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Definition of Risk Groups in Oral Cavity Squamous Cell Carcinoma Patients and Prediction of Their Outcomes by Using 18 F-FDG PET/CT

Thesis

Submitted for the partial fulfillment of M.D. degree in nuclear medicine

By

Yasser Gaber Ali

Assistant Lecturer South Egypt Cancer Institute – Assiut University

Under Supervision of

Professor Dr. Hosna Moustafa

Professor of Nuclear Medicine Faculty of Medicine - Cairo University

Professor Dr. Tzu-Chen Yen

Professor and Chairperson of Nuclear Medicine Department Chang Gung Medical College and University - Taiwan

Dr. Haitham Fouad Abdel-Hameed

Lecturer of Nuclear Medicine Faculty of Medicine - Cairo University

Faculty of Medicine Cairo University

2011

Acknowledgement

Acknowledgement

I would like to express my deepest and sincere gratitude to my professor Dr. Hosna Moustafa, professor of nuclear medicine, Cairo University. I am greatly indebted to her and no words in my humble dictionary can express my appreciation to her kind supervision, meticulous but targeted revision, continuous support, and enormous educational potential.

I am very grateful to Prof. Dr. Tzu-Chen Yen, professor and chairperson of nuclear medicine in Chang Gung Memorial Hospital, Taiwan. She gave me a great opportunity to be among her research team in such amazing and friendly environment in Taiwan. Indeed, I have learnt a lot from her, especially how to think, conduct and analyze a research work.

Also, I would like to thank Dr. Haytham Fouad for his uninterrupted encouragement and fruitful exchange of ideas.

Many thanks to Dr. Liao Chun-Ta, professor of otolaryngology & head and neck surgery in Chang Gung Memorial Hospital, for providing the clinical and follow-up data, in addition to his supportive corrections and advices, and to all my colleagues and friends in Taiwan who helped me throughout the 2 years I have spent there and to my family who are always trying their best to make my life easier.

Table of Contents

Table of Contents

Acknowledgement

i!

ii!

iv

vi!

Table of Contents

List of Figures

List of Tables

List of Abbreviations

vii!

1 !

3

4

Introduction

Aim of the Work

Anatomy of the Oral Cavity

I. !

II. !

Lips

4

5

Oral Cavity Proper

Regional Lymph Nodes

12

I. !

Anatomical Considerations

12

II. !

AJCC Nodal Classification

13

Overview of Oral Cavity Carcinoma

16

Epidemiology of OSCC

16

16

Incidence

Risk Factors

17

22

Pathology of Oral Cavity Carcinoma

I. !

II. !

III. !

Precancerous Lesions of oral cavity

22

26

30

Squamous Cell Carcinoma (SCC)

Verrucous Carcinoma (VC)

Staging of the Lip and Oral Cavity Cancer

31

Diagnosis of OSCC

35

36

Treatment Outlines for OSCC

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

! Prognostic Factors in Oral Cavity Carcinoma

39

40

I. !

Patient-Related Prognostic Factors:

40

II. !

Tumor-Related Prognostic Factors:

41

III. !

Treatment-Related Prognostic Factors:

45

PET Imaging

47

47

48

PET Radiopharmaceuticals

Normal PET Imaging

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

! Limitations of FDG PET in Head and Neck Cancer

55

55

Table of Contents

1. Physiologic FDG Uptake

55

2. Inadequate Scanner Resolution

55

3. Recent Surgery and Inflammatory Response

56

4. Effect of Radiation and Chemotherapy

56

5. Low FDG Avidity

57

6. PET/CT Artifacts

57

Qualitative and Quantitative Parameters from PET

60

I. !

Qualitative Assessment

60

II. !

Quantitative Assessment

61

III. !

Semi-quantitative Assessment

61

Clinical Role of FDG-PET in Oral Cavity Carcinoma

66

I. !

Staging

66

II. !

Restaging and Therapy Monitoring

70

III. !

Prognosis and Risk Stratification

72

The Role of Non-FDG Radiopharmaceuticals

76

Patients and Methods

78

Patients

78

PET/CT Imaging Protocol

78

Data Reading & Analysis

79

Calculation of Total Lesion Glycloysis (TLG)

81

Surgery and Adjuvant Therapy

81

Follow-up Protocol

82

Statistical Analysis

82

Results

84

 

1. Patients

84

2. PET/CT Scores and SUV

88

3. Choice of the Best Contouring Method

89

4. Total Lesion Glycolysis (TLG)

90

5. Association between SUV & TLG and Different Pathological Characteristics

90

6. Univariate Analyses

93

7. Multivariate Analyses

112

8. Risk Score

115

9.

