Precancerous lesions of oral cavity

In relation to Periodontics

1. PRECANCEROUS LESIONS OF ORAL CAVITY by, BIBINA GEORGE MDS Periodontics

2. DEFINITION: Precancerous lesion: A morphologically altered tissue in which cancer is more likely to occur than in its apparently normal counter part. [WHO,1978] Precancerous Condition : A generalized state associated with a significantly increased risk of cancer [ WHO,1978]

3. Premalignant condition ‘It is a group of disorders of varying etiologies , usually tobacco characterized by mutagen associated, spontaneous or hereditary alterations or mutations in the genetic material of oral epithelial cells with or without clinical and histomorphological alterations that may lead to oral squamous cell carcinoma transformation .’ [WHO, 2005]

4. CLASSIFICATION: Premalignant Lesions: Leukoplakia Proliferative Verrucous Leukoplakia Intraepithelial carcinoma (Carcinoma in situ) Erythroplakia Palatal changes associated with reverse smoking R.V. Subramanyam

5. Premalignant Conditions: OSMF Lichen Planus (erosive type) Sideropenic dysphagia (Plummer- Vinson Syndrome) Syphilis – Syphilitic glossitis Discoid lupus erythematosus Xeroderma pigmentosum Epidermolysis Bullosa R.V. Subramanyam

6. Premalignant / Precancerous / Potentially malignant oral lesions involve Skin lining of the mouth (known as the epithelium) At risk for transforming into an oral cancer Difficult to predict which lesions will transform and how long it will take   VICTOR BABES, 1875 Introduction

7. Etiopathogenesis Salivary thiobarbituric acid reacting substance & advanced glycation end pdts Expression of CK8 & CK18 Expression of Podoplanin & ABCG2 Prevalence of p53 mutations Salivary advanced oxidation products Vascular endothelial growth factor Sialotransferase and Neuraminidase Salivary IL-8 concentration ( Vlkov á et al) (Nanda et al) (Qin et al) ( Puniyani et al) (Feng et al) No Significant difference

8.   Age group ≥ 40 Poor oral hygiene ; Genetic theory (???) Habits such as : Tobacco (Smoking, Smokeless or inhaled) Pan masala, Betel nut quid Heavy alcohol use Although such lesions can also be found in younger individuals and/or those without classic risk factors. Risk Factors

9. Clinical Features Lesion ≥ 14 days require a diagnostic biopsy even after irritant is removed Anatomical Location: Epithelial dysplasia rate: 21.8% - Buccal mucosa 13.7%- Palate 12.3%- Floor of the mouth Leukoplakia : 25.2% - Mand . Mucosa & Sulcus 21.9% - Buccal mucosa (Shafer and Waldron)

10. Age: Mean age for diagnosis: 37 – 59 <5% : < 30 yrs Sex: Epithelial dysplasia: Male Oral SCC : Decrease in M:F rate

11. DYSPLASIA: Definition: It comprises a loss in the uniformity of individual cells, as well as loss in their architectural orientation. It is characteristically associated with protracted chronic irritation or inflammation.

12. Histomorphological changes of dysplasia Loss of basal cell polarity  Parabasilar hyperplasia Increased nuclear:cytoplasmic ratio  Drop-shaped rete ridges Abnormal epithelial maturation Increased mitotic activity Mitoses in the superficial half of the surface epithelium Cellular pleomorphism Nuclear hyperchromaticity Enlarged nucleoli Loss of cellular cohesiveness Individual cell keratinization in the spinous cell layer.

13. Leukoplakia DEFINITION : “A white patch or plaque in the oral cavity which cannot be scrapped off or stripped off easily & more over, which cannot be characterized clinically or pathologically as any other disease ” (WHO 1978) Originates from Greek words – “ leucos ” - white and “ plakia ” – patch “ A predominantly white lesion of the oral mucosa that cannot be characterised as any other definable lesion. ” (WHO,2012) SCHWIMMER,1877

14. Classification of leukoplakia Based on CLINICAL TYPE: Homogenous : Smooth,Furrowed , Ulcerative Non homogenous : Ulcerative, Verrucous, Speckled Based on ETIOLOGY: Tobacco associated Idiopathic Based on EXTENT: Localized Diffuse ( Axell & Pindborg et al 1983)

15. Based on risk of MALIGNANT TRANSFORMATION High risk sites Floor of mouth Lateral/ventral surface of tongue Soft palate Low risk sites Dorsum of tongue Hard palate Based on HISTOLOGY: Dysplastic Non dysplastic ( Axell & Pindborg et al 1983)

16. Sharp’s staging of leukoplakia Stage I - Earliest lesion-non palpable, faintly translucent, white discoloration Stage II - Localized or diffuse, slightly elevated plaque of irregular outline. It is opaque white & may have a fine granular texture Stage III - Thickened white lesion showing induration and fissuring

