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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
i
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
ii
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
Table of Contents
iii
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 5: Score 3-patient with a survival of 21 months..................................................................123 Case 6: Score 3-patient with a survival of 15 months..................................................................124 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
List of Figures
iv
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
List of Figures
v
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).....................................................................................................................................................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 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
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
vi
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
characteristics, SUV and TLG. .............................................................................................106 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
characteristics, SUV and TLG. .............................................................................................109 Table 17: Univariate analysis of 3-year overall survival (OS) according to pathological
characteristics.........................................................................................................................110 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.........................................................................................................................111
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
List of Abbreviations
vii
List of Abbreviations AJCC American Joint Committee on Cancer AUC Area Under Curve CCRT Concomitant ChemoRadioTherapy CGMH Chang Gung Memorial Hospital CI Confidence Interval COX Cycolooxygenase CRT ChemoRadioTherapy CT Computed Tomography CWU Conventional Work-Up DFS Disease Free Survival DICOM Digital Imaging and Communications in Medicine DMFS Distant Metastases Free Survival DOD Died Of Disease cancer death DSS Disease Specific Survival ECS Extra-capsular Spread EORTC European Organisation for Research and Treatment of Cancer FDG Fluodeoxyglucose FLT Fluoromisonidazole FMISO Fluoromisonidazole FWHM Full Width at Half Maximum HIF Hypoxia Inducible Factor HNC Head and Neck Cancer HNSCC Head and Neck Squamous Cell Carcinoma HPV Human Papilloma Virus HR Hazards Ratio JD Jugulodigastric JD Jugulo-Digastric JO Jugulo-omohyoid LC Local Control LGI Larson Ginsberg Index LN Lymph Node LND Lymph Node Dissection MD Moderately-Differentiated MIC Molecular Imaging Center MRI Magnetic Resonance Imaging MS Masticator Space MTV Metabolic Tumor Volume MVA Multivariate Analyses NC Neck Control
List of Abbreviations
viii
NCCN National Comprehensive Cancer Network NER No Evidence of Recurrence ns Not significant NSUV Standardized Uptake Value of the Lymph Nodes NTLG Total Lesion Glycolysis of Lymph Nodes OL Oral Leukoplakia OS Overall Survival OSCC Oral Squamous Cell Carcinoma PD Poorly-Differentiated PET/CT Positron Emission Tomography/Computed Tomography PVE Partial Volume Effect RMT Retromolar Trigone ROC Receiver Operating Characteristics ROI Region Of Interest RT Radiotherapy RTOG Radiation Therapy Oncology Group S/B Ratio Signal to Background Ratio SCC Squamous Cell Carcinoma SCM Sternocleidomastoid SD Standard Deviation SIL Squamous Intraepithelial Lesion SOHND Supra-Omohyoid Neck Dissection SUV Standardized Uptake Value SUVavg Average Standardized Uptake Value SUVlean Standardized Uptake Value normalized to Lean Body Mass SUVmax Maximum Standardized Uptake Value SUVpeak Peak Standardized Uptake Value TLG Total Lesion Glycolysis TNM Tumor, Node and Metastasis TSUV Standardized Uptake Value of the Primary Tumor TTLG Total Lesion Glycolysis of the Primary Tumor UADT Upper Aerodigestive Tract US Ultrasound UVA Univariate Analyses VC Verrucous Carcinoma VEGF Vascular Endothelial Growth Factor VEGF Vascular Endothelial Growth Factor VOI Volume Of Interest WD Well-Differentiated WHO World Health Organization
Introduction
1
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 18F-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 (5-
10). 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.
Introduction
2
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
3
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
4
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
Review of literature Chapter 1: Anatomy of the Oral Cavity
5
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).
Review of literature Chapter 1: Anatomy of the Oral Cavity
6
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
Review of literature Chapter 1: Anatomy of the Oral Cavity
7
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).
Review of literature Chapter 1: Anatomy of the Oral Cavity
8
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 clinically-
important space called the masticator space (MS) (Figure 5), which is a fascial
Review of literature Chapter 1: Anatomy of the Oral Cavity
9
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).
Review of literature Chapter 1: Anatomy of the Oral Cavity
10
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).
Review of literature Chapter 1: Anatomy of the Oral Cavity
11
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
Review of literature Chapter 1: Anatomy of the Oral Cavity
12
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
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13
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
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14
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).
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15
Figure 10: Schematic diagram indicating the location of the lymph node levels in the neck (20).
Review of literature Chapter 2: Overview of Oral Cavity Carcinoma
16
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).
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17
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 pre-
disposition 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
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18
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).
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19
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).
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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).
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21
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).
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22
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).
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23
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
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24
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
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25
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
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26
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.
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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).
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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).
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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).
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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).
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31
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.
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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.
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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).
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Stage Grouping Stage 0 : Tis, N0, M0
Stage I : T1, N0, M0
Stage II : T2, N0, M0
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
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35
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).
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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. Post-
operative 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).
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37
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
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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 gloss