Oral Submucous Fibrosis: A Guide to Diagnosis and Management (Textbooks in Contemporary Dentistry)

Foreword
Preface
Contents
Contributors
Abbreviations
I: Introduction to Oral Submucous Fibrosis
	1: Oral Submucous Fibrosis: A Historical Perspective
		1.1	 Introduction
		1.2	 A Sweep Across Time
		1.3	 Other Relevant Ayurvedic Literature
		1.4	 Studies on OSF During the Past Century
			1.4.1	 Studies from South and SE Asia
				1.4.1.1 India
				1.4.1.2	 Sri Lanka
				1.4.1.3	 Taiwan
				1.4.1.4	 China
				1.4.1.5	 Burma
				1.4.1.6	 Nepal
				1.4.1.7	 Malaysia
				1.4.1.8	 Papua New Guinea
				1.4.1.9	 South Africa
		1.5	 Summary of Recent History
		Summary
		References
	2: Epidemiology of Oral Submucous Fibrosis: Prevalence and Trends
		2.1	 Introduction
		2.2	 Epidemiology of OSF
		2.3	 Prevalence Data from the Indian Subcontinent
		2.4	 Prevalence Data from Other Countries in the South Asian Region
		2.5	 International Prevalence Studies
			2.5.1	 Western Countries
			2.5.2	 South Africa
		2.6	 Gender
		2.7	 Age
			2.7.1	 Prevalence of OSF Among Children and Adolescents
		2.8	 Trends in Etiology
		2.9	 Discussion
		2.10 Conclusion
		Summary
		References
	3: Clinical Features: Oral Submucous Fibrosis
		3.1 Introduction
		3.2 Brief Review of the Literature
		3.3 General Aspects: Age and Sex
		3.4 Signs and Symptoms
		3.5 Burning Sensation
		3.6 Blanching of the Mucosa
		3.7 Depigmentation
		3.8 Leathery Mucosa
		3.9 Marble-Like Appearance
		3.10 Depapillation of Tongue
		3.11 Vesicles
		3.12 Petechia
		3.13 Ulceration and Stomatitis
		3.14 Fibrous Bands
		3.15 Distorted Uvula
		3.16 Limited Mobility of Tongue
		3.17 Limited Mouth Opening
		3.18 Other Associated Clinical Conditions
		3.19 Mastication and Deglutition
		3.20 Extraoral
		Summary
		References
	4: Associated Conditions of Oral Submucous Fibrosis
		4.1	 Introduction
		4.2	 Conditions Affecting the Dental Hard Tissues and Periodontium
		4.3	 Conditions Affecting the Soft-Tissue Lining of the Oral Cavity
			4.3.1	 Quid Stain on Oral Mucosa
			4.3.2	 Chewer’s Mucosa
			4.3.3	 Oral Candidiasis
			4.3.4	 Oral Lichenoid Contact Reactions to Betel Quid
			4.3.5	 Oral Lichen Planus (OLP)
			4.3.6	 Oral Leukoplakia
			4.3.7	 Proliferative Verrucous Leukoplakia (PVL)
			4.3.8	 Erythroplakia
			4.3.9	 Verrucopapillary Lesions
				4.3.9.1	 Oral Squamous Papilloma
				4.3.9.2	 Exophytic Verrucous Hyperplasia (EVH) (Oral Verrucous Hyperplasia—OVH)
				4.3.9.3	 Oral Verruciform Xanthoma (VX)
				4.3.9.4	 Oral Verrucous Carcinoma (VC)
				4.3.9.5	 Oral Squamous Cell Carcinoma (OSCC)
		Summary
		References
	5: Oral Submucous Fibrosis in Childhood
		5.1	 Introduction
		5.2	 Epidemiology
		5.3	 Aetiology
		5.4	 Vulnerability Factors for Areca Nut Chewing Habits and Developing OSF
		5.5	 Clinical Features
		5.6	 Diagnosis
		5.7	 Management
		5.8	 Prevention
		5.9	 Malignant Transformation and Associated Risk Factors of Malignant Transformation
		Summary
		References
	6: Classification Systems for Oral Submucous Fibrosis
