from the head to the proximal thigh according to a standardized
protocol. The following settings were used: transverse 10-mm collimation, 16-slice
mode, 120 kVp, auto mAs (range 10300), 0.5 s tube rotation, 17.5 mm/s table speed
and pitch 1.75. No intravenous contrast materials were administered for the CT scan.
CT data was resized from a 512 512 matrix to a 128 128 matrix to match the PET
data to allow for image fusion and generation of CT transmission maps. Emission
data were acquired from the head to the proximal thigh. Data were acquired in twodimensional mode (3 min per table position). The study was performed with the arms
positioned along the side of the body. No head holder was used. After CT-based AC,
PET images were reconstructed with an ordered subset expectation maximization
iterative reconstruction algorithm (4 iterations and 15 subsets). Slice thickness was
3.75 mm.
Data Reading & Analysis
All data were transferred automatically to the processing workstation (Xeleris
Workstation, GE Healthcare). PET/CT images were evaluated in the axial, sagittal,
and coronal planes in the default window level. Standardized uptake value (SUV)
was defined as the greatest activity concentration per injected dose per body weight
(in kilograms) after correction for radioactive decay.
Any abnormal FDG uptake was visually scored on a 5-point scoring system
(190), varying from 0 = no uptake, 1 = faint uptake (likely benign), 2 = mild uptake
(equivocal), 3 = moderate uptake (likely malignant), 4 = intense uptake (definitely
malignant). Discrepancies between different imaging modalities were solved by
79
consensus among the head and neck oncology group, which includes physicians from
otolaryngology, plastic surgery, radiation oncology, medical oncology, pathology,
radiology, in addition to nuclear medicine.
At time of analysis, all data were transferred via Digital Imaging and
Communications in Medicine (DICOM) protocol to another processing workstation
(Siemens Syngo MI.PET/CT 2010A). Cross calibration between the two processing
units was assured and SUV values were the same.
The primary tumor and lymph nodes volumes were measured using a
semiautomatic contouring software (Siemens TrueD, Siemens Medical Solutions).
The tumor boundaries were identified and drawn large enough to include all the
tumor volume but careful enough to exclude areas of physiological uptake (e.g.
tonsils, salivary glands.. etc). Then an isocontour connecting the outlines of the
volume of interest (VOI) was set. The selected volumes were based on two semiautomatic contouring methods: (1) Absolute SUV values: tumors were delineated at
absolute SUV 2.5, 3, 3.5 and 4; and (2) Thresholding: tumors were contoured based
on 30%, 40%, 50%, 60%, 70% and 80% of the within-volume maximum SUV.
Among all these methods, the best contouring method was selected based on
the highest correlation analysis (R2) between the maximum axial tumor diameter
from the fixed pathology specimens and the maximum axial diameter from the
delineated PET/CT volumes according to the different methods. That turned out to be
absolute SUV 3 for the primary tumor and absolute SUV 2.5 for lymph node
delineation.
The lymph nodes, which were delineated, were considered metastatic based on
consensus agreement among the head and neck oncology group according to clinical
data, examination and conventional modalities (CT/MRI). In the presence of multiple
metastatic LNs, the one with the highest SUVmax was selected for delineation.
80
To minimize the partial volume effect (PVE) of the primary tumor volume,
patients with T1 disease were excluded. However, PVE was inevitable in delineating
small neck lymph nodes. No correction for PVE was available.
Calculation of Total Lesion Glycloysis (TLG)
After delineation, each of the generated metabolic volumes from PET (MTV)
was multiplied by the average SUV within the same volume to get the value of TLG.
TLG = (MTV) X (Average SUV)
That was done for both the primary tumor to get the primary tumor TLG
(TTLG) and for the neck lymph node with highest uptake to calculate the nodal TLG
(NTLG).
Surgery and Adjuvant Therapy
The primary tumors were excised with 1 cm safety margins (both peripheral
and deep margins). Classic radical, or modified, neck dissection (ND) from Level I to
III or V was performed in patients with clinically positive nodal disease. Supraomohyoid ND (Level IIII) was performed in clinically node-negative patients and
all T2-T4 patients. Bilateral ND was performed if the primary tumor reached or
crossed the midline sagittal plane of the oral cavity.
The tumor margins were cryosectioned. If a margin was positive, additional
tissue was excised and cryosectioned to ensure that the margin was free of tumor. The
surgical defects were repaired with primary closure or reconstructed immediately by
plastic surgeons using free or local flaps.
Postoperative radiotherapy (RT) was performed in patients with stage pT4
tumor, pathologic positive lymph nodes, or pathologically close margins ( 4 mm).
RT was scheduled within 4-8 weeks after surgery. The prescribed dose was 1.82
Gy/fraction daily, given 5 days/week. The total radiation dose was 66 Gy/6.5 weeks
81
for patients with multiple positive neck lymph nodes and/or extracapsular spread
(ECS)
and
60
Gy/6
weeks
for
the
remaining
patients.
Concomitant
chemoradiotherapy (CCRT) with cisplatin-based agents was administered to patients

with ECS or metastases in multiple lymph nodes.
Follow-up Protocol
Postoperative clinical follow-up was performed regularly according to the
following schedule: every 13 months for the first year; every 2-4 months for the
second year, every 4-6 months in the 3-5 years after operation, and yearly thereafter.
Neck ultrasound was done as needed.
Imaging follow-up was performed with either CT or MRI at 3, 9 months, and
every 1-year for the first 5 years after adjuvant therapy or in the presence of any
symptoms or signs of persistent or recurrent disease. In addition, patients underwent
chest radiographs, bone scan, and liver ultrasound in the first 3 years after adjuvant
therapy.
All patients were followed up till death or at least 24 months from the date of
their surgery.
Statistical Analysis
The data of the patients were prospectively collected until the end of followup. Descriptive statistics were summarized using frequencies, percentages, means,
medians, standard deviations, and ranges.
Continuous parameters from FDG PET SUV, MTV, TLG were compared in
patients with different clinicopathological characteristics using T-test (for two-group
comparisons) and one-way ANOVA (for more than two-group comparisons) if they
were normally distributed, while Mann-Whitney and KruskalWallis tests were used
for skewed distributions, respectively. Categorical data were analyzed using the Chisquared (2) test.
82
The accuracy of TLG data in predicting some pathological characteristics e.g.

ECS was analyzed using Receiver Operating Characteristics (ROC) curve analysis
(238). Dichotomization of PET parameters was done using the median value of each.
Values above the median SUV or TLG were referred to as high SUV or high TLG
groups, respectively.
Local primary tumor control (LC), neck lymph nodes control (NC), distant
metastases free survival (DMFS), disease-free survival (DFS), disease-specific
survival (DSS), and overall survival (OS) rates were computed using the KaplanMeier method starting from the date of surgery to the date of confirmed event or last
follow-up. The events were development of local recurrence for calculation of LC,
development of neck recurrence for NC, development of distant failure for DMFS,
the first treatment failure for DFS, cancer death for DSS and death from any cause for
OS.
Univariate analysis of control rates and survival was performed using the logrank test. Variables with P value < 0.05 were further selected for multivariable
analyses (MVA), which was performed using the Cox proportional hazards model
with a forward selection procedure. The three most significant independent
prognostic factors derived from MVA were used to develop a risk score to divide the
study population into four categories according to the presence or absence of one or
more of the resulting 3 factors. In all analyses, P < 0.05 (two-tailed) were considered
statistically significant.
83
Results
Results
1.
Patients
A total of 134 consecutive patients with previously untreated OSCC were
scheduled for radical surgery between June 2006 and January 2008 at the Chang
Gung Memorial Hospital, Taiwan. The follow-up continued till February 2010 (the
time of analysis) giving a median follow-up 31.3 months (range: 24.7 48.9 months).
Among the patients, 8 patients were excluded due to T1 disease, leaving a valid
cohort of 126 patients. The median age of the study population was 49.5 years
(range: 28-83). Most of the tumors originated in the buccal mucosa (39%) or the
tongue (30%) (Figure 35).
Figure 35: The tumor subsites seen .

The majority of patients were males (94%), smokers (87%), drinkers (71%)
and betel quid chewers (87%). About 48% of them presented with advanced clinical
stage (IV) and more than half of them have nodal disease at time of presentation
(Table 2).
84
Results
The primary tumor was right-sided in 55 patients (44%), left in 57 (45%),

central in 5 patients (4%) and lateralizing to one side but crossing the midline in 9
patients (7%). Wide resection was done with ipsilateral neck dissection in all patients
(59 elective and 39 therapeutic ND of level I-III & 2 elective and 26 therapeutic ND
of level I-IV). Contralateral ND was performed in 22 patients (16 elective and 2
therapeutic ND of level I-III & 4 therapeutic ND of level I-V). Surgery was followed
by RT/CCRT in 64% of patients after a median of 47 days from surgery. The general
clinical characteristics are summarized in (Table 2).
Table 2: General Clinical Characteristics of the Study Participants
Characteristic
n
Percentage
Gender
Female
8
(6.3)
Male
118
(93.7)
Clinical T status
cT2
62
(49.2)
cT3
19
(15.1)
cT4
45
(35.7)
Clinical N status
cN0
61
(48.4)
cN1
22
(17.5)
cN2a
2
(1.6)
cN2b
34
(27)
cN2c
7
(5.6)
Clinical TNM stage (AJCC 1997)
cStage II
42
(33.3)
cStage III
23
(18.3)
cStage IV
61
(48.4)
Treatment
Surgery
45
(35.7)
Surgery + RT
30
(23.8)
Surgery + CCRT
51
(40.5)
The primary tumor size detected by histopathology ranged from 1 to 8 cm
(median: 2.9 cm), with tumor depth varying from 0.1 to 4 cm (median: 1.1 cm). The
tumor size in pathologic LNs ranged from 0.1 to 3.7 cm (median: 1.4 cm). Nearest
surgical margin varied from 0.1 to 1.8 cm (median: 0.8 cm). Nine patients had close
85
Results
margin less than 0.5 cm. Other general pathological characteristics are summarized in
(Table 3).
Table 3: General Pathological Characteristics of the Study Participants
Characteristic
n
Percentage
Pathological T status
pT2
65
(51.6)
pT3
17
(13.5)
pT4
44
(34.9)
Pathological N status
pN0
59
(46.8)
pN1
21
(16.7)
pN2b
39
(31)
pN2c
7
(5.6)
Pathological TNM stage (AJCC 1997)
pStage II
34
(27)
pStage III
25
(19.8)
pStage IV
67
(53.2)
Differentiation
WD SCC
22
(17.5)
MD SCC
82
(65.1)
PD SCC
22
(17.5)
Pathologic level IV-V lymph node metastases
No
120
(95.2)
Yes
6
(4.8)
Extracapsular spread (ECS)
No
86
(68.3)
Yes
40
(31.7)
Skin invasion
No
111
(88.1)
Yes
15
(11.9)
Perineural invasion
No
70
(55.6)
Yes
56
(44.4)
Vascular invasion
No
125
(99.2)
Yes
1
(0.8)
Lymphatic invasion
No
122
(96.8)
Yes
4
(3.2)
Bone marrow invasion
No
104
(82.5)
Yes
22
(17.5)
86
Results
Sixty-five patients (51.6%) were in pT2, while pT4 were seen in 44 patients
(35%). About 53% have pathologically positive nodal disease, and more than half of
the patients proved to be TNM stage IV and 65% of the tumors were moderately
differentiated SCC (Table 3).
The median follow-up for the whole study population was 31.3 months while
the median follow-up for surviving populations was 37.6 months (range: 24.7-48.9
months).
Figure 36: The pattern of recurrence in the 45 patients who experienced treatment
failure (percentages are given among the 45 patients).
By the end of follow-up, 45 patients experienced a recurrence (3-year DFS =
63%). The pattern of recurrence is illustrated in (Figure 36). There was isolated local
recurrence in 11 patients (24%), regional recurrence in 9 patients (20%), distant
metastases in 11 patients (24%). Local recurrence was associated with regional
failure in 5 patients (11%), with distant metastases in 2 patients (5%), and with both
87
Results
regional and distant failures in 4 patients (9%). Regional and distant metastasis was
seen in the remaining 3 patients (7%).
In total, 22 patients recur locally (3-year LC = 79.8%), 21 had regional failure
(3-year NC = 82.1%) and 20 patients had distant metastases (3-year DMFS =
83.1%).
Forty-six patients died (3-year OS = 62.5%); 37 of them because of cancer (3year-DSS = 68.7%).
2.
PET/CT Scores and SUV

PET/CT study was performed before a median of 2 days prior to the scheduled
surgery.
Primary tumor SUVmax ranged from 3.7 to 31.8 (median: 13.7). The primary
tumor was scored 4 in 122 patients, scored 3 in 2 patients, scored 2 in one patient,
and scored 0 in another. For the latter case, delineation of the primary tumor was
based on MRI findings (Figure 36).
(A)
(B)
Figure 37: A 65-year-old male with left buccal cancer. (A) Axial T1 post-contrast
image showed enhancement in a small area (2.7 cm) of irregular mucosal thickening
in the left buccal area. (B) Fused PET/CT images revealed low FDG uptake in that
site (SUVmax 4.34) and accordingly was scored 0.
88
Results
The SUV of lymph nodes varied from 2.9 to 30.6 (median: 7.5). PET/CT
considered positive in 71 patients, 20 of them were falsely positive according to the
pathology (sensitivity = 76% and positive predictive value = 72%). Among the 55
PET negative patients, 16 proved positive on histopathological examination
(specificity = 66% and negative predictive value = 71%). The overall accuracy of
lymph node staging on patient basis was 71% with a 95% confidence interval (CI)
ranging from 64 to 79%.
3.
Choice of the Best Contouring Method

Among the different contouring methods used for delineating the primary
tumor volume on PET/CT studies, the absolute SUV value 3 gave the best correlation
with the axial tumor diameter from the fixed pathology specimen (R2 = 0.72; P <
0.001) (Figure 38-A).
For the lymph nodes, absolute SUV value of 2.5 gave the best correlation with
the maximum fixed axial diameter of the pathologic neck lymph nodes (R2 = 0.45; P
= 0.002) (Figure 38-B).
(B)
Pathologic tumor diameter
Pathologic LN diameter
(A)
Primary tumor diameter at absolute SUV 3.0
LN diameter at absolute SUV 2.5
Figure 38: Scatter plots for (A) the relation between maximum pathologic axial diameter
of the fixed primary tumor and the diameter derived from tumor delineation using absolute
SUV value of 3, and (B) the relation between maximum diameter of the pathologic lymph
nodes and the diameter derived from lymph node delineation using absolute SUV value of
2.5.
89
Results
4.
Total Lesion Glycolysis (TLG)

The primary tumor metabolic tumor volume (TMTV) varied from 0.44 to 202.4
ml, while primary tumor TLG (TTLG) from 1.5 to 1356.1 (median: 71.4). Lymph
node MTV (NMTV) varied between 0.2 and 72.1 ml (median: 3.5 ml); and nodal
TLG (NTLG) ranged from 0.4 to 526.1 (median: 15.4).
5.
Association between SUV & TLG and Different Pathological

Characteristics
The mean primary tumor SUV (TSUVmax) was significantly higher with
locally advanced tumors (pT3 & pT4) or with tumors showing perineural invasion or
depth 1 cm. Also primary tumor TLG (TTLG) was associated with advanced local
disease (pT3 & pT4), pathologically positive neck disease (pN+), positive ECS or
tumor depth more than 1 cm. Furthermore, it was significantly higher in patients with
skin, perineural or bone marrow invasion (Table 4).
ROC analysis identified TTLG value of 92.19 as the best predicitve cut-off
value for the presence of ECS. This point gave modest accuracy of only 68.1% (95%
CI: 59.2-76.1%; P = 0.001) (Figure 39-A).
(A)
(B)
Figure 39: ROC analyses of TTLG (A) and NTLG (B) in relation to presence of ECS.
The best cut-off values identified were 92.19 and 18.51, respectively. NTLG was
significantly more accurate than TTLG for predicting ECS (P < 0.001).
90
Results
Table 4: Relation of primary tumor TSUV and TTLG to different pathological

