2. ORAL EPITHELIAL DYSPLASIA (OED)
• DEFINED: abnormal growth in response to an inciting stimulus and characterized by cellular atypia and
loss of normal maturation and stratification
• Synonyms: Intraepithelial dysplasia, epithelial atypia, premalignant oral lesions, OPMD
• Prevalence world-wide: 5%
• Oral Cancers preceded by OED: 80%
• Most common clinical presentation: Leukoplakia
• Most common associated histologic diagnoses of leukoplakia: hyperplasia, hyperkeratosis, OED, squamous cell
carcinoma
• Prevalence of OED in erythroplakia: >90%
3.
4. WHAT CAUSES THE CHANGE?
• Chemical (tobacco)
• Biologic (viral, autoimmune)
• Radiation (Actinic Keratosis)
• Associated lesions
• Leukoplakia- hyperplasia, verrucous keratoses, proliferative keratoses
• Erythroplakia
• Submucous fibrosis
• Lichen planus
• inherited genetic syndromes - Fanconi anemia, dyskeratosis congenita, and xeroderma pigmentosa
• Immunosuppression - graft-versus-host disease, HIV, and human papillomavirus (HPV)
5. • Rule of 3rds
• Loss of polarity of basal cells
• Basaloid appearance in more than one layer of cells
• An increased nuclear-cytoplasmic ratio
• Drop-shaped rete pegs
• Irregular epithelial stratification
• Increased number of mitotic figures
• Mitotic figures in the superficial half of the epithelium
• Cellular polymorphism
• Nuclear hyperchromatism
• Enlarged nucleoli
• Reduction of cellular cohesion
• Keratinization of single cells or cell groups in the prickle cell layer
(Kramer et al., 1978).
6.
7. MALIGNANT TRANSFORMATION
• Malignant transformation is the singular concern for OED. It is a continuum from epithelial hyperplasia
to squamous cell carcinoma. HOW MANY MORE MUTATIONS TO CROSS-OVER?
• Multiple studies have suggested transformation rates between 1% - 35%: WHY SUCH A RANGE?
Largely due to great variance in:
• Follow-up times
• Tobacco habit/exposure types
• Study Groups
8. MALIGNANT TRANSFORMATION: RISK FACTORS
• Female gender
• Long duration of leukoplakia (greater than 3 years)
• Non-smokers (idiopathic leukoplakia)
• Tongue and floor of mouth
• Non-homogenous
• Speckled and erosive ( 40-95%)
• Size >200mm2
• Molecular markers exist and a multitude have been identified but have yet to hone predictability
13. Female gender
Long duration of leukoplakia (greater than 3 years)
Non-smokers (idiopathic leukoplakia)
Tongue and floor of mouth
Non-homogenous
Speckled and erosive ( 40-95%)
Size >200mm2
14.
15. VERRUCIFORM XANTHOMA
• Hyperplastic epithelium
• affecting the mouth, skin and
Genitalia
• The cause is unknown
• Whites – males; age 40-70yrs
• Most on the gingiva and alveolar
mucosa; oral site
• Surface epithelium covered by a
thickened layer of parakeratin
• Accumulation of lipid-laden
histiocytes beneath the epithelium -
foamy cells are known as xanthoma
cells
• TX: Conservative excision
16. Female gender
Long duration of leukoplakia (greater than 3
years)
Non-smokers (idiopathic leukoplakia)
Tongue and floor of mouth
Non-homogenous
Speckled and erosive ( 40-95%)
Size >200mm2
17.
18. SMOKERS STOMATITIS
• Hyperkeratosis and acanthosis of epithelium
• Mild, patchy chronic inflammation
• Squamous metaplasia of the excretory ducts
– Epithelial dysplasia rarely seen TX: Discontinue à smoking
– Reversible NOTE:
– Persisting white lesion of palate after 1 month of habit cessation à
true leukoplakia
19. Female gender
Long duration of leukoplakia (greater than 3 years)
Non-smokers (idiopathic leukoplakia)
Tongue and floor of mouth
Non-homogenous
Speckled and erosive ( 40-95%)
Size >200mm2
20. Shows variable microscopic appearance
• Early – hyperkeratosis that is indistinguishable from other leukoplakic lesion
• Progression into papillary, exophytic proliferation similar to verrucous
leukoplakia / verrucous hyperplasia
• Later stages, down growth of well-differentiated sq epith with broad, blunt rete
ridges (invasion) – at this stage indistinguishable from verrucous carcinoma
• Final stages, invading epith becomes less differentiated à SCC
21. Female gender
Long duration of leukoplakia (greater than 3 years)
Non-smokers (idiopathic leukoplakia)
Tongue and floor of mouth
Non-homogenous
Speckled and erosive ( 40-95%)
Size >200mm2
22.