		6.1 Introduction
		6.2 Oral Submucous Fibrosis (OSF): Classification Systems
			6.2.1 Desa (1957)
			6.2.2 Pindborg and Sirsat (1966)
			6.2.3 Wahi and Kapur et al. (1966)
			6.2.4 Ahuja and Agarwal (1971)
			6.2.5 Bhatt and Dholakia (1977)
			6.2.6 Gupta and Golhar (1980)
			6.2.7 Warnakulasuriya (1987)
			6.2.8 Pindborg (1989)
			6.2.9 Katharia et al. (1992)
			6.2.10 Bailoor (1993)
			6.2.11 Racher (1993)
			6.2.12 Khanna and Andrade (1995)
			6.2.13 Lai et al. (1995)
			6.2.14 Maher et al. (1996)
			6.2.15 Haider et al. (2000)
			6.2.16 Ranganathan et al. (2001)
			6.2.17 Rajendran (2003)
			6.2.18 Utsonumiya et al. (2005)
			6.2.19 Bose and Balan (2007)
			6.2.20 Kumar et al. (2007)
			6.2.21 Mehrotra et al. (2009)
			6.2.22 More et al. (2011)
			6.2.23 Kerr et al. (2011)
			6.2.24 Patil and Maheshwari (2014)
			6.2.25 Arakeri et al. (2018)
		Summary
		6.3 Conclusion and Recommendations
		References
	7: Malignant Transformation of Oral Submucous Fibrosis
		7.1 Introduction
		7.2 Insight into the Literature
		7.3 Malignant Transformation Rate among OSF Patients
		7.4 Epithelial Dysplasia and OSF
		7.5 Potential Risk Factors of Malignant Transformation among OSF Patients
			7.5.1 Areca Nut Usage as a Major Carcinogen
		7.6 Pathological Mechanisms of the Malignant Transformation of OSF
			7.6.1 Hypoxia
			7.6.2 Angiogenesis
			7.6.3 Alterations in Cell Cycle
			7.6.4 Epithelial-Mesenchymal Transition
		7.7 Prognosis of OSF Malignant Transformation
		7.8 Conclusion
		Summary
		References
II: Aetiology of Oral Submucous Fibrosis
	8: Lifestyle Factors
		8.1 Introduction
		8.2 A Review of Methodological Issues
		8.3 Epidemiological Studies Contributing to the Evidence
			8.3.1 Risk from Betel Quid and Areca Nut without Added Tobacco
			8.3.2 Risk from Betel Quid and Areca Nut with Added Tobacco
		8.4 Tobacco, Alcohol, and Synergistic Effect
		8.5 Dose-Response Effect of Betel Quid and Areca Nut
		8.6 Dose-Response of Betel Quid and Areca Nut in Increasing Severity of OSF and Malignant Transformation
		8.7 Conclusions
		Summary
		References
	9: Genetic Aspects of Oral Submucous Fibrosis
		9.1 Introduction
		9.2 Genetic Susceptibility and Gene Expression in Tissue/Organ Fibrosis
		9.3 Genetic Susceptibility in Oral Submucous Fibrosis (OSF)
			9.3.1 Collagen 1A1 and Collagen 1A2 (COL1A1 and COL1A2) Gene
			9.3.2 Matrix Metalloproteinases (MMPs)
			9.3.3 Collagenase-1 (COLase-1, MMP-1)
			9.3.4 MMP-2 (Gelatinase-A) and MMP-9 (Gelatinase-B)
			9.3.5 MMP-3 (Stromelysin-1)
			9.3.6 TGF-β and SMAD
			9.3.7 Lysyl Oxidase (LOX)
			9.3.8 Cystatin C (CST3)
			9.3.9 Plasminogen Activator Inhibitor (PAI-1)
			9.3.10 TIMPs (Tissue Inhibitor Matrix Metalloproteinases)
			9.3.11 Vascular Endothelial Growth Factor (VEGF)
			9.3.12 Cytochrome P450 (CYP3A) Gene
			9.3.13 DNA Repair Gene Polymorphism
				9.3.13.1 X-Ray Cross-Complementing (XRCC) Polymorphism
				9.3.13.2 NADPH Quinone Oxidoreductase 1 (NQ01) C609T