characteristics
Pathological characteristics
TSUVmax
(Mean SD)
T status
pT2
65
(12.46.7)
pT3-T4
61
(15.65.5)
N status
pN0
59
(12.86.7)
pN+
67
(14.95.8)
TNM stage
pStage II
34
(116.3)
pStage III-IV
92
(156)
ECS
ECS (-)
86
(13.46.6)
ECS (+)
40
(15.25.7)
Differentiation
WD-MD SCC
104
(13.96.4)
PD SCC
22
(14.16.1)
Skin invasion
No
111
(13.66.3)
Yes
15
(16.65.7)
Perineural invasion
No
70
(12.76.2)
Yes
56
(15.66.2)
Lymphatic invasion
No
122
(13.96.3)
Yes
4
(14.16.5)
Marrow invasion
No
104
(13.86.3)
Yes
22
(14.66.5)
Close margin
> 0.7 cm
71
(13.86.6)
0.7 cm
55
(14.16.1)
Tumor depth
< 1 cm
52
(10.65.5)
1 cm
74
(16.35.8)
The asterisk (*) indicates statistically significant result
TTLG
(Mean SD)
0.003*
(47.762.4)
(228.5250)
<0.001*
0.058
(104.8198)
(162.1200.4)
0.002*
0.001*
(39.866.3)
(170.5221.4)
<0.001*
0.13
(108.9181.5)
(192228.6)
0.001*
0.921
(140.9215.7)
(108.3101.3)
0.758
0.087
(107.3130.9)
(342.4415)
0.005*
0.01*
(85.8130.6)
(197.1251)
<0.001*
0.958
(134.3200.6)
(165.5225.6)
0.738
0.608
(106162.8)
(273.6291.7)
<0.001*
0.813
(99.8108.6)
(181272.1)
0.162
<0.001*
(40.458.6)
(201.9235.7)
<0.001*
The mean lymph nodal SUV (NSUVmax) and NTLG were significantly higher
in patients with pN+ disease and positive ECS. A borderline association was seen
91
Results
with lymphatic invasion. No relation was detected with the tumor differentiation and
other pathological factors (Table 5). ROC analysis identified NTLG value of 18.51 as
the best predictive cut-off value for the presence of ECS. This point gave high
accuracy of 83.9% (95% CI: 59.2-76.1%; P < 0.001) (Figure 39-B).
Table 5: Relation of nodal
characteristics
NSUV
and
NTLG
Pathological
NSUVmax
n
characteristics
(Mean SD)
P
T status
pT2
65
(9.78)
0.797
pT3-T4
61
(9.24.9)
N status
pN0
59
(5.22.5)
<0.001*
pN+
67
(10.76.4)
TNM stage
pStage II
34
(40.7)
<0.001*
pStage III-IV
92
(106.2)
ECS
ECS (-)
86
(6.75.8)
0.003*
ECS (+)
40
(11.35.7)
Differentiation
WD-MD SCC
104
(9.35.9)
0.846
PD SCC
22
(9.77.2)
Skin invasion
No
111
(9.26.4)
0.606
Yes
15
(10.35)
Perineural invasion
No
70
(95.6)
0.696
Yes
56
(9.76.6)
Lymphatic invasion
No
122
(96)
0.096
Yes
4
(14.37.7)
Marrow invasion
No
104
(9.76.5)
0.554
Yes
22
(8.55.1)
Close margin
> 0.7 cm
71
(9.67)
0.766
0.7 cm
55
(9.15)
Tumor depth
< 1 cm
52
(9.37.7)
0.941
1 cm
74
(9.45.6)
The asterisk (*) indicates statistically significant result
92
to different pathological
NTLG
(Mean SD)
(33.162.8)
(69.4123.6)
0.127
(918.7)
(70.4117.5)
0.001*
(1.81.3)
(62.1110.4)
<0.001*
(9.616)
(89.3129.2)
<0.001*
(64120.3)
(32.536.3)
0.639
(49.197)
(90.8145.4)
0.267
(49.694.6)
(436.9)
0.881
(38.165.1)
(308.3231)
0.101
(46.984.6)
(86.4158.7)
0.903
(53.490.4)
(59.6125.8)
0.887
(37.968.3)
(62.7117)
0.688
Results
6.
Univariate Analyses
a.
Local Control
Among all the studied clinical and pathological variables, 5 factors proved
significant in UVA, these are: age, treatment modality, TTLG, pathological T status
and presence of bone marrow invasion. Age groups 40 years, treatment with
surgery followed by RT/CCRT, high TTLG (Figure 40), advanced local disease (pT3
& pT4) or the presence of bone marrow invasion (Figure 41) were linked to
significantly worse local disease control (Tables 6 & 7).
Figure 40: Local control

rate according to the
primary tumor TLG .
Figure 41: Local control

presence or absence of
bone marrow invasion .
93
Results
Table 6: Univariate analysis of 3-year local control (LC) according to clinical

characteristics, SUV and TLG.
Local Control
Clinical characteristics
n
Events (LC rate %)
P
Gender
Female
8
1 (87.5)
0.593
Male
118
21 (79.2)
Age (years)
> 40
100
14 (83)
0.034*
40
26
8 (66.7)
Cigarette smoking
No
16
2 (87.5)
0.456
Yes
110
20 (78.5)
Alcohol drinking
No
36
4 (84.9)
0.298
Yes
90
18 (78.1)
Betel-quid chewing
No
17
0 (100)
0.059
Yes
109
22 (76.9)
Cancer sub-site
Buccal
49
8 (82)
0.513
Tongue
38
9 (73.9)
Gum-others
39
5 (84.2)
Treatment
Surgery alone
45
4 (90.7)
0.032*
Surgery + RT/CCRT
81
18 (73)
Primary tumor SUVmax
63
8 (85.2)
0.118
TSUVmax < 13.7
63
14 (73.8)
TSUVmax 13.7
Primary tumor TLG
63
7 (87.5)
0.017*
TTLG < 71.4
63
15 (71)
TSTLG 71.4
Nodal SUVmax
96
17 (80.8)
0.528
NSUVmax < 7.5
30
5 (76.4)
NSUVmax 7.5
Nodal TLG
96
18 (79.7)
0.923
NTLG < 15.4
30
4 (81)
NTLG 15.4
Asterisk (*) indicates a statistically significant result (P < 0.05)
94
Results
Table 7: Univariate analysis of 3-year local control (LC) according to

pathological characteristics.
Local Control
n
Pathologic characteristics
Events (LC rate %) P
T status
pT2
65
6 (89.7)
0.002*
pT3-T4
61
16 (67.2)
N status
pN0
59
9 (84.6)
0.183
pN+
67
13 (75.3)
TNM stage
pStage II
34
3 (91.1)
0.064
pStage III-IV
92
19 (74.8)
ECS
ECS (-)
86
15 (82.1)
0.417
ECS (+)
40
7 (72.9)
Differentiation
WD-MD SCC
104
19 (79)
0.775
PD SCC
22
3 (84)
Skin invasion
No
111
19 (80.3)
0.502
Yes
15
3 (75.5)
Perineural invasion
No
70
11 (82.4)
0.332
Yes
56
11 (76)
Lymphatic invasion
No
122
22 (79.6)
0.595
Yes
4
0 (100)
Marrow invasion
No
104
14 (84.8)
0.001*
Yes
22
8 (51.6)
Close margin
> 0.7 cm
71
12 (79.6)
0.878
0.7 cm
55
10 (79.7)
Tumor depth
< 1 cm
52
7 (84.6)
0.150
1 cm
74
15 (76.1)
95
Results
b.
Neck Control
High NTLG showed borderline association with neck recurrence (Figure 42 &
Table 8). Poorly differentiated tumors were significantly linked to more neck failures
(Figure 43). Surprisingly, more neck failures were seen in patients with nearest
resection margin > 0.7 cm. Other associations did not show significance in the current
analysis (Table 9).
Figure 42: Neck control

neck lymph nodal TLG .
Figure 43: Neck control

histopathological
differentiation.
96
Results
Table 8: Univariate analysis of 3-year neck control (NC) according to clinical

characteristics, SUV and TLG.
Neck Control
n
Events (NC rate %) P
Gender
Female
8
1 (85.7)
0.655
Male
118
20 (81.9)
Age (years)
> 40
100
17 (82)
0.880
40
26
4 (82.9)
Cigarette smoking
No
16
3 (80.8)
0.951
Yes
110
18 (82.4)
Alcohol drinking
No
36
7 (78.9)
0.528
Yes
90
14 (83.5)
Betel-quid chewing
No
17
2 (87.1)
0.566
Yes
109
19 (81.5)
Cancer sub-site
Buccal
49
6 (87.3)
0.209
Tongue
38
10 (72.6)
Gum-others
39
5 (85.4)
Treatment
Surgery alone
45
7 (84)
0.751
Surgery + RT/CCRT
81
14 (80.6)
63
10 (81.9)
0.880
TSUVmax < 13.7
63
11 (80.7)
TSUVmax 13.7
Primary tumor TLG
63
10 (84.1)
0.566
TTLG < 71.4
63
11 (79.7)
TTLG 71.4
Nodal SUVmax
96
14 (86)
0.115
NSUVmax < 7.5
30
7 (73.3)
NSUVmax 7.5
Nodal TLG
96
14 (84.9)
0.094
NTLG < 15.4
7 (72.2)
30
NTLG 15.4
97
Results
Table 9: Univariate analysis of 3-year neck control (NC) according to

Neck Control
n
Events (NC rate %) P
T status
pT2
65
11 (82.8)
0.862
pT3-T4
61
10 (81.1)
N status
pN0
59
8 (86.4)
0.231
pN+
67
13 (77.7)
TNM stage
pStage II
34
6 (82.4)
0.957
pStage III-IV
92
15 (81.7)
ECS
ECS (-)
86
14 (83.5)
0.514
ECS (+)
40
7 (78.9)
Differentiation
WD-MD SCC
104
13 (86.6)
0.002*
PD SCC
22
8 (60.2)
Skin invasion
No
111
19 (81.8)
0.844
Yes
15
2 (84.6)
Perineural invasion
No
70
10 (85.3)
0.333
Yes
56
11 (77.3)
Lymphatic invasion
No
122
20 (82.6)
0.322
Yes
4
1 (66.7)
Marrow invasion
No
104
19 (81.1)
0.429
Yes
22
2 (86.6)
Close margin
> 0.7 cm
71
17 (75)
0.017*
0.7 cm
55
4 (91.7)
Tumor depth
< 1 cm
52
11 (78.8)
0.386
1 cm
74
10 (84.5)
98
Results
c.

Treatment with surgery followed by RT/CCRT or high TTLG (Figure 44),
NSUVmax
or NTLG were associated with significantly higher rates of distant failure
(Table 10). Also, the presence of pN+, ECS (Figure 45), lymphatic invasion or bone
marrow invasion predicted for statistically significant worse 3-year distant control.
Advanced local disease and presence of perineural invasion or tumor depth 1 cm
showed borderline association with the development of distant metastases (Table 11).
Figure
44:
Distant
metastases free survival
primary tumor TLG.
Figure
45:
Distant
according to the presence
or absence of extracapsular spread in the
neck lymph nodes of 126
patients with oral cavity
cancer.
99
Results
Table 10: Univariate analysis of 3-year distant metastases free survival

(DMFS) according to clinical characteristics, SUV and TLG.
n
Events (DMFS rate %) P
Gender
Female
8
2 (75)
0.597
Male
118
18 (83.8)
Age (years)
> 40
100
15 (84.1)
0.522
40
26
5 (79.3)
Cigarette smoking
No
16
1 (93.3)
0.234
Yes
110
19 (81.6)
Alcohol drinking
No
36
6 (81.9)
0.819
Yes
90
14 (83.6)
Betel-quid chewing
No
17
2 (85.7)
0.650
Yes
109
18 (82.7)
Cancer sub-site
Buccal
49
9 (80.6)
0.296
Tongue
38
3 (91.2)
Gum-others
39
8 (78.4)
Treatment
Surgery alone
45
2 (95.4)
0.008*
Surgery + RT/CCRT
81
18 (75.8)
63
5 (89.9)
0.051
TSUVmax < 13.7
63
15 (76.2)
TSUVmax 13.7
Primary tumor TLG
63
4 (93.3)
0.002*
TTLG < 71.4
63
16 (72.3)
TTLG 71.4
Nodal SUVmax
96
6 (93.4)
< 0.001*
NSUVmax < 7.5
30
14 (48.6)
NSUVmax 7.5
Nodal TLG
96
7 (92.3)
< 0.001*
NTLG < 15.4
30
13 (52)
NTLG 15.4
100
Results
Table 11: Univariate analysis of 3-year distant metastases free survival (DMFS)
according to pathological characteristics.
n
Events (DMFS rate %) P
T status
pT2
65
7 (88.7)
0.057
pT3-T4
61
13 (77.3)
N status
pN0
59
1 (98.3)
< 0.001*
pN+
67
19 (67.5)
TNM stage
pStage II
34
1 (97.1)
0.013*
pStage III-IV
92
19 (77.4)
ECS
ECS (-)
86
5 (94)
< 0.001*
ECS (+)
40
15 (55.8)
Differentiation
WD-MD SCC
104
15 (84.7)
0.259
PD SCC
22
5 (74.8)
Skin invasion
No
111
18 (82.8)
0.950
Yes
15
2 (86.7)
Perineural invasion
No
70
8 (88.1)
0.092
Yes
56
12 (76.3)
Lymphatic invasion
No
122
17 (85.2)
< 0.001*
Yes
4
3 (0)
Marrow invasion
No
104
13 (86.6)
0.011*
Yes
22
7 (65.9)
Close margin
> 0.7 cm
71
12 (81.6)
0.732
0.7 cm
55
8 (84.8)
Tumor depth
< 1 cm
52
5 (90)
0.071
1 cm
74
15 (78.1)
101
Results
d.

Treatment modality, TTLG (Figure 46), NSUVmax or NTLG were significantly
linked with disease free survival (Table 12). The presence of advanced local disease
(pT3 & pT4), pN+ (Figure 47), ECS, perineural invasion, lymphatic invasion or
marrow invasion predicted for significantly lower 3-year DFS (Table 13).
Figure 46: Disease free

survival rate according
to the primary tumor
TLG.

to the pathologic status
of neck lymph nodes.
102
Results
Table 12: Univariate analysis of 3-year disease free survival (DFS) according
to clinical characteristics, SUV and TLG.
n
Events (DFS rate %)
P
Gender
Female
8
2 (75)
0.415
Male
118
43 (62.2)
Age (years)
> 40
100
36 (62.6)
0.990
40
26
9 (64)
Cigarette smoking
No
16
5 (68.8)
0.570
Yes
110
40 (62.1)
Alcohol drinking
No
36
12 (63.9)
0.871
Yes
90
33 (62.8)
Betel-quid chewing
No
17
3 (80.4)
0.137
Yes
109
42 (60.5)
Cancer sub-site
Buccal
49
15 (68.9)
0.631
Tongue
38
15 (58.7)
Gum-others
39
15 (60.4)
Treatment
Surgery alone
45
8 (81.7)
0.004*
Surgery + RT/CCRT
81
37 (52.8)
63
18 (68.4)
0.198
TSUVmax < 13.7
63
27 (57.5)
TSUVmax 13.7
Primary tumor TLG
63
16 (73.9)
0.007*
TTLG < 71.4
63
29 (51.6)
TSTLG 71.4
Nodal SUVmax
96
28 (69.7)
0.001*
NSUVmax < 7.5
30
17 (41.5)
NSUVmax 7.5
Nodal TLG
96
29 (68.7)
0.003*
NTLG < 15.4
30
16 (44)
NTLG 15.4
103
Results
Table 13: Univariate analysis of 3-year disease free survival (DFS) according to
n
Events (DFS rate %)
P
T status
pT2
65
16 (74.3)
0.004*
pT3-T4
61
29 (50.8)
N status
pN0
59
14 (76.3)
0.003*
pN+
67
31 (50.8)
TNM stage
pStage II
34
7 (79.4)
0.041*
pStage III-IV
92
38 (56.5)
ECS
ECS (-)
86
24 (72)
0.002*
ECS (+)
40
21 (42)
Differentiation
WD-MD SCC
104
36 (64.3)
0.327
PD SCC
22
9 (56.4)
Skin invasion
No
111
38 (64.3)
0.225
Yes
15
7 (53.3)
Perineural invasion
No
70
19 (71.6)
0.018*
Yes
56
26 (51.9)
Lymphatic invasion
No
122
41 (65.1)
< 0.001*
Yes
4
4 (0)
Marrow invasion
No
104
32 (68.2)
0.005*
Yes
22
13 (37.5)
Close margin
> 0.7 cm
71
29 (57.3)
0.198
0.7 cm
55
16 (70)
Tumor depth
< 1 cm
52
17 (66.7)
0.369
1 cm
74
28 (60.4)
104
Results
e.

Treatment with surgery and adjuvant RT/CCRT or high TSUVmax, TTLG
(Figure 48), NSUVmax or NTLG were associated with significantly higher rates of
cancer related deaths (Table 14). The presence of advanced local disease (pT3 &
pT4; Figure 49), pN+, ECS, perineural, lymphatic or bone marrow invasion
predicted for statistically significant worse 3-year DSS while the presence of skin
invasion or tumor depth 1 cm showed borderline association (Table 15).
Figure
48:
Disease
specific survival rate
according to the primary
tumor TLG.
Figure
49:
Disease
specific
survival
according
to
the
pathologic status of neck
lymph nodes.
105
Results
Table 14: Univariate analysis of 3-year disease specific survival (DSS) according
to clinical characteristics, SUV and TLG.
n
Events (DSS rate %)
P
Gender
Female
8
2 (75)
0.672
Male
118
35 (68.3)
Age (years)
> 40
100
28 (69.7)
0.461
40
26
9 (64)
Cigarette smoking
No
16
4 (75)
0.500
Yes
110
33 (68)
Alcohol drinking
No
36
9 (73.1)
0.639
Yes
90
28 (67)
Betel-quid chewing
No
17
3 (79.8)
0.353
Yes
109
34 (67.3)
Cancer sub-site
Buccal
49
15 (66.8)
0.873
Tongue
38
10 (71.9)
Gum-others
39
12 (67.6)
Treatment
Surgery alone
45
5 (87.9)
0.001*
Surgery + RT/CCRT
81
32 (58.5)
63
12 (78.3)
0.033*
TSUVmax < 13.7
63
25 (59.3)
TSUVmax 13.7
Primary tumor TLG
63
10 (83.6)
< 0.001*
TTLG < 71.4
63
27 (53.1)
TSTLG 71.4
Nodal SUVmax
96
20 (78.1)
< 0.001*
NSUVmax < 7.5
30
17 (38.9)
NSUVmax 7.5
Nodal TLG
96
21 (77)
< 0.001*
NTLG < 15.4
30
16 (42.3)
NTLG 15.4
106
Results
Table 15: Univariate analysis of 3-year disease specific survival (DSS)

according to pathological characteristics.
n
Events (DSS rate %)
P
T status
pT2
65
11 (81.5)
0.001*
pT3-T4
61
26 (54.8)
N status
pN0
59
8 (85.9)
< 0.001*
pN+
67
29 (53)
TNM stage
pStage II
34
4 (88.2)
0.006*
pStage III-IV
92
33 (61.1)
ECS
ECS (-)
86
17 (79.6)
< 0.001*
ECS (+)
40
20 (44.2)
Differentiation
WD-MD SCC
104
29 (70.4)
0.291
PD SCC
22
8 (60.5)
Skin invasion
No
111
30 (70.9)
0.069
Yes
15
7 (52.5)
Perineural invasion
No
70
14 (77.6)
0.007*
Yes
56
23 (56.8)
Lymphatic invasion
No
122
33 (71)
< 0.001*
Yes
4
4 (0)
Marrow invasion
No
104
26 (73.3)
0.005*
Yes
22
11 (46.2)
Close margin
> 0.7 cm
71
22 (66.4)
0.640
0.7 cm
55
15 (71.5)
Tumor depth
< 1 cm
52
12 (76.5)
0.092
1 cm
74
25 (63.2)
107
Results
f.
Overall Survival
Three year overall survival was significantly lower in patients with high
TSUVmax, TTLG, NSUVmax
(Figure 50) or NTLG, or in those patients treated by
surgery plus adjuvant RT/CCRT (Table 16). The presence of advanced local disease
(pT3 & pT4), pN+ (Figure 51), ECS, perineural, lymphatic, bone marrow invasions
or tumor depth 1 cm were linked to statistically significant worse 3-year survival
while the presence of skin invasion showed borderline association (Table 17).
Figure
50:
Overall
to the neck lymph nodal
SUV.
Figure
51:
Overall
to the pathologic status
of neck lymph nodes.
108
Results
Table 16: Univariate analysis of 3-year overall survival (OS) according to

clinical characteristics, SUV and TLG.
Overall Survival
n
Events (OS rate %)
P
Gender
Female
8
2 (75)
0.452
Male
118
44 (61.7)
Age (years)
> 40
100
36 (62.6)
0.697
40
26
10 (61.5)
Cigarette smoking
No
16
4 (75)
0.249
Yes
110
42 (60.8)
Alcohol drinking
No
36
14 (60.3)
0.701
Yes
90
32 (63.4)
Betel-quid chewing
No
17
6 (64.7)
0.952
Yes
109
40 (62.3)
Cancer sub-site
Buccal
49
18 (61.7)
0.904
Tongue
38
13 (65.8)
Gum-others
39
15 (60)
Treatment
Surgery alone
45
8 (81.9)
0.002*
Surgery + RT/CCRT
81
38 (52.3)
63
17 (72.7)
0.033*
TSUVmax < 13.7
63
29 (52.6)
TSUVmax 13.7
Primary tumor TLG
63
12 (80.7)
< 0.001*
TTLG < 71.4
63
34 (44.8)
TTLG 71.4
Nodal SUVmax
96
< 0.001*
26 (72.2)
NSUVmax < 7.5
30
20 (32.1)
NSUVmax 7.5
Nodal TLG
96
< 0.001*
28 (70.1)
NTLG < 15.4
30
18 (39)
NTLG 15.4
109
Results
Table 17: Univariate analysis of 3-year overall survival (OS) according to