Risk Groups Based on ECS & N SUV

! Case Presentation

118

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

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

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

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

31

Figure 17: Methods of measuring tumor

43

Figure 18: Mechanism of FDG uptake

48

Figure 19: Normal PET/CT scan

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

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)

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, Figure 28: Axial view of FDG-PET showing periodontal/dental

Figure 29: (A) Hypermetabolic thyroid adenoma at the left lobe; (B) H ϋ rthle cell carcinoma at the

53 !

54 !

right lobe

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

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

58

59

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87

88

value of 3, and (B) the relation between maximum diameter of the pathologic lymph nodes and

Figure 34: Truncation artifact

Figure 35: The tumor subsites seen

Figure 36: The pattern of recurrence in the 45 patients who experienced treatment failure (percentages are given among the 45

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

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

the diameter derived from lymph node delineation using absolute SUV value of

89

Figure 39: ROC analyses of T TLG (A) and N TLG (B) in relation to presence of ECS. The best cut-

off values identified were 92.19 and 18.51, respectively. N TLG was significantly more accurate

than T TLG for predicting ECS (P < 0.001)

90

93

93

96

96

99

Figure 40: Local control rate according to the primary tumor TLG

Figure 41: Local control rate according to the presence or absence of bone marrow invasion

Figure 42: Neck control rate according to the neck lymph nodal TLG

Figure 43: Neck control rate according to the histopathological differentiation

Figure 44: Distant metastases free survival rate according to the primary tumor

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

102

102

105

105

108

108

116

116

118

Figure 46: Disease free survival rate according to the primary tumor TLG

Figure 47: Disease free survival rate according to the pathologic status of neck lymph nodes

Figure 48: Disease specific survival rate according to the primary tumor TLG

Figure 49: Disease specific survival according to the pathologic status of neck lymph

Figure 50: Overall survival rate according to the neck lymph nodal SUV

Figure 51: Overall survival rate according to the pathologic status of neck lymph

Figure 52: Disease free survival rate according to the proposed risk

Figure 53: Disease specific survival rate according to the proposed risk

Figure 54: Distant metastases free survival rate according to nodal SUV in 40 patients with positive

Figure 55: Disease specific survival rate according to nodal SUV in 40 patients with positive ECS.

118

List of Tables

List of Tables

Table 1: Common β + emitters of clinical importance

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 T SUV and T TLG to different pathological characteristics

91 !

Table 5: Relation of nodal N SUV and N TLG to different pathological characteristics

Table 6: Univariate analysis of 3-year local control (LC) according to clinical characteristics,

92 !

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 Table 15: Univariate analysis of 3-year disease specific survival (DSS) according to pathological characteristics Table 16: Univariate analysis of 3-year overall survival (OS) according to clinical characteristics, SUV and TLG Table 17: Univariate analysis of 3-year overall survival (OS) according to pathological characteristics 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 Table 19: Multivariate analysis of 3-year local primary tumor control (LC) Table 20: Multivariate analysis of 3-year neck control (NC) Table 21: Multivariate analysis of 3-year distant metastases free survival (DMFS) Table 22: Multivariate analysis of 3-year disease free survival (DFS) Table 23: Multivariate analysis of 3-year disease specific survival (DSS) Table 24: Multivariate analysis of 3-year overall survival (OS) Table 25: Multivariate analysis of 3-year disease free (DFS) and disease specific survival (DSS), according to the proposed risk score Table 26: Some of the characteristics of patients with score 3

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List of Abbreviations

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

NCCN

National Comprehensive Cancer Network

NER

No Evidence of Recurrence

ns

Not significant

SUV

N

Standardized Uptake Value of the Lymph Nodes

N

TLG

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

SUV

T

Standardized Uptake Value of the Primary Tumor

T

TLG

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

Introduction

Oral cancer is the eighth most common cancer worldwide, with epidemiologic variations between different geographic regions (1). The World Health Organization (WHO) expects a worldwide rising incidence in the next decades (2).

Surgery is the main stay for resectable oral squamous cell carcinoma (OSCC). Post-operative radiotherapy (RT) or chemoradiotherapy (CRT) is indicated in the presence of specific adverse features (3).

Numerous prognostic factors have been identified including clinical, anatomical and pathological risk factors; however, and in spite of the ready accessibility of the oral cavity to direct examination, these malignancies still often not detected until a late stage, and the survival rate for oral cancer has remained essentially unchanged over the past three decades (4).

The possibility of identifying novel prognostic factors in oral cancer may help in stratifying different risk groups and personalizing the cancer management process.

Recently, standardized uptake value (SUV), a simplified index of glucose uptake of the tumor measured from 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-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

Their results set the stage for other groups at Memorial Sloan-Kettering Cancer Center to study TLG among other parameters in evaluation of lung cancer after radiation treatment (13) and to predict long-term outcomes in patients with rectal cancer (14). They found good correlation between TLG with treatment response and outcomes. TLG also was investigated in patients with esophageal cancer (15, 16), soft tissue sarcoma (17), osteosarcoma (18) and melanoma (19), with encouraging results.