			9.3.14 Tumor Necrosis Factor-α (TNF-α)
			9.3.15 p53 Gene Mutations
			9.3.16 Cytotoxic T-lymphocyte-Associated Antigen 4 (CTLA-4); CD 152 (Cluster of Differentiation 152) Gene Polymorphism
			9.3.17 Major Histocompatibility Complex (MHC) Class I Chain-Related Gene A (MICA) Polymorphism
			9.3.18 Glutathione S-Transferase (GST) Polymorphism
			9.3.19 Apoptosis-Associated Genes FAS and FASL Polymorphism
			9.3.20 Loss of Heterozygosity (LOH)
		9.4 Conclusion
		Summary
		References
	10: Diet and Micronutrients
		10.1 Introduction
		10.2 Epidemiological Evidence on Diet and Nutrition
		10.3 Role of Trace Elements in OSF
			10.3.1 Role of Copper
			10.3.2 Role of Zinc
			10.3.3 Role of Iron
			10.3.4 Role of Selenium
		10.4 Role of Vitamins
		10.5 Interventional Studies
		Summary
		References
III: Aetiopathogenesis of Oral Submucous Fibrosis
11: In Vivo and In Vitro Experimental Evidence
	11.1 Introduction
	11.2 In Vivo Experimental Evidence on OSF
		11.2.1 In Vivo Animal Models of OSF Induced by ANE/Commercial Areca Nut Products
		11.2.2 In Vivo Experimental Evidence of Chili as a Risk Factor of OSF
		11.2.3 In Vivo Human Experimental Studies Dealing with OSF Patients
			11.2.3.1 Inflammatory Cytokine Production by Peripheral Blood Mononuclear Cells
			11.2.3.2 Elevated Levels of Copper from Areca Nut and Drinking Water Reduce Collagen Degradation
			11.2.3.3 Genetic Susceptibility in Individuals with OSF
		11.2.4 In Vivo Experimental Evidence of Analysis of Areca Nut Alkaloids in Saliva
			11.2.4.1 Pro-inflammatory Cytokines in Serum and Saliva in OSF Patients
			11.2.4.2 Oxidative Stress Generated by ANE in OSF Patients
			11.2.4.3 Involvement of Autoimmunity in the Etiology of OSF
			11.2.4.4 Involvement of Micronutrients in the Etiology of OSF
	11.3 In Vitro Experimental Evidence Supporting the Role Played by Areca Nut/Betel Quid in OSF
		11.3.1 Collagen Synthesis
		11.3.2 In Vitro Experimental Evidence Supportive of Inflammation Induced by Arecoline/ANE
			11.3.2.1 Contribution of Pro-inflammatory Cytokines
			11.3.2.2 Contribution of Pro-inflammatory Enzymes and Molecules
		11.3.3 Experimental Evidence Supporting Arecoline/ANE in Stimulating Fibrogenic Cytokines
		11.3.4 Experimental Evidence of Areca Nut Extract/Arecoline Contributing to Myofibroblast Activation
		11.3.5 Experimental Evidence of Decreased Collagen Degradation and Clearance by Areca Nut
		11.3.6 In Vitro Evidence of Oxidative Stress and ROS Generation by Betel Quid
		11.3.7 The Role of Arecoline-Induced Autophagy in OSF
	11.4 Experimental Evidence-Based Outline of Mechanisms by Which Etiological Agents Contribute to the Development of OSF
	11.5 Experimental Evidence That Is Required to Complete the Etiological Picture of OSF
	Summary
	References
12: Fibrogenic Factors and Molecular Mechanisms
	12.1 Introduction
	12.2 Areca Nut in the Molecular Pathogenesis of OSF
	12.3 Inflammation in Oral Submucous Fibrosis
	12.4 Regulation of Inflammatory Mediators in Oral Submucous Fibrosis