17. Clinical presentation Solitary or multiple, “White patches” Varies from a non-palpable faintly translucent white area to a thick fissured, papillomatous or indurated lesion 70% in buccal mucosa, commissural areas, followed by lower lip, floor of the mouth, palate & gingiva

18. SYMPTOMS Feeling of increased thickness of mucosa Ulcerated or nodular type: c/o burning sensation Enlarged cervical lymph nodes (metastasis) Homogeneous/ Leukoplakia Simplex Speckled/Nodular Ulcerative

19. Histopathological features Keratinization pattern Thickness of epithelium Changes in underlying connective tissue Waldron & Shafer (1975) 80% lesions show benign hyperkeratosis with/without acanthosis Dysplastic changes typically begin in basal & parabasal zones of epithelium

20. Conservative management Elimination of etiological factor Restraining from smoking or chewing tobacco To remove sharp broken down teeth Correction & replacement of overhanging or faulty metal restorations with a metal bridge

21. 1 ) Isoretinoin / 13- cis - retinoic acid 2 ) Beta carotene -30mg TID 3 ) Topical Bleomycin – 0.5-1% solution/2wks 4 ) 5-Fluorouracil & Cisplatin CHEMOPREVENTION

22. Surgical Excision: entire lesion excised if it is >1cm in size, following modalities used: a) Scalpel – surgical stripping b) Cryosurgery – with liquid nitrogen c) Electrocautery d) Laser ablation

23. Erythroplakia DEFINITION: “Any lesion of the oral mucosa that presents as a bright red velvety patch or plaque, which cannot be characterized clinically or pathologically as any other recognizable condition ” [WHO] Reported by Querat in 1911

24. Clinical variants Homogenous erythroplakia Erythroplakia interspersed with patches of leukoplakia Granular or Speckled erythroplakia CLASSIFICATION

25. - Smooth and granular/nodular, well defined - May have an irregular, red granular surface interspersed with white or yellow foci - Soft on palpation

26. Management Biopsy should be performed Treatment guided by histopathologic diagnosis Recurrence , multifocality common Careful long term follow up

27. Intraepithelial carcinoma (Ca in Situ) Most severe stage of epithelial dysplasia Striking feature – dysplastic epithelial cells do not invade into connective tissue Common among elderly, with a male prediliction Present as white plaques or ulcerated, & reddened areas Site – floor of the mouth, tongue, lips Has combined features of leuko & erythroplakia

28. No accepted treatment Surgical excision, irradiation & cauterization Treatment

29. Oral lichen planus Named by E Wilson ( British physician) 1869 Lichen – latin for primitive plants (symbiotic algae & fungi) Planus – latin for flat Definition : “ A common chronic immunologic inflammatory mucocutaneous disorder that varies in appearance from keratotic (reticular or plaque like) to erythematous and ulcerative, affecting the stratified squamous epithelium”

30. Etiology & pathogenesis Both antigen-specific & non-specific mechanisms may be involved in pathogenesis of OLP Antigen-specific mechanisms: antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8 + cytotoxic T-cells Non-specific mechanisms: mast cell degranulation and matrix metalloproteinase (MMP) activation

31. These mechanisms may combine to cause T-cell accumulation in superficial lamina propria Basement membrane disruption Intra-epithelial T-cell migration & Keratinocyte apoptosis

32. Clinical features Lesions usually symmetrical Frequently affects buccal mucosa, tongue , gingiva, lip and palate Extra-oral mucosal involvements - anogenital area, conjunctivae, oesophagus /larynx Approx 1.2% - 5.3% lesions undergo malignant changes Hence regular follow up mandatory

33. On skin- Flat-topped purple polygonal & pruritic papular rash Oral Cavity- Asymptomatic Reticular – Wickham’s striae + discrete erythematous border Plaque-like – Resemble leukoplakia , common in smokers

34. Clinical features Symptomatic Atrophic – Diffuse red patch, peripheral radiating white striae Erosive – Irregular erosion covered with a pseudomembrane Bullous – Small bullae / vesicles that may rupture easily

35. Histology Shklar -3 classic microscopic features of OLP Overlying hyperkeratinization A bandlike layer of chronic inflammatory cells within underlying connective tissue Liquefaction degeneration of basal cell zone

36. Diagnosis Oral biopsy Direct Immunofluorescence

37. Management Reticular type is asymptomatic & treatment often unnecessary Erosive type presents significant management problems All patients should optimize oral hygiene Oral candidiasis should be excluded/treated Cortico steroids, is the treatment of choice eg : Fluocinonide or Clobetasol gel for 2 weeks, with 3months follow-up