The potential prognostic role of baseline SUV and TLG measured at the primary tumor and neck lymph nodes has not been studied in patients with OSCC.

Aim of the Work

Aim of the Work

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

Review of literature

Chapter 1: Anatomy of the Oral Cavity

Anatomy of the Oral Cavity

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

into oral cavity proper and lip vermilion (Figure 1) (4). Figure 1: Anatomical sites and sub-sites

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

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

e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 2:

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:

! The tip drains to the submental then jugulo-digastric (JD) nodes

! 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

! 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

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).

and/or internal jugular nodes (levels 1 and 2). 3. Buccal Mucosa and Cheek Figure 3: Diagram

3. Buccal Mucosa and Cheek

Figure 3: Diagram of lymph drainage of the tongue(24)

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

e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 4:
e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 4:

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

8

Review of literature

Chapter 1: Anatomy of the Oral Cavity

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

e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 6:

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).

and a cross-section of the tongue and floor of mouth (21). Figure 7: Trans-oral view of

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

e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 8:

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

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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Chapter 1: Anatomy of the Oral Cavity

the first physical finding to suggest an otherwise clinically silent tongue tumor (Figure 9) (28).

otherwise clinically silent tongue tumor (Figure 9) (28). Figure 9: Lymph vessels and nodes of the

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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Chapter 1: Anatomy of the Oral Cavity

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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Chapter 1: Anatomy of the Oral Cavity

e r a t u r e Chapter 1: Anatomy of the Oral Cavity Figure 10:

Figure 10: Schematic diagram indicating the location of the lymph node levels in the neck (20).

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Chapter 2: Overview of Oral Cavity Carcinoma

Overview of Oral Cavity Carcinoma

The oral cavity is a common site for squamous cell cancers of the upper

aerodigestive tract (UADT), probably because it is the first entry point for many

carcinogens; therefore, the incidence may vary according to cultural habits. OSCC

tends to spread regionally to lymph nodes of the submandibular region (Level I) and

to the upper and middle jugular chain lymph nodes (Levels II and III). OSCC may be

less sensitive to chemotherapy and radiation relative to oropharyngeal or laryngeal

cancers, moreover it can be readily accessible to surrounding bony structures. Thus,

primary treatment for most tumors is surgical. Adjuvant treatment by radiotherapy

(RT) or chemoradiotherapy (CRT) is given in advanced and high risk patients.

Follow-up for detection of residual or recurrent tumor is mandatory in view of the

limitations of current anatomical modalities following combined treatment modalities

(30).

Epidemiology of OSCC

Incidence

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).

Oral

cancer

holds

the

eighth

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Chapter 2: Overview of Oral Cavity Carcinoma

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.

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

1.

17

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Chapter 2: Overview of Oral Cavity Carcinoma

younger patients (37-39). In Taiwan, the peak incident rate in the period from 1989 to

1993 was for people aged 50–59 years, but this shifted to 40–49 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 35–40% of all

malignancies in India, compared with approximately 9% in Taiwan and 2–4% in

Western countries 5 .

Before age 55, oral cancer is the sixth most common cancer in white men but is

the fourth most common cancer in black men (40).

4. Presence of Other Upper Aerodigestive Track Cancers When a cancer of the upper aerodigestive track is found, it is important to

assess the patient for the presence of another primary malignancy of the associated

structures. Several researchers have reported that patients with an OSCC have a

greater risk for a synchronous or metachronous malignancy of the upper

aerodigestive track (42, 43).

18

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Chapter 2: Overview of Oral Cavity Carcinoma

Tobacco Depending on the product, tobacco contains more than 50 established or

potential carcinogens that may increase relative risks for cancers by differing

5.

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 smoker’s palate (Figure 16), which has been

associated with a significant risk of malignant transformation (44).

with a significant risk of malignant transformation (44). Figure 11: Palatal lesion associated with reverse smoking.

Figure 11: Palatal lesion associated with reverse smoking. Note the crate-like ulcerated areas covered with fibrin (45).

19

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Chapter 2: Overview of Oral Cavity Carcinoma

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).

Alcohol Alcohol abuse seems to be the second largest risk factor (after smoking

tobacco) for developing OSCC. A strong correlation exists between excessive alcohol

6.

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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Chapter 2: Overview of Oral Cavity Carcinoma

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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Chapter 3: Pathology of Oral Cavity Carcinoma

Pathology of Oral Cavity Carcinoma

Both keratinized and non-keratinized epithelium share in the formation of oral mucosa. It is stratified keratinized squamous epithelium over the attached gingiva, hard palatal mucosa, and specialized keratinized gustatory mucosa of the dorsum of the tongue, while it is non-keratinized type over mucosal surfaces of the inner lips and cheeks, loose gingiva, ventral tongue, floor of the mouth, and soft palate (60).