Overall Survival
n
Events (OS rate %)
P
T status
pT2
65
14 (77.5)
< 0.001*
pT3-T4
61
32 (46.5)
N status
pN0
59
9 (83.3)
< 0.001*
pN+
67
37 (44.2)
TNM stage
pStage II
34
4 (88.2)
0.001*
pStage III-IV
92
42 (53.1)
ECS
ECS (-)
86
20 (75.9)
< 0.001*
ECS (+)
40
26 (34.4)
Differentiation
WD-MD SCC
104
36 (64.1)
0.244
PD SCC
22
10 (54.5)
Skin invasion
No
111
38 (64.6)
0.095
Yes
15
8 (46.7)
Perineural invasion
No
70
19 (70.6)
0.011*
Yes
56
27 (51.8)
Lymphatic invasion
No
122
42 (64.6)
< 0.001*
Yes
4
4 (0)
Marrow invasion
No
104
33 (67.2)
0.005*
Yes
22
13 (40.4)
Close margin
> 0.7 cm
71
28 (58.7)
0.472
0.7 cm
55
18 (67.1)
Tumor depth
< 1 cm
52
12 (76.5)
0.006*
1 cm
74
34 (52.9)
110
Results
All the statistically significant results of univariate analyses for different study
end points; namely LC, NC, DMFS, DFS, DSS and OS, according to different clinical
and pathologic criteria, are summarized in (Table 18).
Table 18: Univariate analyses of 3-year local control (LC), neck control (NC), distant
metastases free survival (DMFS), disease free survival (DFS), disease specific survival (DSS)
and overall survival (OS) according to clinical data, SUV, TLG, and pathological
characteristics.
Characteristic
Gender
Age
Cigarette smoking
Alcohol drinking
Betel-quid chewing
Cancer sub-site
Treatment modality
Primary tumor TLG
Nodal SUVmax
Nodal TLG
Pathologic T status
Pathologic N status
Pathologic TNM stage
ECS
Differentiation
Skin invasion
Perineural invasion
Lymphatic invasion
Marrow invasion
Close margin
Tumor depth
ns = not significant
P-Value
LC
NC
DMFS
DFS
DSS
OS
ns
0.034
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
0.008
ns
0.004
ns
0.002
<0.001
<0.001
ns
0.007
0.001
0.003
0.004
0.003
0.041
0.002
ns
ns
0.001
0.033
<0.001
<0.001
<0.001
0.001
<0.001
0.006
<0.001
ns
ns
0.002
0.033
<0.001
<0.001
<0.001
<0.001
<0.001
0.001
<0.001
ns
ns
0.018
<0.001
0.005
ns
ns
0.007
<0.001
0.005
ns
ns
0.011
<0.001
0.005
ns
0.032
ns
0.017
ns
ns
0.002
ns
ns
ns
ns
ns
ns
ns
0.001
ns
ns
<0.001
0.013
<0.001
ns
ns
ns
0.002
ns
ns
ns
ns
<0.001
0.011
ns
ns
0.017
ns
111
0.006
Results
7.
Multivariate Analyses
a.
Local Control
Both age at diagnosis and invasion of bone marrow by the primary tumor were
independent prognostic factors for local control with significant difference (Table
19).
Table 19: Multivariate analysis of 3-year local primary tumor control (LC).
Risk factor
Age at diagnosis (years)
(> 40/ 40)
Pathologic T status
(pT2/pT3-T4)
Pathologic marrow invasion
(No/Yes)
LC
HR (95% CI)
(100/26)
4 (1.5 - 10.7)
0.006 *
(65/61)
2.8 (1 - 8)
0.059
(104/22)
3.4 (1.1 - 10)
0.029 *
Table is showing only the factors that remained in the final step of Cox-proportional hazard
model, forward stepwise method
b.
Neck Control
Poor tumor differentiation was the only factor remained in the hazard model as
risk factor for neck nodes recurrence with significant difference (Table 20).
Table 20: Multivariate analysis of 3-year neck control (NC).

Risk factor
Differentiation
(WD-MD/PD)
Close margin
(>0.7/ 0.7 cm)
NC
HR (95% CI)
(104/22)
3 (1.2 - 7.4)
0.015 *
(71/55)
0.3 (0.1 - 1)
0.052
112
Results
c.

Positive neck nodes, high nodal SUV and presence of lymphatic invasion were
independent bad prognosticator for DMFS with significant difference (Table 21).
Table 21: Multivariate analysis of 3-year distant metastases free survival
(DMFS).
Risk factor
Primary tumor TLG (TTLG)
( 71.4/< 71.4)
Nodal SUVmax (NSUVmax)
( 7.5/ < 7.5)
Pathologic N status
(pN0/pN+)
Pathologic lymphatic invasion
(No/Yes)
DMFS
HR (95% CI)
(63/63)
3.4 (1.1 - 10.3)
0.031 *
(96/30)
4 (1.5 - 11.1)
0.007 *
(59/67)
9.7 (1.2 - 77.9)
0.032 *
(122/4)
5.5 (1.5 - 20.5)
0.011 *
d.

Pathologically positive neck nodes, invasion of bone marrow and presence of
lymphatic invasion were independent bad prognosticators for DFS with significant
difference (Table 22).
Table 22: Multivariate analysis of 3-year disease free survival (DFS).
Risk factor
( 71.4/< 71.4)
Pathologic marrow invasion
(No/Yes)
Pathologic N status
(pN0/pN+)
(No/Yes)
DFS
HR (95% CI)
(63/63)
1.8 (0.9 - 3.4)
0.098
(104/22)
2.1 (1 - 4.2)
0.048 *
(59/67)
2.2 (1.1 - 4.4)
0.018 *
(122/4)
4.2 (1.4 - 12.8)
0.011 *
113
Results
e.

Primary tumor TLG, pathologic N status, lymphatic invasion and nodal SUV
were independent prognostic factors for DSS with significant difference (Table 23).
Table 23: Multivariate analysis of 3-year disease specific survival (DSS) .
Risk factor
( 71.4/< 71.4)
( 7.5/ < 7.5)
Pathologic N status
(pN0/pN+)
(No/Yes)
DSS
HR (95% CI)
(63/63)
3.3 (1.5 - 6.9)
0.002 *
(96/30)
2.3 (1.1 - 4.6)
0.024 *
(59/67)
2.8 (1.2 - 6.5)
0.017 *
(122/4)
10.5 (3.2 - 33.7)
< 0.001 *
f.
Overall Survival
Pathologic T & N status, lymphatic invasion and nodal SUV were independent
prognostic factors for DSS with significant difference (Table 24).

Table 24: Multivariate analysis of 3-year overall survival (OS).
Risk factor
Pathologic T status
(pT2/pT3-T4)
( 7.5/ < 7.5)
Pathologic N status
(pN0/pN+)
(No/Yes)
OS
HR (95% CI)
(65/61)
3.4 (1.8 - 6.5)
< 0.001 *
(96/30)
2.1 (1.1 - 3.9)
0.023 *
(59/67)
4.2 (1.9 - 9.1)
< 0.001 *
(122/4)
5.3 (1.7 - 16.2)
0.004 *
114
Results
8.
Risk Score
The risk factors most consistently identified as independent prognostic factors
for disease specific survival were used to formulate a risk score based on the presence
or absence of three parameters: primary tumor TLG 71.4, positive neck nodes and
nodal SUV 7.5. Patients were scored 0 if they do not have any of these risk factors,
scored 1 for having one, scored 2 if they have two and scored 3 for having the three
risk factors together. Four risk groups were identified, that showed significant
differences in terms of outcome (Table 25, Figures 52 & 53). Respectively, 3-yearDFS was 83%, 60%, 67%, and 19% (P < 0.001). Similarly, 3-year-DSS was 94%,
70%, 67% and 13% (P < 0.001).
The difference between score 0 and score 3 patients was statistically significant
for all the events. Patients with score 3 (n = 19) showed up to 32 times the risk of
score 0 patients for cancer death and survival does not exceed 13% (Table 25).
Table 25: Multivariate analysis of 3-year disease free (DFS) and disease specific
survival (DSS), according to the proposed risk score.
DFS
Score
Events
HR
(DFS%)
Score 0 # 36
Score 1
DSS
P
Events
HR
(95% CI)
(DSS%)
(95% CI)
6
(83.3%)
2
(93.9%)
39
15
(59.9%)
2.6
(1 - 6.6)
0.053
11
(70.4%)
5.6
(1.2 - 25.4)
0.025 *
Score 2
32
10
(66.7%)
2.4
(0.9 - 6.5)
0.097
10
(66.7%)
7.6
(1.7 - 34.9)
0.009 *
Score 3
19
14
(18.7%)
8
(3.1 - 21.1)
< 0.001 *
14
(12.8%)
32.2
(7.2 - 143)
< 0.001 *
Hash sign (#) points to the reference group where hazard ratio equals 1
Some of the important features of score 3 patients is summarized in (Table 26).

Eighteen out of the 19 patients were pTNM stage IV (only #19 is stage III) and17
patients had ECS. Fourteen out of these 19 patients developed metastatic spread.
115
Results
Only 6 out of the 19 patients were alive for more than 12 months from the date of
surgery.

to the proposed risk
score.
Figure
53:
Disease
according
to
the
proposed risk score.
116
Results
Table 26: Some of the characteristics of patients with score 3

Tumor Near
Nodes
Tumor
TLG
SUV
No.
pT Depth
Margin pN
With
N
Subsite T
cm
cm
ECS
1
Buccal
1173
14 T4
4.0
0.7 N2b
2
2
Gum
501
19 T4
3.5
0.5 N2b
3
3
Gum
393
12 T4
1.7
0.9
N1
2
4
Gum
380
15 T4
1.5
1.5 N2b
2
5
Buccal
364
13 T3
3.3
1.5 N2b
6
Buccal
351
19 T3
3.5
1.3 N2b
2
7
Gum
295
10 T4
3.4
1.0 N2c
3
8
Buccal
263
24 T2
1.2
1.0 N2b
8
9
Tongue
239
17 T4
2.6
0.7 N2b
9
10
Tongue
211
11 T4
1.4
0.8 N2b
2
11
Buccal
171
10 T4
1.1
0.6 N2b
1
12
Buccal
163
8 T4
1.5
0.6 N2b
8
13
Tongue
156
31 T2
0.9
1.3 N2b
14
Tongue
151
8 T4
2.0
1.2 N2c
5
15
Tongue
127
13 T4
2.2
0.6 N2b
4
16
Gum
114
15 T4
1.5
0.7 N2b
1
17
Buccal
96
19 T4
1.6
0.7 N2c
121
18
Buccal
73
14 T4
0.8
1.0 N2b
1
19
Buccal
72
20 T2
1.0
1.3
N1
1
Relapse
Pattern
M
M
M
M
TNM
M
TN
TM
TNM
NM
M
M
TM
M
Relapse
Duration
3
7
4
7
6
18
30
13
14
2
2
5
2
13
24
Final
Status
DOD
DOD
DOD
DOD
DOD
Died*
NER
DOD
NER
DOD
DOD
DOD
NER
DOD
NER
DOD
DOD
DOD
DOD
FU
Duration
5
8
5
8
8
7
21
19
30
16
17
4
36
4
15
6
3
19
34
* Patient number 6 received only 800 cGy of adjuvant radiotherapy and one cycle of chemotherapy then died of sepsis and
aspiration pneumonia at oncology ward. He was considered non-cancer death.
117
Results
9.
Risk Groups Based on ECS & NSUV

Stratification of DMFS and DSS according to the NSUVmax and the presence
or absence of ECS reveals that patients with positive ECS and high NSUVmax are at
higher risk for developing distant metastases and cancer death relative to those with
positive ECS but low NSUVmax. The 3-year DMFS was 40% in the first group
compared to 83% in the second group with significant difference (P = 0.019; Figures
54). The 3-year-DSS = 28% vs. 68% for the second group with significant difference
(P = 0.024; Figures 55).
Figure
54:
Distant
rate according to nodal
SUV in 40 patients with
positive ECS.
Figure
55:
Disease
according to nodal SUV
in 40 patients with
positive ECS.
118
Case Presentation
Case Presentation
Case 1: Score 0-patient
Male patient, 69-year-old, he had the habits of smoking cigarettes, alcohol
drinking, and betel nut chewing. He
presented to the hospital with MD SCC
of the right tongue, clinically staged
cT2 N1 M0
PET/CT revealed an FDG avid
lesion in right tongue mucosa, TSUV 11
& TTLG 26.
Radical surgery was planned on
5th July 2006 with elective ipsilateral
level I-III neck dissection.
Pathology
showed
nearest
margin 1.8 cm, tumor depth = 0.5 cm.

Negative
lymphatic,
for
skin,
perineural
bone
marrow,
or
vascular
invasions. All the 40 dissected LNs

were negative.
The patient was treated by
surgery alone, with no recurrence till
his last follow-up 47 months after
surgery.
119
Case Presentation
Case 2: Score 1-patient (pN+)

presented to the hospital with MD
SCC of the left buccal mucosa,
clinically staged cT2 N0 M0
lesion in left buccal mucosa, TSUV 14
& TTLG 61 (and also suggested a left
level I LN).
18th July 2006 with elective ipsilateral
level I-III neck dissection.
Pathology
showed
nearest

Negative for skin, bone marrow,
lymphatic
or
vascular
invasions.
Perineural invasion was positive. One

of the 46 dissected LNs was positive
(pT2 N1) and showing micro ECS.
The patient was treated by
surgery followed with CCRT, with no recurrence till his last follow-up 47 months
after surgery.
120
Case Presentation
Case 3: Score 2-patient (high NSUV & pN+)

Male patient, 44-year-old, he had the habits of alcohol drinking and betel nut
chewing. He presented to the hospital with MD SCC of the left buccal mucosa,
clinically staged cT3 N1 M0
PET/CT revealed an FDG
avid lesion in left buccal mucosa,
TSUV
16 & TTLG 130 (and also
suggested a left level I LN, with

NSUV
=5 & NTLG = 3).

Radical
surgery
was
planned on 21st June 2006 with

therapeutic ipsilateral level I-III
neck dissection.
Pathology showed nearest
margin 1 cm, tumor depth = 1.6
cm. Negative for skin, bone
marrow, lymphatic or vascular
invasions. Perineural invasion was
positive. One of the 48 dissected
LNs was positive (pT2 N1) and
showing macro ECS.
The patient was treated by surgery followed with CCRT.
During follow-up, an irregular soft tissue mass of about 1.7 cm in size is noted
at the anteroinferior margin of the flap, however, aspiration was negative for
malignancy and follow-up showed no evidence of recurrence till his last follow-up 48
months after surgery.
121
Case Presentation
Case 4: Score 3-patient with a survival of 34 months

drinking, and betel nut chewing. He presented to the hospital with WD SCC of the
right buccal mucosa, clinically
staged cT2 N1 M0
PET/CT revealed an FDG
avid
lesion
in
right
buccal
mucosa, TSUV 23 & TTLG 71 and

positive
level
Ib
lymphadenopathy, NSUV 20.

Radical
surgery
was
planned on 28th February 2007

with level I-III neck dissection.
Pathology showed nearest margin
1.3 cm, tumor depth = 1 cm.
Negative for skin, bone marrow
lymphatic or perineural invasions
vascular invasion. One out of 40
lymph nodes were positive with
ECS.
CCRT was initiated. He
was
free
on
follow-up.
On
December 2008 (23 months from

surgery), he developed right lower lung nodule. After biopsy, this nodule was
resected, with post-operative CTH. On November 2009, recurrence of lung lesion
with mediastinal lymphadenopathy and pleural effusion occurred.
122
Case Presentation

drinking, and betel nut chewing. He presented to the hospital with WD SCC of the
right gum, clinically staged cT4b N2b M0
PET/CT revealed an FDG avid lesion in right lower gum, TSUV 16 & TTLG
295
and
positive
level
Ib
lymphadenopathy, SUV 10.