38. In symptomatic patients with apparent contact dental factor, patch test with replacement of amalgam In those with no apparent contact factor, topical or intralesional steroid - first line treatment. A short course of systemic steroid for more rapid control

39. Oral submucous fibrosis DEFINITION: “It is an insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx. Although occasionally preceded by or associated with vesicle formation ,it is always associated with juxta -epithelial inflammatory reaction followed by a fibro-elastic changes of the lamina propria with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat .” (J.J Pindborg and Sirsat 1966) First described by Joshi (1952) and by Schwatz among East Indian Women . “

40. Clinical presentation Common site – buccal mucosa, retromolar area, uvula, palate, etc Initially , pain and a burning sensation upon consumption of hot & spicy foods Vesicle & ulcers Excessive or reduced salivation & defective gustation Hearing loss

41. Depapillation & atrophy of tongue and uvula Depigmented & loss of stippling over gingiva Nasal tone in the voice Difficulty in deglutition Impaired mouth movements ( eg , eating, whistling, blowing, sucking)

42. Mortality/morbidity High rate of morbidity - progressive inability to open mouth, resulting in difficulty eating & consequent nutritional deficiencies Significant mortality rate - can transform into oral cancer, particularly SCC (7.6%) Prodromal symptoms

43. Clinical stages Three stages based on physical findings: Stage 1: Stomatitis includes erythematous mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation & mucosal petechiae Stage 2: Fibrosis occurs in ruptured vesicles & ulcers when they heal, hallmark of this stage   (Pindborg,1989)

44. Stage 3: Sequelae of OSMF   Leukoplakia is found in more than 25% of individuals with OSMF Speech and hearing deficits may occur because of involvement of the tongue and the eustachian tubes  ( Pindborg,1989)

45. Group I : Only Symptoms, No mouth opening Group II : Mouth opening > 20mm Group III : Mouth opening < 20mm Group IV: Limited mouth opening, precancerous & cancerous changes throughout mucosa RANGANATHAN K (2001)

46. Histopathology Hyperkeratinized , atrophic epithelium with flattening & shortening of rete pegs Nuclear pleomorphism & severe inter-cellular edema Finely fibrilar collagen & increased fibroblastic activity in early stage showing dilated & congested blood vessels with areas of hemorrhage

47. Advanced stage shows “homogenization” and “hyalinization” of collagen fibers (important feature) Degeneration of muscle fibers and chronic inflammatory cell infiltration in the connective tissue

48. Management 1. Behavioral therapy - Patient counseling, Stoppage of habit 2. Medicinal therapy - Hyaluronidase : Topically, shown to improve symptoms more quickly than steroids alone - Mild cases – intralesional inj. Dexamethasone 4 mg to reduce symptoms & surgical splitting / excision of fibrous bands - Recent study – intralesional inj. of gamma interferon 3 times a week , improves mouth opening significantly

49. Emerging Trends HPV 16 and 18 : Cervical Carcinoma (90%) Oncogenes E6 and E7 (Tumor Supressor Proteins) Degradation (-) Apoptotic pathway in these cells Overproliferation

50. OPPORTUNITIES & BARRIERS TO PROGRESS Validating Histopathological criteria/ biomarkers Identifying C/F of premalignancy that predict higher probability of malignant change Clarifying premalignant risk of lichen planus Comparing efficacy of conventional scalpel excision with laser excision for control of oral leukoplakias Identifying an accurate biomarker for premalignant state would aid in diagnosis

51. CONCLUSION Patient presenting with Potentially malignant disorders should undergo a careful examination to identify any causative factors, which are best eliminated at the first stage of the treatment. However, many patients may not have any obvious causative factor. A biopsy of the lesion is necessary to demonstrate the histological features of the lesion and detect any existing invasive carcinoma. Frequent monitoring of histopathological changes is essential to obtain an accurate assessment of histological activity of the lesion and to try to predict its future behavior. The subsequent management of the patient depends on how “high risk” the lesion is.

52. REFERENCES: Textbook of Oral Pathology, Shafers , 1 st edition. Dr. R.V. Subramanyam. Classification of oral lesions. Neville BW et al. Oral cancer and Precancerous lesions. CA Cancer J Clin 2002;52:195-215. Carnelio S, Rodrigues GS et al. A Brief Review of Common Oral Premalignant Lesions with Emphasis on Their Management and Cancer Prevention. Indian J Surg (July–August 2011 ); 73(4): 256–261. Yardimci G, Kutlubay Z et al. Precancerous lesions of oral mucosa. World J Clin Cases 2014 December 16; 2(12): 866-872. Nourelahi M, Roshannia B et al. The relation between periodontal diseases and Neoplasms of the oral cavity: A Review article. Middle East J Rehabil Health. 2016 October; 3(4):e39234 .