The epithelium is three to four times the thickness of skin epidermis. Beneath the epithelium is the lamina propria of fibrous tissue and blood vessels, underneath which, in turn, is the densely fibrous periosteum of the hard palate or the alveolus of the maxilla and mandible. The term submucosa is sometimes loosely applied to the deep connective tissue just above the muscle layer, in which the minor salivary glands are often embedded (60).

The transition from normal squamous epithelium to invasive SCC is a comprehensive and multistage process that involves distinct histological changes called squamous intraepithelial lesions (SILs) which are causally related to progressive accumulation of genetic changes. Particular interest should be focused on potentially malignant or precancerous SILs. These lesions have been defined as histomorphological disorders of the squamous epithelium which changes to invasive cancer in significantly higher percentage than from other epithelial lesions (61).

I. Precancerous Lesions of oral cavity

1. Oral Leukoplakia (OL)

As defined by the World Health Organization (WHO), leukoplakia is “a white patch or plaque that cannot be scraped off or characterized clinically or pathologically as any other disease”(62).

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Chapter 3: Pathology of Oral Cavity Carcinoma

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).

irregularly flat, nodular or exophytic (Figure 11) (61). (A) (B) Figure 12: Oral leukoplakia: (A) Gross

(A)

flat, nodular or exophytic (Figure 11) (61). (A) (B) Figure 12: Oral leukoplakia: (A) Gross picture

(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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Chapter 3: Pathology of Oral Cavity Carcinoma

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).

is rarely possible because of the widespread growth (61). Figure 13: Proliferative verrucous leukoplakia involving

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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Chapter 3: Pathology of Oral Cavity Carcinoma

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).

the intense heat generated from pipe and cigar smoking (4). Figure 14: Nicotine Stomatitis : Rough,

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 smoker’s 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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Chapter 3: Pathology of Oral Cavity Carcinoma

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).

rimmed by elevated, firm, rolled borders (Figure 14) (65). Figure 15 : Squamous cell carcinoma of
rimmed by elevated, firm, rolled borders (Figure 14) (65). Figure 15 : Squamous cell carcinoma of

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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Chapter 3: Pathology of Oral Cavity Carcinoma

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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Chapter 3: Pathology of Oral Cavity Carcinoma

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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Chapter 3: Pathology of Oral Cavity Carcinoma

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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Chapter 3: Pathology of Oral Cavity Carcinoma

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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Chapter 3: Pathology of Oral Cavity Carcinoma

t u r e Chapter 3: Pathology of Oral Cavity Carcinoma Figure 16 : Verrucous carcinoma.

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

T X Primary tumor cannot be assessed.

T 0 No evidence of primary tumor.

T is Carcinoma in situ.

T 1 Tumor 2cm or less in greatest dimension.

T 2 Tumor more than 2cm but not more than 4 cm in greatest dimension.

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Chapter 3: Pathology of Oral Cavity Carcinoma

T 3 Tumor more than 4 cm in greatest dimension.

T 4a (Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face, i.e., chin or nose.

T 4a (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.

T 4b 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

N X Regional lymph nodes cannot be assessed.

N 0 No regional lymph node metastasis.

N 1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension.

N 2 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.

N 2a Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension.

N 2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension.

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Chapter 3: Pathology of Oral Cavity Carcinoma

N 2c Metastasis in bilateral or contra-lateral lymph nodes, none more than 6 cm in greatest dimension.

N 3 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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Chapter 3: Pathology of Oral Cavity Carcinoma

Stage Grouping

Stage 0

:

T is , N 0 , M 0

Stage I

:

T 1 , N 0 , M 0

Stage II :

T 2 , N 0 , M 0

Stage III :

T 3 , N 0 , M 0 or T 1-2 , N 1 , M 0

Stage IV A :

T 4a , N 0-1 , M 0 or T 1-3 , N 2 , M 0

Stage IV B :

Any T, N 3 , M 0 or T 4b , any N, M 0

Stage IV C :

Any T, any N, M 1

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Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

Diagnosis of OSCC

National Comprehensive Cancer Network (NCCN) guidelines recommend the following procedures for the staging work-up:

History and complete physical examination including a complete head and neck exam; mirror and fiberoptic examination as clinically indicated

Biopsy

Chest X-ray

CT with contrast and/or MRI with contrast of primary and neck as indicated

Consider PET-CT for stage III-IV disease

Examination under anesthesia, if indicated

Dental evaluation, including panorex as indicated

Nutrition, speech & swallowing evaluation/therapy as indicated

Multidisciplinary consultation as indicated (3).