Radical
surgery
was
planned on 21st March 2007 with

level
I-III
Pathology
neck
showed
dissection.
nearest
margin 1 cm, tumor depth = 3.4

cm. Positive for skin and bone
marrow invasion. Negative for
lymphatic, vascular or perineural
invasions. Three out of 104
lymph nodes were positive, 3 of
them had ECS.
After finishing his adjuvant CCRT, he was free on follow-up. He developed
second primary tumor (lower gum T4a), which was resected. However, recurrence
with progression took place. He died of second primary tumor, 21 months after the
primary surgery.
123
Case Presentation

presented to the hospital with MD SCC
of the left tongue, clinically staged
cT4a N2b M0
lesion in right buccal mucosa, TSUV 12
&
TTLG
127 and positive level Ib

14th December 2006 with level I-III
neck dissection. Pathology showed
nearest margin 0.6 cm, tumor depth =
2.2 cm. Negative for skin, bone marrow
lymphatic
or
perineural
invasions
vascular invasion. Five out of 31 lymph

nodes were positive, 4 of them had
ECS.
CCRT was completed but the
patient developed extensive esophageal
second primary tumor. Death from
second primary occurred 15 months
from his primary surgery.
124
Case Presentation
Case 7: Patient with positive ECS and low nodal SUV

Male patient, 50-year-old, he had
the habits of smoking cigarettes and
alcohol drinking. He presented to the
hospital with MDSCC of the right floor
of mouth, clinically staged cT2 N1 M0.
PET/CT revealed a right floor of
the mouth lesion, which is mildly FDG
avid TSUV 6 & TTLG 17 and positive
level II lymphadenopathy, SUV 3.
Radical surgery was performed on
30th August 2007 with level I-III neck
dissection. Pathology showed nearest
Positive for lymphatic and perineural
invasions.
Negative
for
skin,
bone
marrow or vascular invasion. Three out

of 95 lymph nodes were positive; ECS
was seen in 2 nodes.
After one cycle of adjuvant CCRT,
he developed oral mucosal lesion (Nov.
2008). CT revealed no evidence of
recurrence locally, however, PET/CT showed possible recurrence at left tongue (SUV
6.6) in addition to right upper lung and multiple mediastinal and hilar
lymphadenopathy. Two months later dissemination of the metastases to liver, lung,
lymph nodes and bones. He died of cancer 3 months later (20 months from surgery).
125
Case Presentation
Case 8: Patient with positive ECS and high nodal SUV

Male patient, 64-year-old, he had the habits of smoking cigarettes and betel nut
chewing. He presented to the hospital with MDSCC of the right buccal mucosa,
clinically staged cT2 N2b M0.
PET/CT revealed a right buccal
FDG avid lesion, TSUV 15 & TTLG 33
and positive level Ib, II, III, IV, V
11th October 2006 with ipsilateral level IV neck dissection and contralateral level
I-III
dissection.
Pathology
showed
nearest margin 0.9 cm, tumor depth = 0.5

cm. Negative for skin, bone marrow,
lymphatic,
vascular,
or
perineural
invasions. Twenty out of 47 lymph nodes

were positive, including one positive
node in level IV, ECS was seen in 7
nodes.
CCRT was initiated. Four months after surgery, while the patient is still on
CCRT, he started to complain of seizure. CT revealed right scalp soft tissue
component, which was aspirated to reveal SCC. Two months later dissemination of
the metastases to skin, bilateral neck, retropharyngeal area, chest wall, upper
mediastinum. He died of cancer two months later (8 months from surgery).
126
Discussion
Discussion
The World Health Organization expects a worldwide rising OSCC incidence in
the next decades (2). Currently, oral cancer represents the eighth most common
cancer worldwide, but the incidence varies between different geographic regions (1).
In Taiwan, OSCC is ranked fourth in cancer incidence and fifth in cancer mortality
among Taiwanese men (34). The mortality rate jumped more than two folds over the
last decade (35). Furthermore, the malignant process and its treatment can
compromise speech, mastication, swallowing and appearance, leading to a
detrimental effect on quality of life and patient well-being (239). Considerable
research on the prevention, early diagnosis, risk stratification and management is
ongoing.
This work was done in molecular imaging center in Chang Gung Memorial
Hospital, Taiwan as part of a larger prospective project, aiming at better
understanding of the molecular basis of OSCC in addition to risk stratification using
novel markers.
The identification of novel prognosticators in cancer is essential for tailoring
the therapeutic approach. Classically, prognostic factors in cancer have been derived
from anatomical and morphological rather than functional risk factors. Evidence
suggests that the biological information obtained from 18F-FDG PET/CT could be of
paramount importance for modifying or customizing the therapeutic approach.
In the current work, multiple pathological and clinical factors including PET
parameters have been explored for possible relation to the prognosis of OSCC.
Younger age was found to be a bad sign for local control. Although the age is a
controversial factor, younger age has been associated with worse outcomes in the
works of Iype et al (37) (38), Myers et al (39) and Liao et al (79). It was suggested
that oral neoplasia in young patients may represent a special disease entity (240, 241).
127
Discussion
Bone marrow invasion was also associated with poorer local control. This is
also a controversial finding. Some authors report unfavorable outcomes (242-245),
others did not find that association (246-248). Reports vary in their guidelines of
bone resection in the presence of cortical or marrow invasion, and also vary in their
post-operative management. More consistent methodology is needed to further
evaluate whether marrow invasion affects the control rates and outcome or not.
Tumor differentiation is important predictor of occult neck metastases (249)
and it has also been reported to be an independent bad prognostic factor for worse
regional control (245, 250). Also we found that poor tumor differentiation is linked to
poor regional control. Poorly differentiated tumors have an increased propensity for
regional metastasis and a poorer prognosis.
It is established that poor survival is linked to poor loco-regional control (71,
73, 74). Liao et al emphasized the bad prognostic impact of nodal metastases,
especially with ECS and lower neck levels IV& V (72, 214, 245). In this work, both
T and N status were independently associated with shorter survival. The presence of
ECS alone did not achieve statistical significance, most likely due to relatively small
number of patients having ECS (n = 40).
Tumor depth was associated with survival in many studies, but the exact cutoff was variable and standardization of the measurement method is lacking. We
choose a cut-off of 1 cm as described by Liao et al in their analysis of local control
for 827 patients (71). In the present work, it was strongly associated with poor
survival in univariate analysis, but it does not withstand in multivariate analysis.
Among the clinical factors, the potential prognostic role of presurgical
18
F-
FDG PET/CT has been studied using two main objective semiquantitative parameters
were examined (SUV and TLG) at the primary tumor and neck lymph nodes.
128
Discussion
Being more robust, reproducible, and less affected by the size and placement of
the region of interest (ROI) (131), SUVmax was used in this work, and also it has
been widely used for most of the routine work (120, 153). However, the SUVmax
reflects the glucose avidity of the tumor at the most active pixel only, regardless the
volume and the heterogeneity of the tumor, which may not represent a real index of
the tumor burden.
Similarly, the pT stage is not representative of the three-dimensional tumor
volume. Therefore, it can be expected that tumor burden, measured by a threedimensional volumetric method, may be more reliable for the assessment of tumor
extent, and serve as a better independent prognostic factor than pT stage (166).
The tumor volume, although labor-intensive, can be measured by CT and MRI,
and found to correlate well with the treatment outcomes in some head and neck
cancers (251, 252). In PET/CT, the high tumor to background ratio (contrast
resolution) makes it easier to measure the metabolic tumor volume (MTV) (253).
Nevertheless the tumor edge on PET scan appears fuzzy to the contouring
physician, that is in contrast to CT and MRI, where tumors have well-defined
anatomic margins due to much better spatial resolution (161).
Different methods for contouring the PET volumes have been proposed but
hampered by the difficulty of pathological validation of these methods (254, 255).
Tumor geometry, tissue retraction and tumor heterogeneity are the main obstacles for
full pathological volume estimation (256).
In this work, the best contouring method was selected based on the best
correlation between the maximum axial diameter in the pathology specimen and the
corresponding diameter obtained from different contouring methods. The absolute
threshold based on SUVmax 3 gave the best correlation for the primary tumor, while
that of SUVmax 2.5 was the best correlation for the cervical lymph nodes.
129
Discussion
Baek et al. have previously found that absolute threshold (SUVmax 3.5) could
predict the pathological volume in two groups of oral cavity cancer patients (with and
without dental artifacts). It was reported that dental artifacts might increase the
uptake in CT corrected images and cause elevation of the SUV (180). That might
partially explain why our threshold for volume assessment was less. In addition, the
number of patients with locally advanced tumor (n =10) in their study was far less
than in the current study. It worth noting that a detailed description of the
pathological methods used to overcome tissue retraction was not described in that
work (180).
Seitz et al. prospectively used a cut-off value of 3.5 to delineate the tumor in
66 patients with oropharyngeal and oral cavity SCC. The pathological volume was
determined from visualization of gross tumor infiltration in the fresh specimens,
which were collected en bloc in the operation room and were placed in a polystyrene
cast marked longitudinally in the three dimensions and filled with gelatin solution in
order to avoid shrinkage of the specimen. They found no differences between
PET/CT and MRI regarding the diagnostic performance (185). It is known that higher
thresholds will result in smaller volumes, that may explain the higher SUV cut-off
value especially if we know that their study included only 20 patients with advanced
local disease. Whether or not the application of different threshold for each cancer
stage will give better correlation with the pathologic specimen needs further
evaluation.
Furthermore, Daisne et al compared CT, MRI, and FDG PET for delineation of
tumor volume in pharyngolaryngeal SCC, with the results validated by surgical
specimen fixed by non-retratction methods. They indicated that FDG PET was the
most accurate modality for measuring tumor volume (171). They developed a
customized home-made segmentation algorithm to delineate the tumor volume
automatically based on the measured signal-to-noise ratio (257). Their methods may
make it difficult to compare their work to others.
130
Discussion
In this work, it seems that the prognostic significance of
18
F-FDG PET
parameters may vary depending on the specific endpoint. Primary tumor SUV
(TSUVmax) did not show significance for any of the study outcomes. Previous work
by Liao et al showed that TSUVmax was linked to poor LC and death in OSCC (214).
However, they focused on patients with pathologically positive neck nodes and they
used a cut-off for SUV of 19.3. It was selected based on the lowest P-value obtained
from log-rank test, for each SUV value with LC, a method that might be criticized for
being biased to the clinical outcome.
In order to have more accurate and representative measures of the metabolic
tumor burden, we added the TLG in this analysis, in addition to SUVmax, as a
relatively new semiquantitative parameter derived from FDG PET.
The concept of total lesion glycolysis (TLG) was first suggested by Larson et
al. It refers to the product of MTV multiplied by the average SUV within the tumor
volume. It was suggested as a better index for both functional tumor burden (MTV)
and biological aggressiveness (SUV) (12).
Few recent studies have demonstrated that MTV is associated with prognosis
in head and neck cancer patients treated by either surgery or RT/CRT (253, 258,
259). Studies discussing the relation of TLG to outcomes in HNC were scarce. Chan
et al measured SUVmax, MTV, TLG in 57 patients with nasopharyngeal carcinoma
(NPC) and concluded that these metabolic parameters were positively correlated with
T-stage in primary NPC and suggested their complementary role to TNM staging in
prognostication of NPC patients (260). Another larger study using baseline TLG in
196 patients with stage IV NPC patients found that TLG values greater than 330
independently predicted disease-free survival and overall survival (261). Analysis of
both TLG and mean SUV in 88 patients with HNC showed that both parameters are
statistically significant although mean SUV seems to be more strong prognosticator
(262).
131
Discussion
In the present work, TLG of the primary tumor (TTLG) was shown to be
independent prognostic factor for distant metastases free survival (DMFS), disease
free survival (DFS) and disease specific survival (DSS). Other studies demonstrated
that metabolic activity of FDG reflects tumor burden, cellular density and
proliferation indices (201). These criteria could be linked to disease aggressive
behavior.
One of the major determinants of prognosis in OSCC is the presence of
cervical LN metastases (263, 264). It was reported that FDG PET/CT has suboptimal
diagnostic sensitivity and specificity for primary staging of the neck in OSCC patient
(185, 190, 197, 265). The diagnostic performance results from the current work
confirm these previous reports with modest sensitivity and specificity. One of the
sources of high false positive rates is the presence of reactive lymphadenopathy,
which expresses GLUT1 in their secondary follicles (266). Add to that, and because
of limited spatial resolution, PET appears insufficiently sensitive to identify small
neck lymph node metastases in OSCC patients (190). It worth noting that in the
current work 21% (14 out of 67 pN+ patients) had a LN diameter < 1 cm and 37%
had a LN diameter < 1.5 cm.
Nevertheless, an important strength of the use of PET is the ability to measure
the intensity of metabolic activity by means of SUV, MTV and TLG. Nodal SUV
(NSUVmax) has been shown to correlate with the outcome in OSCC (190, 217, 219).
In the current work, NSUVmax was also shown to be independent prognostic factor
for DMFS, DSS and OS.
Furthermore, NSUVmax could be used to further stratify the patients with
positive extra-capsular spread (ECS). ECS is generally considered to be one of the
most important independent risk factors for survival in patients with head and neck
cancer (73, 115, 116). Interestingly, of the 40 patients with positive ECS, 15 had
NSUVmax
< 7.5, only 2 of them showed distant metastasis and 4 died of cancer
(DMFS rate = 83%, DSS = 68%). On the other hand, 13 out of the remaining 25
132
Discussion
patients with NSUVmax 7.5 developed distant relapse and 16 had cancer related
death (DMFS = 40%, DSS = 28%). The statistical difference for both DMFS and
DSS was significant (P = 0.019 & 0.024, respectively). It is thus suggested that novel
therapeutic strategies and close follow-up schedules aiming to increase distant control
rate or survival should be especially pursued in patients with ECS combined with
high NSUVmax.
However, till now there is no published clinical trial in oral cavity cancer based
on the prognostic data results from PET, possibly because most of these prognostic
reports belong to a single center experience, and the cut-off value for the worse
outcome varied between the published studies.
As a new prognostic parameter, TLG of neck lymph nodes was studied the
current work; however, nodal TLG did not show prognostic significance for different
outcome endpoints. Many obstacles hamper the accuracy of LN volume delineation
on FDG PET; (a) The limited spatial resolution, (b) The problem of partial volume
effect, which lead to underestimation of FDG uptake in the small sized LNs, (c) The
absence of established objective criteria for identifying the PET positive LNs, and (d)
The technical difficulty of delineating multiple LNs in one or multiple neck levels.
In this work, a cut-off SUV of 2.5 was used to for delineation, based on the
best correlation to the pathologic diameters. It is known that many pathological LNs
may have SUV less than 2.5 (185, 190) but we choose to stick to the same
methodology used for the primary tumor delineation. In addition, only the LN with
the highest uptake was delineated, which may not be a real index of the total nodal
biological tumor burden. Further studies that classify LNs into groups according to
their diameters and specify different cut-off value for each category may give
different results.
A prognostic scoring system based on the presence or absence of the 3 most
consistent prognostic factors obtained from MVA was formulated. These factors are:
133
Discussion
positive pathological nodal status, high TTLG and high NSUV. That scoring system
identified 4 groups of patients with no, only one, two or the three risk factors.
Respectively, 3-year-DFS was 83%, 60%, 67%, and 19% (P < 0.001). Similarly, 3year-DSS was 94%, 70%, 67% and 13% (P < 0.001). Score 1 patients (n = 36) had
good cancer control and excellent survival using the current treatment and follow-up
approach; however, it seems that score 1 and score 2 patients (n = 39 & 32,
respectively) had intermediate control and survival rates. Further work is needed to
study the differences within this group of patients and further identify their prognosis.
In contrast, patients with score 3 (n = 19) were at notably higher risk for recurrence
and cancer death compared to patients lacking these risk factors (P < 0.001 for both;
HR = 8 & 32, respectively).
Within score 3 patients, 17 of the 19 patients died during the follow-up period
(Table 26). Fourteen of them died due to cancer, two because of development of a
second primary tumor, which was in the alveolar ridge patient number 7 or in the
esophagus patient number 15, and one died due to sepsis and aspiration pneumonia
during the course of adjuvant CCRT patient number 6.
The fourteen patients suffered treatment failure and did not survive. The
pattern of relapse was mainly distant failure (13/14 patients had distant metastases).
In 8 patients, distant metastases was isolated, it was associated with local recurrence
in 2 patients number 11 & 18, regional recurrence in 1 patient number 14, and
both local and regional in the remaining 2 patients number 5 & 12. The remaining
patient had locoregional failure after 11 months from surgery number 10. The
median time for development of relapse in these 14 patients was 7 months (range: 224 months) and the median interval between confirmed diagnosis of recurrence and
death ranged from 1 week to 11 months (median = 2 months). Interestingly, within
score 3 patients, the mean TTLG tends to be higher among the patients with poorest
survival (those who survived less than 9 months) compared to those who survived
more than 9 months (mean TTLG = 368 & 178, respectively; P = 0.09). Such findings
134
Discussion
may reflect aggressive tumor behavior, which is at least partly unleashed by the
metabolic activity seen in the high primary tumor TLG and nodal SUV.
It is realized that these results cannot represent the basis for changing the
management, but it may set the stage for clinical trials utilizing more aggressive
chemoradiation regimens or novel therapies (e.g. target therapy) that are specifically
directed to the group of patients with the highest risk.
Also, whether or not a more strict and close systemic follow-up protocol for
these patients can pick the distant failures earlier and may help in their management
is open for future work.
This work has some advantages: its prospective design with reasonable sample
size and homogeneous population with a standardized management approach. Also, it
is the first study that reported the prognostic significance of TLG in oral cavity
cancer patients. However, this work also suffers some potential limitations; (a) it is a
single center experience, from Taiwanese population, which limit the generalization
of the results, (b) the follow-up period was 24 months, which is not long enough for
studying the 5-year-survival, (c) the application of anti-retraction pathological
fixation methods was not feasible, and (d) the data from lymph node volume may not
be accurate based on a single cut-off value of 2.5.
135
Conclusion and Recommendations
Conclusion and Recommendations
The metabolic information obtained from FDG PET/CT, measured as total

lesion glycolysis (TLG) and standardized uptake value (SUV) at both primary
tumor and neck lymph nodes, may present independent prognostic data in
patients with oral cavity squamous cell carcinoma for both locoregional control
and survival.
The presence of high SUV in the lymph nodes, together with extracapsular
spread (ECS), can define a group of patients at higher risk for distant
metastasis and poor survival.
A scoring system that incorporates primary tumor TLG and nodal SUV, in
addition to the established pathologic nodal involvement can stratify the risk in
oral cavity SCC into 4 groups. The group having the three risk factors was
identified for having 32 times higher risk for cancer death.
High risk group could be a potential target for clinical trials involving the use
of more aggressive treatment regimens or novel approaches like target therapy.
Multicentric prospective clinical trials may be needed to define the exact