		12.4.1 Pro-inflammatory Cytokines
		12.4.2 Cortisol and Steroids
	12.5 Fibrogenic Factors and Signaling Pathways
		12.5.1 Transforming Growth Factor-Beta (TGF-β Family)
			12.5.1.1 TGF-β Synthesis and Activation
			12.5.1.2 TGF-β Receptors
			12.5.1.3 TGF-β Signaling and Fibrotic Diseases
		12.5.2 Contribution of SMAD and Non-SMAD Signaling Pathways to Fibrosis at the Cellular Level
			12.5.2.1 The Role of Areca Nut and Transforming Growth Factor-β in Oral Submucous Fibrosis Progression
			12.5.2.2 Transforming Growth Factor-β Regulation by Areca Nut
			12.5.2.3 TGF-β in Oral Submucous Fibrosis
			12.5.2.4 Epidermal Growth Factor Receptor
			12.5.2.5 EGFR Role in Fibrosis
			12.5.2.6 Fibroblast Growth Factor Receptor (FGF)
			12.5.2.7 Role of FGF in Fibrosis
			12.5.2.8 Notch
			12.5.2.9 Notch and Myofibroblast Differentiation
			12.5.2.10 Notch and Epithelial-Mesenchymal Transition (EMT)
			12.5.2.11 Integrins
			12.5.2.12 Role of Integrins in Fibrosis
	12.6 Extracellular Matrix, and Epithelial-to-Mesenchymal Transition
		12.6.1 Molecular Characterization/Molecular Pathogenesis of Oral Submucous Fibrosis
			12.6.1.1 Factors Regulating Extracellular Matrix (ECM) Remodeling
			12.6.1.2 Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases (MMPs and TIMPs)
			12.6.1.3 Alpha-Smooth Muscle Actin (α-SMA)
			12.6.1.4 Epithelial-Mesenchymal Transition in Oral Submucous Fibrosis
	12.7 Epithelial Factors
		12.7.1 E-cadherin
		12.7.2 CD147
		12.7.3 Cytokeratin
		12.7.4 Annexin and Filamin
		12.7.5 Loricrin
	12.8 Receptor Tyrosine Kinase Pathway
	12.9 Transcription Factors
	12.10 Wnt Signaling Pathway
	12.11 Tissue Injury in Oral Submucous Fibrosis
	12.12 Anti-fibrotic Factors: Therapeutic Targets for Oral Submucous Fibrosis
	Summary
	References
IV: Investigative Techniques for Oral Submucous Fibrosis
13: Noninvasive Diagnostic Techniques in Oral Submucous Fibrosis
	13.1 Introduction
	13.2 Measurement of Mouth Opening
	13.3 Optical Instruments
		13.3.1 Tissue Autofluorescence
		13.3.2 Ultrasonography
			13.3.2.1 Colored Doppler Ultrasonography
		13.3.3 ATR-FTIR Spectroscopy
		13.3.4 Optical Coherence Tomography
		13.3.5 Contact Endoscopy
	13.4 Biomarkers in Saliva
		13.4.1 Lactate Dehydrogenase
		13.4.2 Trace Elements
		13.4.3 Oxidative Stress/Micronutrients
		13.4.4 Predictive Tumor Markers
	13.5 X-Ray (Lateral Cephalometric Analysis)
	13.6 Discussion
	Summary
	References
14: Pathology of Oral Submucous Fibrosis
	14.1 Introduction
		14.1.1 General Aspects
	14.2 Epithelial Changes
		14.2.1 Epithelial Thickness
		14.2.2 Vesicles and Erosions
		14.2.3 Keratinization
		14.2.4 Epithelial Dysplasia
		14.2.5 Cellular Changes in Keratinocytes and Non-keratinocyte Cells
			14.2.5.1 Keratinocytes and Keratinization
			14.2.5.2 Non-keratinocytes
				Oral Melanocytes
				Langerhans Cells
	14.3 Connective Tissue Changes
		14.3.1 Fibrosis and Hyalinization
		14.3.2 Vascularity
		14.3.3 Inflammation
		14.3.4 Myofibroblast
		14.3.5 Mast Cells
		14.3.6 Muscles