A general medical evaluation is performed, including a thorough head and neck examination by one or more physicians. The location and extent of the primary tumor and any clinically positive cervical lymph nodes is documented. Almost all patients will undergo contrast-enhanced CT and/or MRI to further delineate the extent of local and regional disease. There is some preference to use CT and reserve MRI for situations where further information is required. The scan(s) should be obtained prior to biopsy so that changes from the biopsy are not confused with tumor. A chest x-ray is obtained to determine the presence of distant metastases and/or a synchronous primary lung cancer. Patients with N3 neck disease, as well as those with N2 adenopathy with adenopathy below the level of the thyroid notch, have a 20% to 30% risk of developing distant metastases and should be considered for a chest CT or PET (68).

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Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

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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Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

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:

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

1.

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Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

do not involve the commissure; the treatment is simple and the cosmetic result is

satisfactory (68).

Removal of more of the lip with simple closure usually results in a poor

cosmetic and functional result and therefore requires reconstructive procedures.

Irradiation is often preferred for lesions involving the commissure, for lesions over 2

cm in length, and for upper lip carcinomas. Advanced lesions with bone, nerve, or

node involvement frequently require a combined approach (68).

The regional lymphatics are not treated electively for early cases. Advanced

lesions, high-grade lesions, and recurrent lesions should be considered for elective

neck treatment (68).

2. Floor of the mouth Operation or radiation therapy is equally effective treatment for T1 or T2

lesions. Most patients are treated surgically because of the risk of soft tissue or bone

necrosis after irradiation (68).

The usual recommendation for moderately advanced anterior midline lesions is

rim resection or segmental mandibulectomy and osteomyocutaneous free flap

reconstruction; postoperative irradiation is added as dictated by the findings in the

specimen. The neck, with clinically negative nodes, is usually managed by bilateral

functional neck dissection for midline lesions (68).

3. Oral Tongue A partial glossectomy with primary closure or a skin graft may be done

transorally and is usually the preferred therapy. Depending on the depth of invasion,

an elective neck dissection may be indicated. RT is reserved for cases with adverse

features (68).

The preferred treatment for the majority of patients with T2 or T3 is partial

glossectomy, neck dissection, and postoperative radiotherapy. In contrast, combined

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Chapter 4: Diagnosis and Treatment of Oral Cavity Carcinoma

treatment with surgery and radiation therapy may cure very few T4 patients. Most

patients in this category will receive palliative therapy (68).

4. Buccal Mucosa Small lesions (1 cm or smaller) may be excised with primary closure; small

lesions that involve the lip commissure are sometimes treated by radiation therapy.

Lesions 2 to 3 cm in size can be treated with surgery or by radiation therapy, usually

the former. Larger lesions are usually treated with surgery and postoperative

radiotherapy (68).

5. Lower Gum The majority of lesions are managed by operation. Postoperative irradiation

may be indicated depending on pathologic findings (68).

6. Retromolar Trigone

for discrete early lesions. Radiation therapy is

recommended for superficial lesions involving a large surface area. Advanced

carcinomas are treated with surgery and postoperative irradiation (68).

Surgery

is

preferred

7. Upper Gum and Hard Palate Resection is the usual treatment for most lesions; postoperative radiation

therapy is added as needed. However, if the lesion is superficial and extensively

involves the hard palate or involves a significant portion of the soft palate, then

radiation should be considered for the initial therapy. Bone invasion requires a partial

maxillectomy. The defect usually is repaired with a prosthesis (68).

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

Prognostic Factors in Oral Cavity Carcinoma

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

I. Patient-Related Prognostic Factors:

1. Gender

Most published data showed no prognostic differences between females and males (71-74); however, a Brazilian study reported lower survival rates in females, which might be attributed to delay in seeking medical care and lower acceptance of treatment (75).

2. Age

The prognostic role of age is rather controversial. Many studies showed no age difference in prognosis (71, 73). Old age (> 50 years) was linked to worse prognosis in some reports (76-78), but that seems to be related to co morbid disease rather than age itself. Reports showing the bad prognosis in young age (< 40 years) have been published (37-39, 79, 80).

3. Smoking and Drinking:

Most authors report higher mortality in smokers and alcohol drinkers. A large Swedish case-control study identified smoking and alcohol as risk factors for OSCC. Also they showed that female smokers have a greater risk for recurrence than male smokers at any level of tobacco consumption (81).

Smokers and alcohol drinkers seem to be at higher risk for the development of second primary oral cancer than nonsmokers and nondrinkers, thus facing more onerous outcomes (42).

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

4. Chewing Betel Quid:

Liao et al (71) found that chewing betel quid is an independent prognostic factor for poor local control. Lo et al (74) reported about 20% higher relative risk of death in this category, which is increased up to 5 times with drinking alcohol and smoking cigarettes.

5. Miscellaneous Factors:

Poor oral hygiene, depressed host immunity, comorbid chronic conditions and weight loss have been associated with bad prognosis (82, 83) (84-86). However, there is no consensus on which comorbidity index should be used and how this data may complement the current TNM staging system (87-89).