clinical impact of these results.
136
Summary
Summary
Oral cancer is the eighth most common cancer worldwide. It refers to cancers
developing in both oropharynx and oral cavity. The oral cavity is the one concerned
in this work. It anatomically includes lip, anterior two thirds of the tongue, floor of
the mouth, buccal mucosa, retromolar trigone, upper and lower alveolar ridges, and
hard palate.
Squamous cell carcinoma (SCC) represents more than 90% of cancers arising
in this area. Surgery is the main stay for resectable OSCC.
Post-operative
radiotherapy (RT) or chemoradiation (CRT) is indicated in the presence of adverse

features extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or
N3 nodal disease, selected pT2N0-N1 disease, nodal disease in levels IV or V,
perineural invasion, vascular embolism.
The prognostic factors that may modify the outcome have been described as
patient-related (gender, age, smoking, drinking, chewing betel quid), tumor-related
(site, stage, thickness, extracapsular spread, differentiation, perineural invasion,
angiogenesis, human papilloma virus infection), and treatment-related factors
(resection margin, adjuvant post-operative therapy, and cervical lymph node
dissection).
Although PET scanning has some limitations especially in the head and neck
region, it has been increasingly used for staging, restaging and risk stratification. The
objective semiquantitative parameters derived from FDG PET scan (namely
standardized uptake value SUV and total lesion glycolysis TLG) represent
valuable metabolic information that correlates well with the outcome in many cancers.
This work studied the prognostic role of the presurgical SUVmax and TLG, in
addition to other clinical and pathological factors, in identifying high risk OSCC. The
TLG is defined as the product of metabolic tumor volume [MTV] from FDG PET &
average SUV within the same volume.
The current work recruited 126 patients with pathology proven OSCC
underwent presurgical staging 18F-FDG PET/CT study. All patients were followed up
137
Summary
till death or at least 24 months from the time of their surgery. The data were
prospectively collected but analyzed retrospectively. Primary tumor and metastatic
lymph nodes were delineated using different methods (absolute threshold: SUV 2.5, 3,
3.5 & 4, and percentage of the maximum SUV 30%, 40%, 50%, 60 & 70%). The
lymph nodes, which were delineated, were considered metastatic based on consensus
agreement among the head and neck oncology group according to clinical data,
examination and conventional modalities (CT/MRI). The best threshold for volume
delineation was selected based on the best correlation between the maximum axial
tumor diameter from the pathology specimens and the maximum diameter from the
delineated PET/CT volumes in different thresholds, with no correction for tissue
retraction. Accordingly, MTV of the primary tumor (TMTV) was chosen based on
absolute SUVmax threshold of 3, while that of the lymph nodes (NMTV) was derived
from absolute threshold of 2.5. To minimize the effect of partial volume effect (PVE)
on delineation of the primary tumor volume, patients with T1 disease were excluded.
However, PVE was inevitable in delineating small neck lymph nodes. No correction
for PVE was applied.
The median value of SUVmax and TLG were used to dichotomize the patients
into two categories. Those values above (or equal to) the median were referred to as
high SUVmax and high TLG in contrast to the group with low SUVmax and low
TLG who had these values below the median.
Local control (LC), neck control (NC), distant metastasis free survival (DMFS),
disease-specific (DSS) and overall survival (OS) were calculated by Kaplan-Meier
method and compared in different groups using log-rank test. Cox proportional
hazard model was used to identify the independent study prognosticators. These
independent prognostic factors were used to build a scoring system for OSCC
patients.
In the current work, the median TTLG was 71.4 and median NSUVmax was 7.5.
The presence of high NSUVmax, together with extracapsular spread (ECS), could
further define a group of patients at higher risk for distant metastasis and poor
138
Summary
survival, compared to those with ECS and lower NSUV. Patient with high NSUVmax
7.5 and ECS showed higher rate of distant failure, compared to those with ECS and
NSUVmax
< 7.5 (3-year DMFS = 40% vs. 83%, respectively; P = 0.019). Similarly,
the first group also experienced poor survival (3-year-DSS = 28% vs. 68%,
respectively; P = 0.024).
TTLG
and NSUVmax were found to correlate well with the different study
endpoints in univariate and multivariate analyses. Patient with high TTLG had 3-year
DFS of 52% vs. 74% for patient with low TTLG (P = 0.007), the 3-year-DSS were
53% vs. 84%, respectively (P < 0.001). Similarly, patient with high NSUV had 3-year
DFS of 42% vs. 70% for patient with low NSUV (P = 0.001), the 3-year-DSS were
39% vs. 78%, respectively (P < 0.001).
It has been demonstrated that the primary tumor TLG, neck nodal SUV and
pathological nodal status are independent prognostic factors for OSCC control and
survival. A scoring system that incorporates those three factors was formulated. It
could stratify the risk in OSCC into 4 groups (score 0: have none of the three risk
factors, score 1: have one risk factor, score 2: have 2 risk factors, and score 3
patients have the 3 risk factors). Respectively, 3-year-DFS was 83%, 60%, 67%, and
19% (P < 0.001). Similarly, 3-year-DSS was 94%, 70%, 67% and 13% (P < 0.001).
Score 0 patients (n = 36) had good cancer control and excellent survival using
the current treatment and follow-up approach. Score 1 and score 2 patients (n = 39 &
32, respectively) had intermediate cancer control and survival rates and further work
is needed to study the differences within this group of patients and further identify
their prognosis.
Score 3 patients, who had all the three risk factors, (n = 19) were identified for
having the highest risk for cancer recurrence and poor survival. The hazard of cancer
recurrence and death were 8 & 32 times the reference group lacking the same risk
factors.
139
Summary
Within this group, 13 patients had distant failures and 14 died of cancer, while
3 died due to second primary tumor or sepsis. Only two patients were surviving by
the end of follow-up period.
The median time for development of relapse (n = 14) was 7 months (range: 224 months) and the median interval between confirmed diagnosis of recurrence and
death ranged from 1 week to 11 months (median = 2 months).
The mean TTLG tends to be higher among the patients with poorest survival
(those who survived less than 9 months) compared to those who survived more than 9
months (mean TTLG = 368 & 178, respectively; P = 0.09).
That vigorous cancer behavior may be unleashed by the high metabolic activity
seen at the primary tumor and nodal metastases using TTLG and NSUV, respectively.
It is assumed that this high risk group might be a potential target for clinical
trials involving the use of more aggressive treatment regimens or novel approaches
like target therapy.
Further multicentric prospective clinical trials may be needed to define the
exact clinical impact of these results.
140
References
References
1.
Mignogna MD, Fedele S, Lo Russo L. The World Cancer Report and the burden of oral
cancer. Eur J Cancer Prev. 2004 Apr;13(2):139-42.

2.
Petersen PE. The World Oral Health Report 2003: Continuous improvement of oral health
in the 21st century - the approach of the WHO Global Oral Health Programme. Geneva2003.
3.
Pfister DG, Ang KK, Brizel D, Burtness BA, Cmelak AJ, Colevas AD, et al. NCCN Clinical
Practice Guidelines in Oncology. Head and Neck Cancers.V.2.2010. National Comprehensive

Cancer Network; 2010 [cited 2010 26 December 2010]; Available from:
http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf.
4.
Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin. 2002 Jul-
Aug;52(4):195-215.
5.
Wong RJ, Lin DT, Schoder H, Patel SG, Gonen M, Wolden S, et al. Diagnostic and
prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography for recurrent head

and neck squamous cell carcinoma. J Clin Oncol. 2002 Oct 15;20(20):4199-208.
6.
Minn H, Lapela M, Klemi PJ, Grenman R, Leskinen S, Lindholm P, et al. Prediction of
survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer. J Nucl Med. 1997
Dec;38(12):1907-11.
7.
Allal AS, Dulguerov P, Allaoua M, Haenggeli CA, El-Ghazi el A, Lehmann W, et al.
Standardized uptake value of 2-[(18)F] fluoro-2-deoxy-D-glucose in predicting outcome in head

and neck carcinomas treated by radiotherapy with or without chemotherapy. J Clin Oncol. 2002
Mar 1;20(5):1398-404.
8.
Halfpenny W, Hain SF, Biassoni L, Maisey MN, Sherman JA, McGurk M. FDG-PET. A
possible prognostic factor in head and neck cancer. Br J Cancer. 2002 Feb 12;86(4):512-6.
141
References
9.
Schwartz DL, Rajendran J, Yueh B, Coltrera MD, Leblanc M, Eary J, et al. FDG-PET
prediction of head and neck squamous cell cancer outcomes. Arch Otolaryngol Head Neck Surg.
2004 Dec;130(12):1361-7.
10.
Torizuka T, Tanizaki Y, Kanno T, Futatsubashi M, Naitou K, Ueda Y, et al. Prognostic
value of 18F-FDG PET in patients with head and neck squamous cell cancer. AJR Am J Roentgenol.
2009 Apr;192(4):W156-60.
11.
Keyes JW, Jr. SUV: standard uptake or silly useless value? J Nucl Med. 1995
Oct;36(10):1836-9.
12.
Larson SM, Erdi Y, Akhurst T, Mazumdar M, Macapinlac HA, Finn RD, et al. Tumor
Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using
PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis. Clin
Positron Imaging. 1999 May;2(3):159-71.
13.
Erdi YE, Macapinlac H, Rosenzweig KE, Humm JL, Larson SM, Erdi AK, et al. Use of
PET to monitor the response of lung cancer to radiation treatment. Eur J Nucl Med. 2000
Jul;27(7):861-6.
14.
Guillem JG, Moore HG, Akhurst T, Klimstra DS, Ruo L, Mazumdar M, et al. Sequential
preoperative fluorodeoxyglucose-positron emission tomography assessment of response to

preoperative chemoradiation: a means for determining longterm outcomes of rectal cancer. J Am
Coll Surg. 2004 Jul;199(1):1-7.
15.
Roedl JB, Colen RR, Holalkere NS, Fischman AJ, Choi NC, Blake MA. Adenocarcinomas
of the esophagus: response to chemoradiotherapy is associated with decrease of metabolic tumor

volume as measured on PET-CT. Comparison to histopathologic and clinical response evaluation.
Radiother Oncol. 2008 Dec;89(3):278-86.
16.
Arslan N, Miller TR, Dehdashti F, Battafarano RJ, Siegel BA. Evaluation of response to
neoadjuvant therapy by quantitative 2-deoxy-2-[18F]fluoro-D-glucose with positron emission

tomography in patients with esophageal cancer. Mol Imaging Biol. 2002 Jul;4(4):301-10.
142
References
17.
Benz MR, Allen-Auerbach MS, Eilber FC, Chen HJ, Dry S, Phelps ME, et al. Combined
assessment of metabolic and volumetric changes for assessment of tumor response in patients with
soft-tissue sarcomas. J Nucl Med. 2008 Oct;49(10):1579-84.
18.
Costelloe CM, Macapinlac HA, Madewell JE, Fitzgerald NE, Mawlawi OR, Rohren EM, et
al. 18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma. J

Nucl Med. 2009 Mar;50(3):340-7.
19.
Strobel K, Skalsky J, Steinert HC, Dummer R, Hany TF, Bhure U, et al. S-100B and FDG-
PET/CT in therapy response assessment of melanoma patients. Dermatology. 2007;215(3):192-201.

20.
Greene FL, American Joint Committee on Cancer. AJCC cancer staging atlas. [1st ed. [New
York]: Springer; 2006.

21.
Spiegel J, Deschler D, Day T, Girod D. Anatomy of the Oral Cavity and Related Structures.
In: Day TA, Girod DA, editors. Oral cavity reconstruction. New York: Taylor & Francis Group,
LLC; 2006. p. 11-22.
22.
Eveson J, Cardesa A, Slootweg PJ. Oral Cavity. Pathology Of The Head and Neck:
Springer; 2006. p. 96-8.

23.
Keberle M, Hermans R, Baert AL, Brady LW, Heilmann HP, Molls M, et al. Neoplasms of
the Oral Cavity. In: Robert H, editor. Head and Neck Cancer Imaging. Berlin Heidelberg Springer;
2006. p. 103-7.
24.
Ellis H. The tongue and floor of the mouth. In: Ellis H, editor. Clinical Anatomy: Applied
anatomy for students and junior doctors. 11 ed: Balckwell; 2006. p. 272-6.
25.
Thammaroj J, Bhattacharya J, Butler P, Mitchell AWM, Ellis H. The extracranial head and
neck. In: BUTLER P, A MITCHELL DWM, ELLIS H, editors. Applied Radiological Anatomy for
Medical Student. 1 ed: Cambridge University Press; 2007. p. 96.
26.
Nour SC, Lewin JS, Mafee ME, Valvassori GE, Becker M. Anatomy of the Parapharyngeal
and Masticator Spaces. In: Mafee ME, Valvassori GE, Becker M, editors. Imaging Of The Head
And Neck. 2nd ed. New York: Thieme; 2005. p. 580-92.
143
References
27.
Moore KL, Dalley AF, Agur AMR. Head. In: Moore KL, Dalley AF, Agur AMR, editors.
Clinically oriented anatomy. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 8871038.
28.
Rahman M, Sakamoto J, Fukui T. Bidi smoking and oral cancer: a meta-analysis. Int J
Cancer. 2003 Sep 10;106(4):600-4.

29.
Netter FH, Machado CA, Hansen JT. Lymph Vessels And Nodes Of The Head And Neck
2003.
30.
Deschler DG, Day TA, Sharma AK, Kies MS. Pocket guide to neck dissection classification
and TNM staging of head and neck cancer. 3rd ed. Alexandria, VA: American Academy of
Otolaryngology--Head and Neck Surgery Foundation; 2008.
31.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-
Oct;60(5):277-300.
32.
La Vecchia C, Lucchini F, Negri E, Levi F. Trends in oral cancer mortality in Europe. Oral
Oncol. 2004 Apr;40(4):433-9.

33.
NCI. National Cancer Institute, Cairo University, Egypt. Cancer Registry 2002-2003. Cairo,
Egypt 2004 [cited 2010 26 December 2010]; Available from:

http://www.nci.cu.edu.eg/lectures/NCI%20registry%202002-03.pdf.
34.
Taiwan cancer registry, 2008 annual report. Taipei [Accessed February 5, 2009 ]; Available
from: http://crs.cph.ntu.edu.tw/.
35.
Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, et al. Head and neck cancer in
the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci. 2008
Aug;99(8):1507-14.
36.
Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Reboiras-Lopez MD, Gandara
Rey JM, Garcia-Garcia A. Genetic and molecular alterations associated with oral squamous cell
cancer (Review). Oncol Rep. 2009 Dec;22(6):1277-82.
144
References
37.
Iype EM, Pandey M, Mathew A, Thomas G, Sebastian P, Nair MK. Oral cancer among
patients under the age of 35 years. J Postgrad Med. 2001 Jul-Sep;47(3):171-6.

38.
Mathew Iype E, Pandey M, Mathew A, Thomas G, Sebastian P, Krishnan Nair M.
Squamous cell carcinoma of the tongue among young Indian adults. Neoplasia. 2001 JulAug;3(4):273-7.
39.
Myers JN, Elkins T, Roberts D, Byers RM. Squamous cell carcinoma of the tongue in young
adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol Head Neck
Surg. 2000 Jan;122(1):44-51.
40.
McDowell JD. An overview of epidemiology and common risk factors for oral squamous
cell carcinoma. Otolaryngol Clin North Am. 2006 Apr;39(2):277-94.

41.
Chen YK, Huang HC, Lin LM, Lin CC. Primary oral squamous cell carcinoma: an analysis
of 703 cases in southern Taiwan. Oral Oncol. 1999 Mar;35(2):173-9.

42.
Day GL, Blot WJ. Second primary tumors in patients with oral cancer. Cancer. 1992 Jul
1;70(1):14-9.
43.
Tomek MS, McGuirt WF. Second head and neck cancers and tobacco usage. Am J
Otolaryngol. 2003 Jan-Feb;24(1):24-7.

44.
Pindborg JJ, Mehta FS, Gupta PC, Daftary DK, Smith CJ. Reverse smoking in Andhra
Pradesh, India: a study of palatal lesions among 10,169 villagers. Br J Cancer. 1971 Mar;25(1):1020.
45.
Ramadas K., Lucas E., Thomas G., Mathew B., Balan A., Thara S., et al. A digital manual
for the early diagnosis of oral neoplasia. 2008 [4 November 2010]; Available from:
http://screening.iarc.fr/atlasoral_detail.php?flag=0&lang=1&Id=A1300004&cat=A13,.
46.
Rodu B, Jansson C. Smokeless tobacco and oral cancer: a review of the risks and
determinants. Crit Rev Oral Biol Med. 2004;15(5):252-63.
145
References
47.
Sawair FA, Al-Mutwakel A, Al-Eryani K, Al-Surhy A, Maruyama S, Cheng J, et al. High
relative frequency of oral squamous cell carcinoma in Yemen: qat and tobacco chewing as its
aetiological background. Int J Environ Health Res. 2007 Jun;17(3):185-95.
48.
El-Wajeh YA, Thornhill MH. Qat and its health effects. Br Dent J. 2009 Jan 10;206(1):17-
21.
49.
Nasr AH, Khatri ML. Head and neck squamous cell carcinoma in Hajjah, Yemen. Saudi
Med J. 2000 Jun;21(6):565-8.

50.
Jovanovic A, Schulten EA, Kostense PJ, Snow GB, van der Waal I. Tobacco and alcohol
related to the anatomical site of oral squamous cell carcinoma. J Oral Pathol Med. 1993
Nov;22(10):459-62.
51.
Andre K, Schraub S, Mercier M, Bontemps P. Role of alcohol and tobacco in the aetiology
of head and neck cancer: a case-control study in the Doubs region of France. Eur J Cancer B Oral
Oncol. 1995 Sep;31B(5):301-9.
52.
Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. Betel quid chewing, cigarette
smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 1995
Nov;24(10):450-3.
53.
Gillison ML, Shah KV. Human papillomavirus-associated head and neck squamous cell
carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head
and neck cancers. Curr Opin Oncol. 2001 May;13(3):183-8.
54.
Miller CS, White DK. Human papillomavirus expression in oral mucosa, premalignant
conditions, and squamous cell carcinoma: a retrospective review of the literature. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 1996 Jul;82(1):57-68.
55.
Chen PC, Kuo C, Pan CC, Chou MY. Risk of oral cancer associated with human
papillomavirus infection, betel quid chewing, and cigarette smoking in Taiwan--an integrated
molecular and epidemiological study of 58 cases. J Oral Pathol Med. 2002 Jul;31(6):317-22.
146
References
56.
Goldenberg D, Golz A, Netzer A, Rosenblatt E, Rachmiel A, Goldenberg RF, et al. Epstein-
Barr virus and cancers of the head and neck. Am J Otolaryngol. 2001 May-Jun;22(3):197-205.
57.
Winn DM. Diet and nutrition in the etiology of oral cancer. Am J Clin Nutr. 1995
Feb;61(2):437S-45S.
58.
Garavello W, Lucenteforte E, Bosetti C, La Vecchia C. The role of foods and nutrients on
oral and pharyngeal cancer risk. Minerva Stomatol. 2009 Jan-Feb;58(1-2):25-34.