	14.4 Electron Microscopic (EM) Features in OSF
	14.5 Special Stains
	14.6 Lesions Associated with OSF
		14.6.1 Leukoplakia and OSF
		14.6.2 Verrucous Hyperplasia and OSF
		14.6.3 Coexistence of Lichenoid Features and Fibrosis
	14.7 Oral Cancer and OSF
		14.7.1 Histological Markers for Genetic Damage and Malignant Transformation in OSF
			14.7.1.1 Micronucleus
			14.7.1.2 Silver Staining Nucleolar Organizing Region (AgNOR)
	Summary
	References
15: Biomarkers in Oral Submucous Fibrosis
	15.1 Introduction
	15.2 Epithelial Markers
		15.2.1 Annexin A4 (ANXN A4)
		15.2.2 Beta-Catenin (β-Catenin)
		15.2.3 CD1a, CD303, and CD207
		15.2.4 Cytokeratins (CKs)
		15.2.5 E-Cadherin (E-Cad)
		15.2.6 Epidermal Growth Factor Receptor (EGFR)
		15.2.7 Filamin A (FLNA)
		15.2.8 Loricrin
	15.3 Connective Tissue Markers
		15.3.1 Alpha-Smooth Muscle Actin (α-SMA)
		15.3.2 Bone Morphogenetic Protein-7 (BMP7)
		15.3.3 CD34
		15.3.4 CD68
		15.3.5 CD105
		15.3.6 CD147
		15.3.7 Collagen
		15.3.8 Connective Tissue Growth Factor (CTGF)
		15.3.9 Decorin
		15.3.10 Fibroblast Growth Factor (FGF) and Its Receptors (bFGF, FGF2, FGFR2, and FGFR3)
		15.3.11 Fibronectin
		15.3.12 Hypoxia-Inducible Factor (HIF)
		15.3.13 Mast Cell Tryptase and Mast Cell Chymase
		15.3.14 Matrix Metalloproteinase (MMP; MMP-1, MMP-13)
		15.3.15 Tissue Inhibitors of Matrix Metalloproteinases (TIMPs; TIMP-1, TIMP-2)
		15.3.16 N-Cadherin (N-Cad)
		15.3.17 Osteopontin
		15.3.18 Podoplanin
		15.3.19 S100A4
		15.3.20 Syndecan-1
		15.3.21 Tenascin-C
		15.3.22 Transforming Growth Factor-Beta (TGF-β; TGF-β1, TGF-β2)
		15.3.23 Transglutaminase-2 (TGM-2)
		15.3.24 TWIST
		15.3.25 Vascular Endothelial Growth Factor (VEGF)
		15.3.26 Vimentin
	15.4 Proliferative, Apoptosis, and Senescence Markers
		15.4.1 Bax
		15.4.2 Budding Uninhibited by Benzimidazole-Related 1 (BUBR1)
		15.4.3 Caspases
		15.4.4 C-Jun
		15.4.5 Mesenchymal-Epithelial Transition Factor (c-Met)
		15.4.6 C-Myc
		15.4.7 Cyclin D1
		15.4.8 Fragile Histidine Triad Protein (FHIT)
		15.4.9 Human Telomerase Reverse Transcriptase (hTERT)
		15.4.10 Insulin-Like Growth Factor II mRNA-Binding Protein 3 (IMP3)
		15.4.11 Ki67
		15.4.12 Microtubule-Associated Protein Light Chain 3 (LC3)
		15.4.13 Mouse Double-Minute 2 Homolog (MDM2)
		15.4.14 p16
		15.4.15 p53
		15.4.16 p62
		15.4.17 p63
		15.4.18 Proliferating Cell Nuclear Antigen (PCNA)
		15.4.19 Polo-Like Kinase (PLK)
		15.4.20 Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN)
		15.4.21 Survivin
	15.5 Stemness Markers
		15.5.1 Aldehyde Dehydrogenase (ALDH1)
		15.5.2 B-Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi1)
		15.5.3 CD133
		15.5.4 Stage-Specific Embryonic Antigen (SSEA4)
		15.5.5 STRO1 (in Fibroblasts and Myofibroblasts)
		15.5.6 SRY (Sex-Determining Region on Y Chromosome) Type Homeobox Genes (SOX2)
	15.6 Markers of Signaling Pathway Alterations
		15.6.1 Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3)
		15.6.2 Phosphorylated Extracellular Signal-Regulated Kinases (pERK)