II. Tumor-Related Prognostic Factors:

1. Site:

Different tumor subsites carry different implications in prognosis. Lip cancer is generally readily curable compared with malignancies at other head and neck sites (90). Tiwari (91) reported poorer prognosis in superior gingivolabial sulcus tumors, because cancer at this location has high propensity for lymphatic spread especially with the involvement of the parapharyngeal and retropharyngeal lymph nodes which makes surgical therapy difficult and prognosis is often poor. Reports on buccal cancer prognosis were controversial. Sieczka et al (92) suggested the use of definitive and vigorous treatment, not only for the more advanced buccal squamous cell cancers, but for early lesions as well. They considered the typical disease markers (T-stage and histologic margin) not to be wholly reliable indicators of success with surgical treatment. Comparable results were reported by others (93). However, these results were challenged by other authors (71, 94). In a series of 276 patients, Liao et al (71) reported a 5-year local control rate and disease specific survival of 86% & 78%

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

respectively. It worth noting that buccal cancers represent about 10% in Europe and USA, while it is considered the most common subsite in India and Southern Asia and regarded as having favorable prognosis. Hence, the interpretation of the prognostic data is difficult because the effects of differences in staging and treatment approaches in addition to varying tumor behavior and presentations in different regions of the world.

2. Stage:

OSCC staging is based on TNM system. The vast majority of authors accept that disease staging has a crucial influence on the outcome (95). Lo et al. described 5- year survival rates of 75%, 65.6%, 49%, and 30% for disease stages I, II, III, and IV, respectively (74).

The presence of cervical lymph node metastasis is the single most adverse independent prognostic factor in HNSCC. Cervical node metastases may be classified into 2 distinct categories: overt (clinical) or non-overt (occult, subclinical). The latter may be even “subpathological” or ‘‘submicroscopic’’ metastases, which is detectable only by immunohistochemical and/or molecular analysis of the dissected lymph nodes. It is yet to be determined what is the clinical impact of detecting these submicroscopic occult lymph node (96). The incidence of occult metastases varies according to T-stage and ranges from 13% for T1 to 46% for T4 (97).

3. Tumor Thickness:

The risk of nodal metastases, ECS and mortality rates vary directly with the thickness of the primary tumor and may be more important than clinical and pathological staging (98, 99). However, the cut-off marking decimal prognosis varies between studies. Huang et al, in their meta-analysis, considered a 4-mm tumor thickness to be predictive of nodal metastases and recommended prophylactic management (100). In another meta-analysis (101), a cut-off from 3 up to 10 mm was linked to poor progression free and overall survivals. This report especially

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

emphasized the importance of standardizing measurement technique for tumor

thickness among studies (Figure 17).

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

Figure 17: Methods of measuring tumor thickness. Left: exophytic cancer; right: ulcerative cancer. In all types, tumor thickness is measured to the deepest point of invasion, the starting point varies according to the method of measurement, in A & D: from the summit of tumor surface (exophytic type) or floor of the ulcer (ulcerative type); B & E: from the level of adjacent intact mucosa; C & F: from the level of basal membrane (101).

In a series of 827 patients, Liao et al. showed that DSS was significantly lower

when the tumor thickness was 10 mm or more (69% vs. 91%). They measured the

tumor from the deepest point to the basal membrane and referred to as tumor depth.

They also suggested that tumor depth, rather than tumor size, should be included in

the pathological tumor staging system (71).

4. Extracapsular Spread:

Extracapsular spread (ECS) is indicted when irregular nodal boundaries,

infiltration of adjacent fat planes, thickening of adjacent fascia, and apparent invasion

of adjacent structures are present. CT has been shown to be more specific in

determining extracapsular spread and remains the study of choice for evaluating neck

disease (102).

ECS was noted in the majority of the lymph nodes larger than 3 cm and in

about 40% of clinically and up to 16% of clinically N0 patients (103).

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

ECS was significantly higher with large primary tumor size (> 4 cm), poor differentiation, close and involved surgical margins and positive perineural invasion

(103).

In1971, Bennet et al. showed that aerodigestive tumors with ECS indicate a poor prognosis (104). Since that time, it has been widely documented that patients with OSCC & ECS have a high risk of regional recurrence and distant metastasis, and hence, reduced survival (105). According to NCCN guidelines, the presence of ECS is an indication for post-operative RT or chemoradiation (69). Some authors try to stratify the risk within the patients with OSCC and ECS. Liao et al. found that within all the patients with OSCC and ECS, those with level IV/V metastases appear to have the worst prognoses (5-year DFS, DSS, and OS rates were 14%, 12%, 10%) (72).