59.
Watts JM. The importance of the Plummer-Vinson syndrome in the aetiology of carcinoma
of the upper gastrointestinal tract. Postgrad Med J. 1961 Sep;37:523-33.

60.
Wenig BM. The Head and Neck: Oral Cavity. In: Rubin E, Gorstein F, editors. Rubin's
pathology : clinicopathologic foundations of medicine. 4th ed. Philadelphia: Lippincott Williams &
Wilkins; 2004. p. 1058-61.
61.
Gale N, Zidar N. Benign and Potentially Malignant Lesions of the Squamous Epithelium
and Squamous Cell Carcinoma. In: Cardesa A, Slootweg PJ, editors. Pathology Of The Head and
Neck. Berlin Heidelberg: Springer-Verlag; 2006. p. 12-4.
62.
Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition of leukoplakia and related lesions:
an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol. 1978 Oct;46(4):518-39.
63.
Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus, and other oral keratoses in 23,616 white
Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol. 1986 Apr;61(4):373-81.
64.
Silverman S, Jr., Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54
cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Aug;84(2):154-7.
65.
Lingen MW, Kumar V. Head and Neck. In: Kumar V, Abbas AK, Fausto N, editors.
Robbins and Cotran Pathologic Basis Of Disease. 7 ed. Philadelphia, Pennsylvania.: Elsevier Saunders; 2006. p. 778-80.
147
References
66.
Regezi JA, Sciubba JJ, Jordan RCK. Preneoplastic and Neoplastic Lesions. In: Regezi JA,
Sciubba JJ, Jordan RCK, editors. Oral Pathology: Clinical Pathologic Correlations. Philadelphia:
Saunders:; 2008. p. Accessed online.
67.
Som PM, Brandwein MS. Neck Lymph Nodes. In: Som PM, Curtin HD, editors. Head and
neck imaging. 4th ed. St. Louis, Mo.: Mosby; 2003. p. 1865-935.
68.
Mendenhall WM, Werning JW, Pfister DG. Section 2: Treatment of Head and Neck Cancers.
In: DeVita VT, Lawrence TS, Rosenberg SA, editors. Devita, Hellman & Rosenberg's Cancer:
Principles & Practice of Oncology, 8th Edition. 8th ed: Lippincott Williams & Wilkins; 2008. p.
830-40.
69.
Arlene A. Forastiere, Kie-Kian Ang, David Brizel, Bruce E. Brockstein, Barbara A.
Burtness, Cmelak AJ, et al. NCCN Clinical Practice Guidelines in Oncology: Head and Neck
Cancers. 2010 [cited 2010 25 December 2010]; Available from:
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
70.
Massano J, Regateiro FS, Januario G, Ferreira A. Oral squamous cell carcinoma: review of
prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006
Jul;102(1):67-76.
71.
Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Analysis of risk factors of
predictive local tumor control in oral cavity cancer. Ann Surg Oncol. 2008 Mar;15(3):915-22.
72.
Liao CT, Lee LY, Huang SF, Chen IH, Kang CJ, Lin CY, et al. Outcome Analysis of
Patients with Oral Cavity Cancer and Extracapsular Spread in Neck Lymph Nodes. Int J Radiat
Oncol Biol Phys. 2010 Oct 7.
73.
Liao CT, Wang HM, Chang JT, Ng SH, Hsueh C, Lee LY, et al. Analysis of risk factors for
distant metastases in squamous cell carcinoma of the oral cavity. Cancer. 2007 Oct 1;110(7):1501-8.
74.
Lo WL, Kao SY, Chi LY, Wong YK, Chang RC. Outcomes of oral squamous cell
carcinoma in Taiwan after surgical therapy: factors affecting survival. J Oral Maxillofac Surg. 2003
Jul;61(7):751-8.
148
References
75.
Leite IC, Koifman S. Survival analysis in a sample of oral cancer patients at a reference
hospital in Rio de Janeiro, Brazil. Oral Oncol. 1998 Sep;34(5):347-52.

76.
de Cassia Braga Ribeiro K, Kowalski LP, Latorre Mdo R. Perioperative complications,
comorbidities, and survival in oral or oropharyngeal cancer. Arch Otolaryngol Head Neck Surg.
2003 Feb;129(2):219-28.
77.
Ribeiro KC, Kowalski LP, Latorre MR. Impact of comorbidity, symptoms, and patients'
characteristics on the prognosis of oral carcinomas. Arch Otolaryngol Head Neck Surg. 2000
Sep;126(9):1079-85.
78.
Kowalski LP, Alcantara PS, Magrin J, Parise Junior O. A case-control study on
complications and survival in elderly patients undergoing major head and neck surgery. Am J Surg.
1994 Nov;168(5):485-90.
79.
Liao CT, Wang HM, Hsieh LL, Chang JT, Ng SH, Hsueh C, et al. Higher distant failure in
young age tongue cancer patients. Oral Oncol. 2006 Aug;42(7):718-25.

80.
Annertz K, Anderson H, Biorklund A, Moller T, Kantola S, Mork J, et al. Incidence and
survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young
adults. Int J Cancer. 2002 Sep 1;101(1):95-9.
81.
Rosenquist K. Risk factors in oral and oropharyngeal squamous cell carcinoma: a
population-based case-control study in southern Sweden. Swed Dent J Suppl. 2005(179):1-66.

82.
Mell LK, Dignam JJ, Salama JK, Cohen EE, Polite BN, Dandekar V, et al. Predictors of
competing mortality in advanced head and neck cancer. J Clin Oncol. 2010 Jan 1;28(1):15-20.
83.
Piccirillo JF, Lacy PD, Basu A, Spitznagel EL. Development of a new head and neck
cancer-specific comorbidity index. Arch Otolaryngol Head Neck Surg. 2002 Oct;128(10):1172-9.
84.
Nguyen TV, Yueh B. Weight loss predicts mortality after recurrent oral cavity and
oropharyngeal carcinomas. Cancer. 2002 Aug 1;95(3):553-62.
149
References
85.
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current
vaccines. Nat Med. 2004 Sep;10(9):909-15.

86.
Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Goran Hansson B, Andersson G.
Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal
squamous cell carcinoma. A population-based case-control study in southern Sweden. Acta
Otolaryngol. 2005 Dec;125(12):1327-36.
87.
Piccirillo JF, Spitznagel EL, Jr., Vermani N, Costas I, Schnitzler M. Comparison of
comorbidity indices for patients with head and neck cancer. Med Care. 2004 May;42(5):482-6.
88.
Paleri V, Wight RG, Silver CE, Haigentz M, Jr., Takes RP, Bradley PJ, et al. Comorbidity in
head and neck cancer: a critical appraisal and recommendations for practice. Oral Oncol. 2010
Oct;46(10):712-9.
89.
Riechelmann H, Neagos A, Netzer-Yilmaz U, Gronau S, Scheithauer M, Rockemann MG.
[The ASA-score as a comorbidity index in patients with cancer of the oral cavity and oropharynx].
Laryngorhinootologie. 2006 Feb;85(2):99-104.
90.
Zitsch RP, 3rd, Park CW, Renner GJ, Rea JL. Outcome analysis for lip carcinoma.
Otolaryngol Head Neck Surg. 1995 Nov;113(5):589-96.

91.
Tiwari R. Squamous cell carcinoma of the superior gingivolabial sulcus. Oral Oncol. 2000
Sep;36(5):461-5.
92.
Sieczka E, Datta R, Singh A, Loree T, Rigual N, Orner J, et al. Cancer of the buccal
mucosa: are margins and T-stage accurate predictors of local control? Am J Otolaryngol. 2001 NovDec;22(6):395-9.
93.
Lin CS, Jen YM, Cheng MF, Lin YS, Su WF, Hwang JM, et al. Squamous cell carcinoma of
the buccal mucosa: an aggressive cancer requiring multimodality treatment. Head Neck. 2006
Feb;28(2):150-7.
150
References
94.
Shaw RJ, McGlashan G, Woolgar JA, Lowe D, Brown JS, Vaughan ED, et al. Prognostic
importance of site in squamous cell carcinoma of the buccal mucosa. Br J Oral Maxillofac Surg.
2009 Jul;47(5):356-9.
95.
Greene FL, American Joint Committee on Cancer., American Cancer Society. AJCC cancer
staging manual. 6th ed. New York: Springer-Verlag; 2002.

96.
Ferlito A, Rinaldo A, Robbins KT, Leemans CR, Shah JP, Shaha AR, et al. Changing
concepts in the surgical management of the cervical node metastasis. Oral Oncol. 2003
Jul;39(5):429-35.
97.
Ng SH, Yen TC, Chang JT, Chan SC, Ko SF, Wang HM, et al. Prospective study of
[18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic

resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin
Oncol. 2006 Sep 20;24(27):4371-6.
98.
Gonzalez-Moles MA, Esteban F, Rodriguez-Archilla A, Ruiz-Avila I, Gonzalez-Moles S.
Importance of tumour thickness measurement in prognosis of tongue cancer. Oral Oncol. 2002
Jun;38(4):394-7.
99.
Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of
tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg.
1986 Oct;152(4):345-50.
100.
Huang SH, Hwang D, Lockwood G, Goldstein DP, O'Sullivan B. Predictive value of tumor
thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a
meta-analysis of reported studies. Cancer. 2009 Apr 1;115(7):1489-97.
101.
Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of
invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the
literature. Head Neck. 2005 Dec;27(12):1080-91.
102.
Connor SE, Olliff JF. Imaging of malignant cervical lymphadenopathy. Dentomaxillofac
Radiol. 2000 May;29(3):133-43.
151
References
103.
Shaw RJ, Lowe D, Woolgar JA, Brown JS, Vaughan ED, Evans C, et al. Extracapsular
spread in oral squamous cell carcinoma. Head Neck. 2010 Jun;32(6):714-22.

104.
Bennett SH, Futrell JW, Roth JA, Hoye RC, Ketcham AS. Prognostic significance of
histologic host response in cancer of the larynx or hypopharynx. Cancer. 1971 Nov;28(5):1255-65.
105.
Puri SK, Fan CY, Hanna E. Significance of extracapsular lymph node metastases in patients
with head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg. 2003
Apr;11(2):119-23.
106.
Rahima B, Shingaki S, Nagata M, Saito C. Prognostic significance of perineural invasion in
oral and oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004
Apr;97(4):423-31.
107.
Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT. Perineural invasion in
squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1998
Jun;124(6):637-40.
108.
Shintani S, Li C, Ishikawa T, Mihara M, Nakashiro K, Hamakawa H. Expression of vascular
endothelial growth factor A, B, C, and D in oral squamous cell carcinoma. Oral Oncol. 2004
Jan;40(1):13-20.
109.
Bettendorf O, Piffko J, Bankfalvi A. Prognostic and predictive factors in oral squamous cell
cancer: important tools for planning individual therapy? Oral Oncol. 2004 Feb;40(2):110-9.
110.
Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a
causal association between human papillomavirus and a subset of head and neck cancers. J Natl
Cancer Inst. 2000 May 3;92(9):709-20.
111.
Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM. Human papillomavirus
infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head
Neck Surg. 2001 Jul;125(1):1-9.
152
References
112.
Cook JA, Jones AS, Phillips DE, Soler Lluch E. Implications of tumour in resection margins
following surgical treatment of squamous cell carcinoma of the head and neck. Clin Otolaryngol
Allied Sci. 1993 Feb;18(1):37-41.
113.
Jones AS, Bin Hanafi Z, Nadapalan V, Roland NJ, Kinsella A, Helliwell TR. Do positive
resection margins after ablative surgery for head and neck cancer adversely affect prognosis? A
study of 352 patients with recurrent carcinoma following radiotherapy treated by salvage surgery.
Br J Cancer. 1996 Jul;74(1):128-32.
114.
Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma.
Am J Surg. 1990 Oct;160(4):410-4.

115.
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, et al.
Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and
neck cancer. N Engl J Med. 2004 May 6;350(19):1945-52.
116.
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al.
Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of

the head and neck. N Engl J Med. 2004 May 6;350(19):1937-44.
117.
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. Defining
risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent
postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).
Head Neck. 2005 Oct;27(10):843-50.
118.
Jadvar H, Parker JA. PET Radiotracers. In: Jadvar H, Parker JA, editors. Clinical PET and
PET/CT. London ; New York: Springer; 2005. p. 45-59.

119.
Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics.
2004 Mar-Apr;24(2):523-43.
120.
Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al.
Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med. 2006
May;47(5):885-95.
153
References
121.
Rajadhyaksha CD, Parker JA, Barbaras L, Gerbaudo VH. Normal and benign pathologic in
18FDG-PET and PET/CT: An interactive web-based image atlas. [cited 2011 2 June 2011];
Available from: http://www.med.harvard.edu/JPNM/chetan/popup.html.
122.
Burrell SC, Van den Abbeele AD. 2-Deoxy-2-[F-18]fluoro-D-glucose-positron emission
tomography of the head and neck: an atlas of normal uptake and variants. Mol Imaging Biol. 2005
May-Jun;7(3):244-56.
123.
Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat ("USA-Fat"):
description on 18F-FDG PET/CT. J Nucl Med. 2003 Feb;44(2):170-6.

124.
Barrington SF, Maisey MN. Skeletal muscle uptake of fluorine-18-FDG: effect of oral
diazepam. J Nucl Med. 1996 Jul;37(7):1127-9.

125.
Bar-Shalom R. Muscle uptake of 18-fluorine fluorodeoxyglucose. Semin Nucl Med. 2000
Oct;30(4):306-9.
126.
Blodgett TM, Fukui MB, Snyderman CH, Branstetter BFt, McCook BM, Townsend DW, et
al. Combined PET-CT in the head and neck: part 1. Physiologic, altered physiologic, and artifactual
FDG uptake. Radiographics. 2005 Jul-Aug;25(4):897-912.
127.
Goerres GW, Von Schulthess GK, Hany TF. Positron emission tomography and PET CT of
the head and neck: FDG uptake in normal anatomy, in benign lesions, and in changes resulting from
treatment. AJR Am J Roentgenol. 2002 Nov;179(5):1337-43.
128.
Nakahara T, Fujii H, Ide M, Nishiumi N, Takahashi W, Yasuda S, et al. FDG uptake in the
morphologically normal thymus: comparison of FDG positron emission tomography and CT. Br J
Radiol. 2001 Sep;74(885):821-4.
129.
Abouzied MM, Crawford ES, Nabi HA. 18F-FDG imaging: pitfalls and artifacts. J Nucl
Med Technol. 2005 Sep;33(3):145-55; quiz 62-3.

130.
Fukui MB, Blodgett TM, Snyderman CH, Johnson JJ, Myers EN, Townsend DW, et al.
Combined PET-CT in the head and neck: part 2. Diagnostic uses and pitfalls of oncologic imaging.
Radiographics. 2005 Jul-Aug;25(4):913-30.
154
References
131.
Shah NP, Workman RB, Coleman RE. PET and PET/CT in Head and Neck Cancer. In:
Workman RB, Coleman RE, editors. PET/CT essentials for clinical practice. New York, NY:
Springer; 2006. p. 104-28.
132.
Zhuang H, Yu JQ, Alavi A. Applications of fluorodeoxyglucose-PET imaging in the
detection of infection and inflammation and other benign disorders. Radiol Clin North Am. 2005
Jan;43(1):121-34.
133.
Andrade RS, Heron DE, Degirmenci B, Filho PA, Branstetter BF, Seethala RR, et al.
Posttreatment assessment of response using FDG-PET/CT for patients treated with definitive
radiation therapy for head and neck cancers. Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):131522.
134.
Sureshbabu W, Mawlawi O. PET/CT imaging artifacts. J Nucl Med Technol. 2005
Sep;33(3):156-61; quiz 63-4.

135.
Beyer T, Antoch G, Muller S, Egelhof T, Freudenberg LS, Debatin J, et al. Acquisition
protocol considerations for combined PET/CT imaging. J Nucl Med. 2004 Jan;45 Suppl 1:25S-35S.
136.
Shankar LK, Hoffman JM, Bacharach S, Graham MM, Karp J, Lammertsma AA, et al.
Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in
patients in National Cancer Institute Trials. J Nucl Med. 2006 Jun;47(6):1059-66.
137.
Weber WA. Use of PET for monitoring cancer therapy and for predicting outcome. J Nucl
Med. 2005 Jun;46(6):983-95.

138.
Macdonald K, Searle J, Lyburn I. The role of dual time point FDG PET imaging in the
evaluation of solitary pulmonary nodules with an initial standard uptake value less than 2.5. Clin
Radiol. 2011 Mar;66(3):244-50.
139.
Alkhawaldeh K, Biersack HJ, Henke A, Ezziddin S. Impact of Dual-Time-Point F-18 FDG
PET/CT in the Assessment of Pleural Effusion in Patients With Non-Small-Cell Lung Cancer. Clin
Nucl Med. 2011 Jun;36(6):423-8.
155
References
140.
Dirisamer A, Halpern BS, Schima W, Heinisch M, Wolf F, Beheshti M, et al. Dual-time-
point FDG-PET/CT for the detection of hepatic metastases. Mol Imaging Biol. 2008 NovDec;10(6):335-40.
141.
Ahmadzadehfar H, Sabet A, Nake K, Hinterthaner B, Biersack HJ, Ezziddin S. Dual-time F-
18 FDG-PET/CT imaging for diagnosis of occult non-Hodgkin lymphoma in a patient with

esophageal cancer. Clin Nucl Med. 2009 Mar;34(3):168-70.
142.
Lai CH, Huang KG, See LC, Yen TC, Tsai CS, Chang TC, et al. Restaging of recurrent
cervical carcinoma with dual-phase [18F]fluoro-2-deoxy-D-glucose positron emission tomography.