		15.6.3 Glioma-Associated Oncogene Homolog 1 (GLI1)
		15.6.4 Sonic Hedgehog (Shh)
		15.6.5 WNT Inhibitory Factor 1 (WIF1)
	15.7 Inflammatory Markers, Glycoproteins, and Enzymes
		15.7.1 Alpha-Enolase (ENO1)
		15.7.2 Beta-Integrin (β-Integrin)
		15.7.3 Calreticulin
		15.7.4 C–C Motif Chemokine Ligand 2 (CCL2)
		15.7.5 Cyclooxygenase 2 (COX-2)
		15.7.6 Cyclophilin A
		15.7.7 Fatty Acid Synthase (FASN)
		15.7.8 Fibrinogen Alpha-Chain Precursor (FGA)
		15.7.9 Glucose Transporter 1
		15.7.10 Heat-Shock Protein 70 (Hsp70)
		15.7.11 Hexokinase 2 (HK2)
		15.7.12 Hydroxynonenal (4-HNE)
		15.7.13 Mucin-1 (MUC1)
		15.7.14 Organic Cation Transporter 3 (OCT3)
		15.7.15 Secreted Frizzled-Related Proteins (SFRPs)
	Summary
	References
V: Management of Oral Submucous Fibrosis
16: Medical Management of Oral Submucous Fibrosis
	16.1 Introduction
		16.1.1 Medical Management of OSF
			16.1.1.1	Pharmaceutical Agents
			16.1.1.2	Herbal Remedies
	16.2 Anti-inflammatory Agents
		16.2.1 Corticosteroids
	16.3 Immunomodulators
		16.3.1 Levamisole
		16.3.2 Probiotic Agents
	16.4 Proteolytic/Fibrolytic Enzymes
		16.4.1 Hyaluronidase
		16.4.2 Chymotrypsin
		16.4.3 Collagenase
	16.5 Antioxidants in OSF
		16.5.1 Lycopene
		16.5.2 Curcumin (Turmeric)
		16.5.3 Tulsi/Holy Basil (Ocimum tenuiflorum/Ocimum sanctum Linn)
		16.5.4 Aloe Vera (AV)
		16.5.5 Spirulina
		16.5.6 Tea Pigments
		16.5.7 Salvianolic Acid (Sal-B)
		16.5.8 Epigallocatechin Gallate (EGCG)
	16.6 Vasodilators
		16.6.1 Pentoxifylline (PTX)
		16.6.2 Nylidrin Hydrochloride
		16.6.3 Isoxsuprine
		16.6.4 Xantinol Nicotinate
		16.6.5 Buflomedial Hydrochloride
	16.7 Biogenic Stimulation
		16.7.1 Placental Extract
	16.8 Micronutrients (Vitamins and minerals)
		16.8.1 Vitamins
		16.8.2 Minerals
		16.8.3 Oxitard ™
		16.8.4 Garlic
	16.9 Novel Therapies
		16.9.1 Colchicine
		16.9.2 Interferon Gamma (IFN-γ)
		16.9.3 Anti-TGF-β Drugs
		16.9.4 Valdecoxib
		16.9.5 Meta analysis of intervention in OSF
	Summary and Conclusion
	References
17: Curcumin as a Chemopreventive Agent for Oral Submucous Fibrosis
	17.1 Introduction
	17.2 Turmeric, Curcumin and OSF
	17.3 Mechanism of Curcumin on Inflammation and Inflammatory Pathways
	17.4 Turmeric and Curcumin Against the Hallmarks of OSF
		17.4.1	 Cytokines/Interleukins in OSF and Its Inhibition by Turmeric/Curcumin
		17.4.2	 ECM/Collagen Synthesis in OSF and Its Inhibition by Turmeric/Curcumin
		17.4.3	 Oxidative Stress in OSF and Its Inhibition by Turmeric/Curcumin
		17.4.4	 MMPs in OSF and Its Modulation by Turmeric/Curcumin
		17.4.5	 Fibrosis in OSF and Its Inhibition by Turmeric/Curcumin
		17.4.6	 TGF-β Signaling in OSF and Its Inhibition by Turmeric/Curcumin
	17.5 Experimental Laboratory Studies
	17.6 Clinical Studies
	17.7 Conclusion
	Summary
	References
18: Surgical Management of Oral Submucous Fibrosis
	18.1 Introduction
	18.2 Indications of Surgery
	18.3 Principles of Surgery and Surgical Steps
		18.3.1 Preoperative Evaluation
		18.3.2 Anesthesia, Preparation of the Patient and Intraoperative Evaluation