5. Histologic Differentiation:

Most authors have established significant correlations between lower histologic differentiation and poorer prognosis (71, 74, 83) but others did not find such association (75).

6. Perineural Invasion:

Perineural invasion apparently correlates with higher probability of regional and distant metastases, higher depth of tumor invasion, lower differentiation, and lower 5-year survival rates in OSCC (106, 107).

7. Angiogenesis:

The vascular endothelial growth factor (VEGF) is a key component in tumor angiogenesis, and 4 subtypes have been described (A, B, C, and D). Recently Shintani et al. described its expression in OSCC, correlating subtypes A and B with tumor angiogenesis and subtypes C and D with the risk of nodal metastases (108).

Marked angiogenesis correlated well with the risk of nodal metastases and it is considered an independent predictor of tumor recurrence (109).

44

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

8. Human Papilloma Virus (HPV):

A large study conducted by Gillison et al. has shown that patients with HPV-

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

III. Treatment-Related Prognostic Factors:

1. Resection Margin:

The surgical resection margin is considered “clear or free” when the distance from the invasive tumor front that is 5 mm or more from the resected margin (69).

A strong correlation has been demonstrated between a resection margin free of

disease and higher survival rates (112). It was reported that the 5-year DSS of patients with a positive margin was poorer by 12% than for those patients with a negative margin (113). Close margins (4–5 mm) may represent risk factors for local tumor control, and that patients with close margins should receive adjuvant therapy

(114).

2.

Post-operative Chemoradiation:

The role of chemotherapy in the postoperative management of the patient with adverse prognostic risk factors has been clarified by 2 separate multicenter randomized trials (115, 116) and a combined analysis of data from the 2 trials (117). The US Intergroup trial -the Radiation Therapy Oncology Group (RTOG) trial- randomly assigned patients with 2 or more involved nodes, positive margins, or ECS to receive standard postoperative radiotherapy or the same radiotherapy plus cisplatin

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Chapter 5: Prognostic Factors in Oral Cavity Carcinoma

100 mg/m2 every 3 weeks for 3 doses (115). The European Organisation for Research and Treatment of Cancer (EORTC) trial was designed using the same treatment but also included as high-risk factors the presence of perineural or perivascular disease and nodal involvement at levels 4 and 5 from an oral cavity or oropharynx cancer (116). The RTOG trial demonstrated statistically significant improvement in locoregional control and disease-free survival but not overall survival, whereas the EORTC trial found significant improvement in survival and the other outcome parameters. Both the RTOG and EORTC trials use high-dose cisplatin (100 mg/m2 every 3 weeks).

To better define risk, a combined analysis of prognostic factors and outcome from the 2 trials was performed. This analysis demonstrated that patients in both trials with ECS of tumor and/or positive resection margins benefited from the addition of cisplatin to postoperative radiotherapy. For those with multiple involved regional nodes without extracapsular spread, there was no survival advantage (117).

3. Cervical Lymph Node Dissection:

This procedure is a source of significant postoperative morbidity, namely shoulder dysfunction. Furthermore, recently published work asserts that sparing 1 or both internal jugular veins is associated with a reduction in mortality rates, not endangering the prognosis (96).

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Chapter 6: PET Imaging

PET Imaging

Positron emission tomography (PET) is a powerful metabolic imaging technique utilizing possibly many radiopharmaceuticals; however the most- commonly used one is 18 F-fluorodeoxyglucose (FDG). It yields excellent quality images and has an enormous clinical impact, a demonstrated in many well-conducted studies.

PET Radiopharmaceuticals

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

entry in the table, is the most commonly used one (118). Table 1: Common β +

Table 1: Common β + emitters of clinical importance (118).

Synthesis of FDG is an automated computer-controlled radiochemical process that takes approximately 50 minutes to complete.

47

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Chapter 6: PET Imaging

FDG is a radiopharmaceutical analog of glucose that is taken up by

metabolically active tumor cells using facilitated transport similar to that used by

glucose (Figure 18). Like glucose, it undergoes phosphorylation to form FDG-6-

phosphate; however, unlike glucose, it does not undergo further metabolism, thereby

becoming trapped in metabolically active cells. Uptake of FDG in tumor cells is also

influenced, among other factors, by tumor hypoxia and blood glucose level (119).

factors, by tumor hypoxia and blood glucose level (119). Figure 18: Mechanism of FDG uptake Normal

Figure 18: Mechanism of FDG uptake

Normal PET Imaging

Normal physiologic uptake of 18F-FDG can be seen to some extent in every

viable tissue (Figure 19), including the brain, myocardium (where the uptake is

significant in some patients despite prolonged fasting), breast, liver, spleen, stomach,

intestines, kidneys and urinary bladder, muscle, lymphoid tissue (e.g., tonsils and

adenoids), bone marrow, salivary glands, thymus, uterus, ovaries, testes, and brown

adipose tissue (120).