Cancer. 2004 Feb 1;100(3):544-52.
143.
Yen TC, Ng KK, Ma SY, Chou HH, Tsai CS, Hsueh S, et al. Value of dual-phase 2-fluoro-
2-deoxy-d-glucose positron emission tomography in cervical cancer. J Clin Oncol. 2003 Oct
1;21(19):3651-8.
144.
Okano K, Kakinoki K, Akamoto S, Hagiike M, Usuki H, Yamamoto Y, et al. (1)F-
fluorodeoxyglucose positron emission tomography in the diagnosis of small pancreatic cancer.

World J Gastroenterol. 2011 Jan 14;17(2):231-5.
145.
Harkirat S, Anand S, Jacob M. Forced diuresis and dual-phase F-fluorodeoxyglucose-
PET/CT scan for restaging of urinary bladder cancers. Indian J Radiol Imaging. 2010 Feb;20(1):139.
146.
Caprio MG, Cangiano A, Imbriaco M, Soscia F, Di Martino G, Farina A, et al. Dual-time-
point [18F]-FDG PET/CT in the diagnostic evaluation of suspicious breast lesions. Radiol Med.
2010 Mar;115(2):215-24.
147.
Arena V, Skanjeti A, Casoni R, Douroukas A, Pelosi E. Dual-phase FDG-PET: delayed
acquisition improves hepatic detectability of pathological uptake. Radiol Med. 2008

Sep;113(6):875-86.
148.
Penna D, Varetto T, Deandreis D, Castellano G, Bisi G. Dual-phase F-18 FDG PET/CT
scanning in the suspicion of relapse of ovarian neoplasia. Clin Nucl Med. 2009 Feb;34(2):111-3.
156
References
149.
Zytoon AA, Murakami K, El-Kholy MR, El-Shorbagy E, Ebied O. Breast cancer with low
FDG uptake: characterization by means of dual-time point FDG-PET/CT. Eur J Radiol. 2009
Jun;70(3):530-8.
150.
Stokkel MP, Terhaard CH, Hordijk GJ, van Rijk PP. The detection of local recurrent head
and neck cancer with fluorine-18 fluorodeoxyglucose dual-head positron emission tomography. Eur
J Nucl Med. 1999 Jul;26(7):767-73.
151.
Hustinx R, Smith RJ, Benard F, Rosenthal DI, Machtay M, Farber LA, et al. Dual time point
fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate

malignancy from inflammation and normal tissue in the head and neck. Eur J Nucl Med. 1999
Oct;26(10):1345-8.
152.
Yen TC, Chang YC, Chan SC, Chang JT, Hsu CH, Lin KJ, et al. Are dual-phase 18F-FDG
PET scans necessary in nasopharyngeal carcinoma to assess the primary tumour and loco-regional
nodes? Eur J Nucl Med Mol Imaging. 2005 May;32(5):541-8.
153.
Boellaard R, O'Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, et al.
FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J
Nucl Med Mol Imaging. 2010 Jan;37(1):181-200.
154.
Boellaard R. Standards for PET image acquisition and quantitative data analysis. J Nucl
Med. 2009 May;50 Suppl 1:11S-20S.

155.
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al.
Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and

positron emission tomography: review and 1999 EORTC recommendations. European Organization
for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999
Dec;35(13):1773-82.
156.
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving
Considerations for PET response criteria in solid tumors. J Nucl Med. 2009 May;50 Suppl 1:122S50S.
157
References
157.
Boellaard R, Krak NC, Hoekstra OS, Lammertsma AA. Effects of noise, image resolution,
and ROI definition on the accuracy of standard uptake values: a simulation study. J Nucl Med. 2004
Sep;45(9):1519-27.
158.
Soret M, Bacharach SL, Buvat I. Partial-volume effect in PET tumor imaging. J Nucl Med.
2007 Jun;48(6):932-45.
159.
Boellaard R, Oyen WJ, Hoekstra CJ, Hoekstra OS, Visser EP, Willemsen AT, et al. The
Netherlands protocol for standardisation and quantification of FDG whole body PET studies in
multi-centre trials. Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2320-33.
160.
Lammertsma AA, Hoekstra CJ, Giaccone G, Hoekstra OS. How should we analyse FDG
PET studies for monitoring tumour response? Eur J Nucl Med Mol Imaging. 2006 Jul;33 Suppl
1:16-21.
161.
Paulino AC, Johnstone PA. FDG-PET in radiotherapy treatment planning: Pandora's box?
Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):4-5.

162.
Paulino AC. PET-CT in Radiotherapy Treatment Planning. 1st ed: Saunders; 2008.
163.
Dandekar P, Partridge M, Kazi R, Nutting C, Harrington K, Newbold K. Challenges in
integrating 18FDG PET-CT into radiotherapy planning of head and neck cancer. Indian J Cancer.
2010 Jul-Sep;47(3):260-6.
164.
MacManus M, Nestle U, Rosenzweig KE, Carrio I, Messa C, Belohlavek O, et al. Use of
PET and PET/CT for radiation therapy planning: IAEA expert report 2006-2007. Radiother Oncol.
2009 Apr;91(1):85-94.
165.
Hong R, Halama J, Bova D, Sethi A, Emami B. Correlation of PET standard uptake value
and CT window-level thresholds for target delineation in CT-based radiation treatment planning. Int
J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):720-6.
166.
Nestle U, Kremp S, Schaefer-Schuler A, Sebastian-Welsch C, Hellwig D, Rube C, et al.
Comparison of different methods for delineation of 18F-FDG PET-positive tissue for target volume
158
References
definition in radiotherapy of patients with non-Small cell lung cancer. J Nucl Med. 2005
Aug;46(8):1342-8.
167.
Yaremko B, Riauka T, Robinson D, Murray B, McEwan A, Roa W. Threshold modification
for tumour imaging in non-small-cell lung cancer using positron emission tomography. Nucl Med
Commun. 2005 May;26(5):433-40.
168.
Brambilla M, Matheoud R, Secco C, Loi G, Krengli M, Inglese E. Threshold segmentation
for PET target volume delineation in radiation treatment planning: the role of target-to-background
ratio and target size. Med Phys. 2008 Apr;35(4):1207-13.
169.
Erdi YE, Mawlawi O, Larson SM, Imbriaco M, Yeung H, Finn R, et al. Segmentation of
lung lesion volume by adaptive positron emission tomography image thresholding. Cancer. 1997
Dec 15;80(12 Suppl):2505-9.
170.
Geets X, Lee JA, Bol A, Lonneux M, Gregoire V. A gradient-based method for segmenting
FDG-PET images: methodology and validation. Eur J Nucl Med Mol Imaging. 2007
Sep;34(9):1427-38.
171.
Daisne JF, Duprez T, Weynand B, Lonneux M, Hamoir M, Reychler H, et al. Tumor volume
in pharyngolaryngeal squamous cell carcinoma: comparison at CT, MR imaging, and FDG PET and
validation with surgical specimen. Radiology. 2004 Oct;233(1):93-100.
172.
Goerres GW, von Schulthess GK, Steinert HC. Why most PET of lung and head-and-neck
cancer will be PET/CT. J Nucl Med. 2004 Jan;45 Suppl 1:66S-71S.

173.
Pentenero M, Cistaro A, Brusa M, Ferraris MM, Pezzuto C, Carnino R, et al. Accuracy of
18F-FDG-PET/CT for staging of oral squamous cell carcinoma. Head Neck. 2008
Nov;30(11):1488-96.
174.
Hannah A, Scott AM, Tochon-Danguy H, Chan JG, Akhurst T, Berlangieri S, et al.
Evaluation of 18 F-fluorodeoxyglucose positron emission tomography and computed tomography

with histopathologic correlation in the initial staging of head and neck cancer. Ann Surg. 2002
Aug;236(2):208-17.
159
References
175.
Paulus P, Sambon A, Vivegnis D, Hustinx R, Moreau P, Collignon J, et al. 18FDG-PET for
the assessment of primary head and neck tumors: clinical, computed tomography, and
histopathological correlation in 38 patients. Laryngoscope. 1998 Oct;108(10):1578-83.
176.
Goerres GW, Schmid DT, Schuknecht B, Eyrich GK. Bone invasion in patients with oral
cavity cancer: comparison of conventional CT with PET/CT and SPECT/CT. Radiology. 2005
Oct;237(1):281-7.
177.
Babin E, Desmonts C, Hamon M, Benateau H, Hitier M. PET/CT for assessing mandibular
invasion by intraoral squamous cell carcinomas. Clin Otolaryngol. 2008 Feb;33(1):47-51.

178.
Abd El-Hafez YG, Chen CC, Ng SH, Lin CY, Wang HM, Chan SC, et al. Comparison of
PET/CT and MRI for the detection of bone marrow invasion in patients with squamous cell
carcinoma of the oral cavity. Oral Oncol. 2011 Apr;47(4):288-95.
179.
Nakasone Y, Inoue T, Oriuchi N, Takeuchi K, Negishi A, Endo K, et al. The role of whole-
body FDG-PET in preoperative assessment of tumor staging in oral cancers. Ann Nucl Med. 2001
Dec;15(6):505-12.
180.
Baek CH, Chung MK, Son YI, Choi JY, Kim HJ, Yim YJ, et al. Tumor volume assessment
by 18F-FDG PET/CT in patients with oral cavity cancer with dental artifacts on CT or MR images.
J Nucl Med. 2008 Sep;49(9):1422-8.
181.
Ng SH, Yen TC, Liao CT, Chang JT, Chan SC, Ko SF, et al. 18F-FDG PET and CT/MRI in
oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation.
J Nucl Med. 2005 Jul;46(7):1136-43.
182.
van den Brekel MW. Lymph node metastases: CT and MRI. Eur J Radiol. 2000
Mar;33(3):230-8.
183.
van den Brekel MW, Castelijns JA, Snow GB. Detection of lymph node metastases in the
neck: radiologic criteria. Radiology. 1994 Sep;192(3):617-8.

184.
Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and
differential diagnosis. AJR Am J Roentgenol. 1992 May;158(5):961-9.

160
References
185.
Seitz O, Chambron-Pinho N, Middendorp M, Sader R, Mack M, Vogl TJ, et al. 18F-
Fluorodeoxyglucose-PET/CT to evaluate tumor, nodal disease, and gross tumor volume of

oropharyngeal and oral cavity cancer: comparison with MR imaging and validation with surgical
specimen. Neuroradiology. 2009 Oct;51(10):677-86.
186.
Piao Y, Bold B, Tayier A, Ishida R, Omura K, Okada N, et al. Evaluation of 18F-FDG
PET/CT for diagnosing cervical nodal metastases in patients with oral cavity or oropharynx
carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Dec;108(6):933-8.
187.
Braams JW, Pruim J, Freling NJ, Nikkels PG, Roodenburg JL, Boering G, et al. Detection
of lymph node metastases of squamous-cell cancer of the head and neck with FDG-PET and MRI. J
Nucl Med. 1995 Feb;36(2):211-6.
188.
Laubenbacher C, Saumweber D, Wagner-Manslau C, Kau RJ, Herz M, Avril N, et al.
Comparison of fluorine-18-fluorodeoxyglucose PET, MRI and endoscopy for staging head and
neck squamous-cell carcinomas. J Nucl Med. 1995 Oct;36(10):1747-57.
189.
Jeong HS, Baek CH, Son YI, Ki Chung M, Kyung Lee D, Young Choi J, et al. Use of
integrated 18F-FDG PET/CT to improve the accuracy of initial cervical nodal evaluation in patients
with head and neck squamous cell carcinoma. Head Neck. 2007 Mar;29(3):203-10.
190.
Liao CT, Wang HM, Huang SF, Chen IH, Kang CJ, Lin CY, et al. PET and PET/CT of the
neck lymph nodes improves risk prediction in patients with squamous cell carcinoma of the oral
cavity. J Nucl Med. 2011 Feb;52(2):180-7.
191.
Hyde NC, Prvulovich E, Newman L, Waddington WA, Visvikis D, Ell P. A new approach
to pre-treatment assessment of the N0 neck in oral squamous cell carcinoma: the role of sentinel
node biopsy and positron emission tomography. Oral Oncol. 2003 Jun;39(4):350-60.
192.
Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Is there a role for positron emission
tomography with 18F-fluorodeoxyglucose in the initial staging of nodal negative oral and
oropharyngeal squamous cell carcinoma. Head Neck. 2002 Apr;24(4):345-9.
161
References
193.
Krabbe CA, Dijkstra PU, Pruim J, van der Laan BF, van der Wal JE, Gravendeel JP, et al.
FDG PET in oral and oropharyngeal cancer. Value for confirmation of N0 neck and detection of
occult metastases. Oral Oncol. 2008 Jan;44(1):31-6.
194.
Schoder H, Carlson DL, Kraus DH, Stambuk HE, Gonen M, Erdi YE, et al. 18F-FDG
PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical
examination and CT/MRI. J Nucl Med. 2006 May;47(5):755-62.
195.
Wensing BM, Vogel WV, Marres HA, Merkx MA, Postema EJ, Oyen WJ, et al. FDG-PET
in the clinically negative neck in oral squamous cell carcinoma. Laryngoscope. 2006
May;116(5):809-13.
196.
Yoon DY, Hwang HS, Chang SK, Rho YS, Ahn HY, Kim JH, et al. CT, MR, US,18F-FDG
PET/CT, and their combined use for the assessment of cervical lymph node metastases in squamous
cell carcinoma of the head and neck. Eur Radiol. 2009 Mar;19(3):634-42.
197.
Yen TC, Chang JT, Ng SH, Chang YC, Chan SC, Wang HM, et al. Staging of untreated
squamous cell carcinoma of buccal mucosa with 18F-FDG PET: comparison with head and neck
CT/MRI and histopathology. J Nucl Med. 2005 May;46(5):775-81.
198.
Goerres GW, Schmid DT, Gratz KW, von Schulthess GK, Eyrich GK. Impact of whole
body positron emission tomography on initial staging and therapy in patients with squamous cell
carcinoma of the oral cavity. Oral Oncol. 2003 Sep;39(6):547-51.
199.
Schmid DT, Stoeckli SJ, Bandhauer F, Huguenin P, Schmid S, von Schulthess GK, et al.
Impact of positron emission tomography on the initial staging and therapy in locoregional advanced
squamous cell carcinoma of the head and neck. Laryngoscope. 2003 May;113(5):888-91.
200.
Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant
metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001 JulAug;63(4):202-7.
201.
Kitagawa Y, Sano K, Nishizawa S, Nakamura M, Ogasawara T, Sadato N, et al. FDG-PET
for prediction of tumour aggressiveness and response to intra-arterial chemotherapy and

radiotherapy in head and neck cancer. Eur J Nucl Med Mol Imaging. 2003 Jan;30(1):63-71.
162
References
202.
Hanasono MM, Kunda LD, Segall GM, Ku GH, Terris DJ. Uses and limitations of FDG
positron emission tomography in patients with head and neck cancer. Laryngoscope. 1999
Jun;109(6):880-5.
203.
Fischbein NJ, OS AA, Caputo GR, Kaplan MJ, Singer MI, Price DC, et al. Clinical utility of
positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent

squamous cell carcinoma of the head and neck. AJNR Am J Neuroradiol. 1998 Aug;19(7):1189-96.
204.
Kitagawa Y, Nishizawa S, Sano K, Ogasawara T, Nakamura M, Sadato N, et al. Prospective
comparison of 18F-FDG PET with conventional imaging modalities (MRI, CT, and 67Ga
scintigraphy) in assessment of combined intraarterial chemotherapy and radiotherapy for head and
neck carcinoma. J Nucl Med. 2003 Feb;44(2):198-206.
205.
Klabbers BM, Lammertsma AA, Slotman BJ. The value of positron emission tomography
for monitoring response to radiotherapy in head and neck cancer. Mol Imaging Biol. 2003 JulAug;5(4):257-70.
206.
Abgral R, Querellou S, Potard G, Le Roux PY, Le Duc-Pennec A, Marianovski R, et al.
Does 18F-FDG PET/CT improve the detection of posttreatment recurrence of head and neck
squamous cell carcinoma in patients negative for disease on clinical follow-up? J Nucl Med. 2009
Jan;50(1):24-9.
207.
Moeller BJ, Rana V, Cannon BA, Williams MD, Sturgis EM, Ginsberg LE, et al.
Prospective risk-adjusted [18F]Fluorodeoxyglucose positron emission tomography and computed

tomography assessment of radiation response in head and neck cancer. J Clin Oncol. 2009 May
20;27(15):2509-15.
208.
Kunkel M, Forster GJ, Reichert TE, Jeong JH, Benz P, Bartenstein P, et al. Detection of
recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission

tomography: implications for prognosis and patient management. Cancer. 2003 Nov
15;98(10):2257-65.
209.
Kunkel M, Helisch A, Reichert TE, Jeong JH, Buchholz HG, Benz P, et al. Clinical and
prognostic value of [(18)F]FDG-PET for surveillance of oral squamous cell carcinoma after
surgical salvage therapy. Oral Oncol. 2006 Mar;42(3):297-305.
163
References
210.
Greven KM, Williams DW, 3rd, McGuirt WF, Sr., Harkness BA, D'Agostino RB, Jr., Keyes
JW, Jr., et al. Serial positron emission tomography scans following radiation therapy of patients
with head and neck cancer. Head Neck. 2001 Nov;23(11):942-6.
211.
Suzuki H, Fukuyama R, Hasegawa Y, Tamaki T, Nishio M, Nakashima T, et al. Tumor
thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral
squamous cell carcinomas. Oral Oncol. 2009 Oct;45(10):891-7.
212.
Miyawaki A, Ikeda R, Hijioka H, Ishida T, Ushiyama M, Nozoe E, et al. SUVmax of FDG-
PET correlates with the effects of neoadjuvant chemoradiotherapy for oral squamous cell carcinoma.
Oncol Rep. 2010 May;23(5):1205-12.
213.
Brun E, Kjellen E, Tennvall J, Ohlsson T, Sandell A, Perfekt R, et al. FDG PET studies
during treatment: prediction of therapy outcome in head and neck squamous cell carcinoma. Head
Neck. 2002 Feb;24(2):127-35.
214.
Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Pretreatment primary tumor
SUVmax measured by FDG-PET and pathologic tumor depth predict for poor outcomes in patients
with oral cavity squamous cell carcinoma and pathologically positive lymph nodes. Int J Radiat
Oncol Biol Phys. 2009 Mar 1;73(3):764-71.
215.
Hofele C, Freier K, Thiele OC, Haberkorn U, Buchmann I. High 2-[18F]fluoro-2-deoxy-d-
glucose (18FDG) uptake measured by positron emission tomography is associated with reduced
overall survival in patients with oral squamous cell carcinoma. Oral Oncol. 2009 Nov;45(11):963-7.
216.
Kim SY, Roh JL, Kim JS, Ryu CH, Lee JH, Cho KJ, et al. Utility of FDG PET in patients
with squamous cell carcinomas of the oral cavity. Eur J Surg Oncol. 2008 Feb;34(2):208-15.
217.
Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Preoperative
[18F]fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph

nodes predicts neck cancer control and survival rates in patients with oral cavity squamous cell
carcinoma and pathologically positive lymph nodes. Int J Radiat Oncol Biol Phys. 2009 Jul
15;74(4):1054-61.
164
References
218.
Kubicek GJ, Champ C, Fogh S, Wang F, Reddy E, Intenzo C, et al. FDG-PET staging and
importance of lymph node SUV in head and neck cancer. Head Neck Oncol. 2010;2:19.
219.
Liao CT, Chang JT, Wang HM, Ng SH, Huang SF, Chen IH, et al. Preoperative [18F]-
fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph nodes
may aid in selecting patients with oral cavity squamous cell carcinoma for salvage therapy after
relapse. Eur J Nucl Med Mol Imaging. 2009 Nov;36(11):1783-93.
220.
Shiue CY, Welch MJ. Update on PET radiopharmaceuticals: life beyond
fluorodeoxyglucose. Radiol Clin North Am. 2004 Nov;42(6):1033-53, viii.