		18.3.3 Incision of Fibrous Bands Followed by Adequate Muscular Release
		18.3.4 Masticator Muscle Myotomy
		18.3.5 Bilateral Coronoidectomy
		18.3.6 Resurfacing of the Surgical Defect
			18.3.6.1	 Intraoral Flaps
			18.3.6.2	 Extraoral Flaps
			18.3.6.3	 Distant Flaps
			18.3.6.4	 Radial Forearm Free Flap
			18.3.6.5	 Coverage with Grafts and Membranes
	18.4 Pitfalls and Solutions of Resurfacing Techniques
	18.5 Postoperative Physiotherapy
	18.6 Results of Surgical Intervention
	18.7 Post Surgery Surveillance
	18.8 Summary and Future Perspectives
	18.9 Conclusions
	References
VI: Areca Nut Addiction and Treatment
19: Areca Nut Addiction: Tools to Assess Addiction
	19.1 Introduction
	19.2 Dependence or Addiction to a Substance
	19.3 Methods of Assessment of Addiction/Dependence
		19.3.1 Diagnostic Criteria and Screening Tools
		19.3.2 Biological Assessment Techniques
		19.3.3 Limitations of Existing Instruments for Measuring and or Screening for Dependence
	19.4 Pharmacology of Areca Nut
	19.5 Does Areca Nut Fulfil the Operational Criteria for a Dependence Syndrome?
	19.6 Development of Scales to Measure Betel Quid Depeendence/Use
		19.6.1 Betel Quid Dependence Scale (BQDS)
		19.6.2 Reasons for Betel-Quid Chewing Scale (RBCS)
		19.6.3 DSM-5 Betel-Quid Use Disorder
		19.6.4 Self-Report Screening Test for Areca Quid Abuser (SSTAA)
	19.7 Conclusions and Future Perspectives
	Summary
	References
20: Behavioural Interventions for Areca Nut Cessation in the Prevention and Management of Oral Submucous Fibrosis
	20.1 Introduction
	20.2 The Scope of Behavioral Interventions
	20.3 Review of the Relevant Intervention Studies
		20.3.1 Bangladesh
		20.3.2 Guam
		20.3.3 India
		20.3.4 Pakistan
		20.3.5 Sri Lanka
		20.3.6 Taiwan
	20.4 Discussion
	20.5 Conclusion
	Summary
	References
21: Pharmaceutical Agents for Areca Nut Cessation
	21.1	 Introduction
	21.2	 Betel Quid Addiction Beyond Behavioural Therapy
		21.2.1	 Smokeless Tobacco; Addictive Mechanism
		21.2.2	 Areca nut; Addictive Mechanisms
	21.3	 Pharmacotherapy for Areca Nut Cessation
		21.3.1	 Pharmaco-Therapy for Nicotine Addiction
		21.3.2	 Pharmaceutical Agents for Arecoline Addiction
	21.4	Conclusion
	Summary
	References
22: World Literature: Bibliography
	22.1 Bibliography
		22.1.1 Reviews
		22.1.2 Epidemiology of OSF Worldwide
		22.1.3 Clinical Presentation and Evaluation: Paediatric and Adult Patients of OSF
		22.1.4 Classification, Grading and Staging Systems Used in OSF
		22.1.5 Etiopathogenesis of OSF as an OPMD
		22.1.6 Histopathology and Special Stains in OSF, as OPMD
		22.1.7 Molecular Biology and Genetics of OSF, and Malignant Transformation
		22.1.8 Immunohistochemistry in OSF
		22.1.9 Diagnostic, Serology and Prognostic evaluation
		22.1.10 Therapuetics and Treatment of OSF
		22.1.11 Relation and Conversion of OSF to OSCC
		22.1.12 Research Associated with OSF
Appendix: Prominent Stalwarts in the Study of Oral Submucous Fibrosis
	Living Legends
Index