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Chapter 6: PET Imaging

f l i t e r a t u r e Chapter 6: PET Imaging Figure

Figure 19: Normal PET/CT scan (121).

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

1. Oral Cavity and Lymphoid Tissues

Physiological uptake within the tongue and oropharynx is seen in the shape of an inverted "U" on the midline sagittal view (Figure 20), within which three more prominent foci of uptake are seen:

The first is the most prominent and caused by the sublingual glands and hyoid muscle (mylohoid) insertions on the mandible (Figure 21).

The second is formed by uptake in the soft palate, as well as the opposed surface of the tongue. This is shown axially in (Figure 22).

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Chapter 6: PET Imaging

The third focus of more prominent uptake is a result of uptake within the

lingual tonsil and the base of the tongue (Figure 21) (Burrell and Van den

Abbeele; 2005).

Uptake in the tonsils can be particularly prominent in children and in adults

with some attach of pharyngitis or tonsillitis (Figure 23) (122).

attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with
attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with
attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with
attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with
attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with
attach of pharyngitis or tonsillitis (Figure 23) (122). Figure 20: Midline sagittal view with

Figure

20:

Midline

sagittal

view

with

different

H.

&

N.

structures (122).

Most

prominent uptake in the

sublingual glands and

mylhyoid insertions (122).

muscle

Figure

21:

Figure 22: Uptake in the soft palate (122).

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Chapter 6: PET Imaging

f l i t e r a t u r e Chapter 6: PET Imaging 2.
f l i t e r a t u r e Chapter 6: PET Imaging 2.

2. Brown Fat and Skeletal Muscles

Figure 23: Left: Palatine tonsils uptake, Right: uptake in the pharyngeal tonsil (adenoids)

(122).

Variable uptake may be demonstrated within the skeletal muscles of the head

and neck; some of this uptake is also within brown fat (123).

Uptake in the sternocleidomastoid muscle and at muscular insertion sites into

the occipital bone is commonly seen (Figure 24). Also, uptake in the trapezius,

intercostal muscles may be seen (124).

in the trapezius, intercostal muscles may be seen (124). Figure 24: Focal uptake at insertion of
in the trapezius, intercostal muscles may be seen (124). Figure 24: Focal uptake at insertion of

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).

the

sternocleidomastoid muscle (Figure 25) and can mimic an enlarged lymph node

(125).

Intense

asymmetric

FDG

uptake

can

also

be

seen

within

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Chapter 6: PET Imaging

f l i t e r a t u r e Chapter 6: PET Imaging Figure

Figure 25: Asymmetric sternocleidomastoid muscle uptake. (A) Axial CT right sternocleidomastoid muscle (arrow). (B) Fused PET-CT scan localizes the FDG uptake to the right sternocleidomastoid muscle (arrow). Note also the symmetric FDG uptake within the prevertebral strap muscles (arrowheads)

(126).

Muscles of the mastication also can show asymmetry in their uptake (Figure

26).

also can show asymmetry in their uptake (Figure 26). Figure 26: Asymmetric increased uptake in the
also can show asymmetry in their uptake (Figure 26). Figure 26: Asymmetric increased uptake in the

Figure 26: Asymmetric increased uptake in the muscles of mastication.

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Chapter 6: PET Imaging

3. Laryngeal Uptake

A horizontal band of uptake corresponding to the base of the vocalis muscles

or the transverse arytenoid muscle is frequently seen. Two discrete foci are seen

posteriorly, corresponding with the convergence of the various arytenoid muscles.

The appearance vocal cords is quite variable, however normal uptake should be

relatively symmetric (Figure 27) (122).

uptake should be relatively symmetric (Figure 27) (122). 4. Osseous Uptake Figure 27: Physiologic uptake in

4. Osseous Uptake

relatively symmetric (Figure 27) (122). 4. Osseous Uptake Figure 27: Physiologic uptake in the vocalis muscle,

Figure 27: Physiologic uptake in the vocalis muscle, arytenoid muscles and symmetric vocal cord uptake (122, 126).

In bones composed predominantly of cortical bone, such as the skull, mandible

and maxilla, FDG uptake is virtually absent. In bones containing a large proportion of

marrow, mild-to-moderate FDG uptake is typically seen (e.g. the vertebral bodies)

(122). Discrete foci of uptake within the maxilla and mandible are frequently seen

(Figure 28), almost invariably because of periodontal/dental disease (127).

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Chapter 6: PET Imaging

f l i t e r a t u r e Chapter 6: PET Imaging 5.

5. Orbits

Figure 28: Axial view of FDG-PET showing periodontal/dental (127).

Within the orbits, uptake is frequently seen at the apex as a result of uptake at

the convergence of the extra-ocular muscles. Uptake may also be seen throughout the

length of the extra-ocular muscles (127).