221.
Lindholm P, Leskinen S, Lapela M. Carbon-11-methionine uptake in squamous cell head
and neck cancer. J Nucl Med. 1998 Aug;39(8):1393-7.

222.
Nuutinen J, Jyrkkio S, Lehikoinen P, Lindholm P, Minn H. Evaluation of early response to
radiotherapy in head and neck cancer measured with [11C]methionine-positron emission

tomography. Radiother Oncol. 1999 Sep;52(3):225-32.
223.
Buus S, Grau C, Munk OL, Bender D, Jensen K, Keiding S. 11C-methionine PET, a novel
method for measuring regional salivary gland function after radiotherapy of head and neck cancer.
Radiother Oncol. 2004 Dec;73(3):289-96.
224.
Linecker A, Kermer C, Sulzbacher I, Angelberger P, Kletter K, Dudczak R, et al. Uptake of
(18)F-FLT and (18)F-FDG in primary head and neck cancer correlates with survival.
Nuklearmedizin. 2008;47(2):80-5; quiz N12.
225.
Troost EG, Vogel WV, Merkx MA, Slootweg PJ, Marres HA, Peeters WJ, et al. 18F-FLT
PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck
cancer patients. J Nucl Med. 2007 May;48(5):726-35.
226.
Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of 11C-choline PET and
FDG PET for the differential diagnosis of malignant tumors. Eur J Nucl Med Mol Imaging. 2004
Aug;31(8):1064-72.
165
References
227.
Ito K, Yokoyama J, Kubota K, Morooka M. Comparison of 18F-FDG and 11C-choline
PET/CT for detecting recurrences in patients with nonsquamous cell head and neck malignancies.
Nucl Med Commun. 2010 Nov;31(11):931-7.
228.
Ito K, Yokoyama J, Kubota K, Morooka M, Shiibashi M, Matsuda H. 18F-FDG versus 11C-
choline PET/CT for the imaging of advanced head and neck cancer after combined intra-arterial
chemotherapy and radiotherapy: the time period during which PET/CT can reliably detect nonrecurrence. Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1318-27.
229.
Sun A, Sorensen J, Karlsson M, Turesson I, Langstrom B, Nilsson P, et al. 1-[11C]-acetate
PET imaging in head and neck cancer--a comparison with 18F-FDG-PET: implications for staging
and radiotherapy planning. Eur J Nucl Med Mol Imaging. 2007 May;34(5):651-7.
230.
Sun A, Johansson S, Turesson I, Dasu A, Sorensen J. Imaging Tumor Perfusion and
Oxidative Metabolism in Patients with Head-and-neck Cancer using 1- [(11)C]-acetate PET during
Radiotherapy: Preliminary Results. Int J Radiat Oncol Biol Phys. 2011 Jan 13.
231.
Rajendran JG, Schwartz DL, O'Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor
hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck
cancer. Clin Cancer Res. 2006 Sep 15;12(18):5435-41.
232.
Lee N, Nehmeh S, Schoder H, Fury M, Chan K, Ling CC, et al. Prospective trial
incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-andneck cancer patients undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2009
Sep 1;75(1):101-8.
233.
Choi W, Lee SW, Park SH, Ryu JS, Oh SJ, Im KC, et al. Planning study for available dose
of hypoxic tumor volume using fluorine-18-labeled fluoromisonidazole positron emission

tomography for treatment of the head and neck cancer. Radiother Oncol. 2010 Nov;97(2):176-82.
234.
Minagawa Y, Shizukuishi K, Koike I, Horiuchi C, Watanuki K, Hata M, et al. Assessment
of tumor hypoxia by (62)Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a
pilot study. Ann Nucl Med. 2011 Feb 16.
166
References
235.
Chao KS, Bosch WR, Mutic S, Lewis JS, Dehdashti F, Mintun MA, et al. A novel approach
to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int

J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):1171-82.
236.
Beer AJ, Grosu AL, Carlsen J, Kolk A, Sarbia M, Stangier I, et al. [18F]galacto-RGD
positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in

patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007 Nov 15;13(22
Pt 1):6610-6.
237.
Liao CT, Ng SH, Chang JT, Wang HM, Hsueh C, Lee LY, et al. T4b oral cavity cancer
below the mandibular notch is resectable with a favorable outcome. Oral Oncol. 2007
Jul;43(6):570-9.
238.
Youden WJ. Index for rating diagnostic tests. Cancer. 1950 Jan;3(1):32-5.
239.
Rogers SN, Humphris G, Lowe D, Brown JS, Vaughan ED. The impact of surgery for oral
cancer on quality of life as measured by the Medical Outcomes Short Form 36. Oral oncology.
[Clinical Trial]. 1998 May;34(3):171-9.
240.
Kuriakose M, Sankaranarayanan M, Nair MK, Cherian T, Sugar AW, Scully C, et al.
Comparison of oral squamous cell carcinoma in younger and older patients in India. European
journal of cancer Part B, Oral oncology. [Comparative Study
Research Support, Non-U.S. Gov't]. 1992 Oct;28B(2):113-20.
241.
Sarkaria JN, Harari PM. Oral tongue cancer in young adults less than 40 years of age:
rationale for aggressive therapy. Head & neck. [Case Reports

Research Support, Non-U.S. Gov't
Review]. 1994 Mar-Apr;16(2):107-11.
242.
Brown JS, Lowe D, Kalavrezos N, D'Souza J, Magennis P, Woolgar J. Patterns of invasion
and routes of tumor entry into the mandible by oral squamous cell carcinoma. Head & neck. 2002
Apr;24(4):370-83.
243.
McGregor AD, MacDonald DG. Routes of entry of squamous cell carcinoma to the
mandible. Head Neck Surg. 1988 May-Jun;10(5):294-301.

167
References
244.
Werning JW, Byers RM, Novas MA, Roberts D. Preoperative assessment for and outcomes
of mandibular conservation surgery. Head & neck. 2001 Dec;23(12):1024-30.

245.
Liao CT, Wang HM, Chang JT, Lin CY, Ng SH, Huang SF, et al. Influence of pathological
nodal status and maximal standardized uptake value of the primary tumor and regional lymph nodes
on treatment plans in patients with advanced oral cavity squamous cell carcinoma. Int J Radiat
Oncol Biol Phys. 2010 Jun 1;77(2):421-9.
246.
Shingaki S, Nomura T, Takada M, Kobayashi T, Suzuki I, Nakajima T. Squamous cell
carcinomas of the mandibular alveolus: analysis of prognostic factors. Oncology. 2002;62(1):17-24.

247.
Patel RS, Dirven R, Clark JR, Swinson BD, Gao K, O'Brien CJ. The prognostic impact of
extent of bone invasion and extent of bone resection in oral carcinoma. The Laryngoscope. 2008
May;118(5):780-5.
248.
O'Brien CJ, Adams JR, McNeil EB, Taylor P, Laniewski P, Clifford A, et al. Influence of
bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and
oropharynx. International journal of oral and maxillofacial surgery. [Clinical Trial
Comparative Study]. 2003 Oct;32(5):492-7.
249.
Hiratsuka H, Miyakawa A, Nakamori K, Kido Y, Sunakawa H, Kohama G. Multivariate
analysis of occult lymph node metastasis as a prognostic indicator for patients with squamous cell
carcinoma of the oral cavity. Cancer. 1997 Aug 1;80(3):351-6.
250.
Liao CT, Huang SF, Chen IH, Chang JT, Wang HM, Ng SH, et al. Risk stratification of
patients with oral cavity squamous cell carcinoma and contralateral neck recurrence following
radical surgery. Ann Surg Oncol. 2009 Jan;16(1):159-70.
251.
Mancuso AA, Mukherji SK, Schmalfuss I, Mendenhall W, Parsons J, Pameijer F, et al.
Preradiotherapy computed tomography as a predictor of local control in supraglottic carcinoma. J

Clin Oncol. 1999 Feb;17(2):631-7.
252.
Chong VF, Zhou JY, Khoo JB, Chan KL, Huang J. Correlation between MR imaging-
derived nasopharyngeal carcinoma tumor volume and TNM system. Int J Radiat Oncol Biol Phys.
2006 Jan 1;64(1):72-6.
168
References
253.
La TH, Filion EJ, Turnbull BB, Chu JN, Lee P, Nguyen K, et al. Metabolic tumor volume
predicts for recurrence and death in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2009 Aug
1;74(5):1335-41.
254.
Zaidi H, Vees H, Wissmeyer M. Molecular PET/CT imaging-guided radiation therapy
treatment planning. Acad Radiol. 2009 Sep;16(9):1108-33.

255.
Zaidi H, El Naqa I. PET-guided delineation of radiation therapy treatment volumes: a survey
of image segmentation techniques. Eur J Nucl Med Mol Imaging. 2010 Nov;37(11):2165-87.
256.
Schinagl DA, Vogel WV, Hoffmann AL, van Dalen JA, Oyen WJ, Kaanders JH.
Comparison of five segmentation tools for 18F-fluoro-deoxy-glucose-positron emission

tomography-based target volume definition in head and neck cancer. Int J Radiat Oncol Biol Phys.
2007 Nov 15;69(4):1282-9.
257.
Daisne JF, Sibomana M, Bol A, Doumont T, Lonneux M, Gregoire V. Tri-dimensional
automatic segmentation of PET volumes based on measured source-to-background ratios: influence

of reconstruction algorithms. Radiother Oncol. 2003 Dec;69(3):247-50.
258.
Seol YM, Kwon BR, Song MK, Choi YJ, Shin HJ, Chung JS, et al. Measurement of tumor
volume by PET to evaluate prognosis in patients with head and neck cancer treated by chemoradiation therapy. Acta Oncol. 2010;49(2):201-8.
259.
Choi K-H, Yoo I, Han E, Kim Y, Kim G, Na S, et al. Prognostic Value of Metabolic Tumor
Volume Measured by 18F-FDG PET/CT in Locally Advanced Head and Neck Squamous Cell
Carcinomas Treated by Surgery. Nuclear Medicine and Molecular Imaging. 2011;45(1):43-51.
260.
Chan WK, Mak HK, Huang B, Yeung DW, Kwong DL, Khong PL. Nasopharyngeal
carcinoma: relationship between 18F-FDG PET-CT maximum standardized uptake value, metabolic
tumour volume and total lesion glycolysis and TNM classification. Nucl Med Commun. 2010
Mar;31(3):206-10.
261.
Chan SC, Chang JT, Lin CY, Ng SH, Wang HM, Liao CT, et al. Clinical utility of 18F-FDG
PET parameters in patients with advanced nasopharyngeal carcinoma: predictive role for different
survival endpoints and impact on prognostic stratification. Nucl Med Commun. 2011 Aug 22.
169
References
262.
Higgins KA, Hoang JK, Roach MC, Chino J, Yoo DS, Turkington TG, et al. Analysis of
Pretreatment FDG-PET SUV Parameters in Head-and-Neck Cancer: Tumor SUV(mean) has

Superior Prognostic Value. Int J Radiat Oncol Biol Phys. 2011 Jan 27.
263.
Kowalski LP, Bagietto R, Lara JR, Santos RL, Silva JF, Jr., Magrin J. Prognostic
significance of the distribution of neck node metastasis from oral carcinoma. Head Neck. 2000
May;22(3):207-14.
264.
Woolgar JA. Histopathological prognosticators in oral and oropharyngeal squamous cell
carcinoma. Oral Oncol. 2006 Mar;42(3):229-39.

265.
Stuckensen T, Kovacs AF, Adams S, Baum RP. Staging of the neck in patients with oral
cavity squamous cell carcinomas: a prospective comparison of PET, ultrasound, CT and MRI. J
Craniomaxillofac Surg. 2000 Dec;28(6):319-24.
266.
Nakagawa T, Yamada M, Suzuki Y. 18F-FDG uptake in reactive neck lymph nodes of oral
cancer: relationship to lymphoid follicles. J Nucl Med. 2008 Jul;49(7):1053-9.
170

." * + # ,- ./0 ! "# "$ "% &' # ( )
:# ( ;#< /
2 3,# &4 5 6/ $27 0 2 3,# 8.8 + =7 8- "# + +/ +7
0 ." " " # :# 8- +>
/0 ; " +( +7 # ( %? # )% /@ +> ;
.:
( +( =7 +7 # #8* ! A 8*7 # "',;
8 BC ( "',# ./0 " " ' D

BC
.AC
8 ; " + =7 +7 # "',# " /0 (
- @ "?
E ?$ ( 8*7 #

."#8* "# F ! A
.+( =7 +7 # ,

) ?# /0 "' "',; + G
"?
E ( 8*7 # "; + @ / BC? '
+;7 7 ' "# ' B?;

H'
3,; 88- "(CG ?$ ?
.8?
171

! "
# $$
#%& '( ) * +,- .
/-+ 0 $
1 2)
/!31 /4
5$1 61 ,%)7

!
:
$-; );
7
/8-!

"
'( #
$ %
)
* +
!= $1 >#? / %$ <

4

,(
./
-
'
* * @ / %$ <

4

#0 "' ,(
!
' 1 1
$1 $-; ( A BCD / %$

"
./
-
'
2344

Yasser Gaber Final MD Thesis

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Yasser Gaber Final MD Thesis

Uploaded by

Copyright:

Available Formats

Definition of Risk Groups in Oral Cavity Squamous Cell

Carcinoma Patients and Prediction of Their Outcomes

Yasser Gaber Ali

Professor Dr. Hosna Moustafa

Professor Dr. Tzu-Chen Yen

Dr. Haitham Fouad Abdel-Hameed

American Joint Committee on Cancer

National Comprehensive Cancer Network

F-fluorodeoxyglucose positron emission

tomography/computed tomography (18F-FDG PET/CT), has been strongly introduced

Aim of the Work

Aim of the Work

Chapter 1: Anatomy of the Oral Cavity

Anatomy of the Oral Cavity

Figure 1: Anatomical sites and sub-sites of the oral cavity (20)

Chapter 1: Anatomy of the Oral Cavity

Oral Cavity Proper

The Oral Tongue

Chapter 1: Anatomy of the Oral Cavity

Figure 2: Lateral view

The Floor of the Mouth

Chapter 1: Anatomy of the Oral Cavity

Figure 3: Diagram of lymph

Buccal Mucosa and Cheek

Chapter 1: Anatomy of the Oral Cavity

The main structural component of the cheek is provided by the buccinator

Chapter 1: Anatomy of the Oral Cavity

Retromolar Trigone (RMT)

Alveolar Ridges and Gingivae

Chapter 1: Anatomy of the Oral Cavity

Chapter 1: Anatomy of the Oral Cavity

Figure 8: Vestibule and gingivae

The gingiva is composed of fibrous tissue covered with a mucous membrane. It

Chapter 1: Anatomy of the Oral Cavity

Regional Lymph Nodes

Chapter 1: Anatomy of the Oral Cavity

Figure 9: Lymph vessels and nodes of the head and neck(29)

II. AJCC Nodal Classification

Chapter 1: Anatomy of the Oral Cavity

Chapter 1: Anatomy of the Oral Cavity

Figure 10: Schematic diagram

Chapter 2: Overview of Oral Cavity Carcinoma

Overview of Oral Cavity Carcinoma

Chapter 2: Overview of Oral Cavity Carcinoma

however, several investigators have reported an increase in oral cancers diagnosed in

Chapter 2: Overview of Oral Cavity Carcinoma

Presence of Other Upper Aerodigestive Track Cancers

Chapter 2: Overview of Oral Cavity Carcinoma

Chapter 2: Overview of Oral Cavity Carcinoma

Spit (smokeless) tobacco is another type of tobacco that is usually placed

Chapter 2: Overview of Oral Cavity Carcinoma

complexity of the viral role in carcinogenesis is not understood completely. However,

related to an increased cancer risk (57, 58).Iron deficiency anemia in combination

Chapter 3: Pathology of Oral Cavity Carcinoma

Pathology of Oral Cavity Carcinoma

Precancerous Lesions of oral cavity

Oral Leukoplakia (OL)

patch or plaque that cannot be scraped off or characterized clinically or

Chapter 3: Pathology of Oral Cavity Carcinoma

OL is seen most frequently in middle-aged and older men, with an increasing

Chapter 3: Pathology of Oral Cavity Carcinoma

Another disturbing finding is that OL is more likely to undergo malignant

Erythroplakia (Dysplastic Leukoplakia)

clinically or pathologically as any other condition (62). It occurs most frequently in