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

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


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).


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


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).


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


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).


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).


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


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


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


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).


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).


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


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).


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).


20

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).


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).

Review of literature Chapter 3: Pathology of Oral Cavity Carcinoma

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).


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


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


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


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.


27

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).


28

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).


29

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).


30

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).


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.


32

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.


33

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).


34

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

Review of literature Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

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).


36

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).


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


38

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

yasser gaber final md thesis

Documents

cairo university professor

supervision of professor

university taiwan

tzuchen yen professor

memorial hospital

research work

list of figures

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