23. DYSKERATOSIS CONGENITA
• MILD (low grade) DYSPLASIA
• Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome
• progressive bone marrow failure syndrome
• characterized by the triad of reticulated skin hyperpigmentation, nail
dystrophy, and oral leukoplakia.
24. Female gender
Long duration of leukoplakia (greater than 3 years)
Non-smokers (idiopathic leukoplakia)
Tongue and floor of mouth
Non-homogenous
Speckled and erosive ( 40-95%)
Size >200mm2
25.
26. MOLECULAR MARKERS
• To what degree to molecular markers offer predictive value?
• Leukoplakia that portends dysplasia or cancer
• Villa looked a patients with leukoplakia (keratosis versus known dysplasia)
• Marker P53, a known tumor suppressor protein that plays a critical role in DNA repair
• Results:
• Over a 5 year f/u, half of enrolled patients developed Oral Cancer.
• Of those who developed cancer, ½ had keratosis, ½ had dysplasia.
• P53 characteristics were identical for BOTH groups
• Only difference: Initial dysplasia patients developed cancer quicker and survived shorter
Alessandro Villa, Oral Keratosis of Unknown Significance (KUS) Shares Genomic Overlap with Oral Dysplasia in Oral Diseases 25(7) · July 2019
27. MOLECULAR MARKERS
• Are there any benefits for molecular markers in known benign keratotic
lesions?
• Does benign keratosis show P53 expression?
• Asma, et al., looked at P53 expression in BARK
• BARK (benign alveolar ridge keratosis) ”frictional keratosis” caused by
micro trauma that occurs on the retromolar pad of dentate patients and
the edentate alveolar ridge
• Results:
• P53 positive in 20% of cases
• No long term f/u to report any conversion
28. MOLECULAR MARKERS
• Significance of P16 in HPV associated leukoplakia
• Does P16 portend dysplasia and/or cancer?
• Most pathologists categorize HPV as P16 positive or negative
• Positive P16 is considered high risk for dysplasia and cancer
• Negative P16 can still develop dysplasia but is a lower risk for
cancer
29. MOLECULAR MARKERS
• Conclusion:
• P16 is Sensitive and Specific
• P53 is sensitive but NOT specific
• Expressed in cancer, most dysplasia, some keratosis
• Doesn’t change treatment algorithm
30. TREATMENT ALGORITHM
• Incisional biopsy for larger lesions (may consider multiple sites)
• Excisional for smaller lesions
• Path report:
• Hyperkeratosis and Mild Dysplasia – monitor
• Why monitor Mild Dysplasia?
• Healthy, immunocompetent patient
• Strong likelihood the incisional biopsy will invoke inflammatory
response, heal the wound and eradicate residual dysplasia
31. TREATMENT ALGORITHM
• Path report:
• Mild dysplasia in an unhealthy or immunosuppressed
• Moderate Dysplasia
• Inter-epithelial excision of entire lesion
• Severe Dysplasia
• Full thickness excision
• Or inter-epithelial excision with CO2 laser
ablation of sub-basal tissues
32. ALTERNATIVE TREATMENTS
• OED can be very persistent for some patients with multiple rounds of surgical treatment
• Are there less invasive alternatives?
• Chemoprevention
• Preventing, delaying, or reversing the progression of premalignant lesions to invasive cancer
• Natural, synthetic, or biologic agents
• Topical, systemic
• Population based studies - possible reduction in the rate of developing H&N cancers with the ingestion of
certain nutrients or medications
34. N-ACETYL-L-CYSTEINE
• Nutritional supplement, Allium plants,
Asparagus, Red pepper
• Provided cysteine for the synthesis of
glutathione – major intracellular antioxidant
• Suppress EGFR phosphorylation
• Overexpression of EGFR
• 80%+ of head and neck SCCa
• High recurrence and low survival rates
• 1,200 mg BID or lower – well tolerated
• N, V, D, flushing, epigastric pain, constipation
• Large doses for acetaminophen overdose
• Caution – can cause hypotension
• Potentiates nitroglycerin and related medications
• OTC – 500-1000mg capsules
• $12-15/month
35. TOPICAL BLEOMYCIN
• Antibiotic that inhibits DNA ligase – by oxidative
damage
• Common chemotherapy for lymphoma
• Topical for skin cancer, Kaposi’s
• Side effect - mucocutaneous toxicity
• 1% solution had a very good response
• 50% return of lesions after 3 months of cessation
36. BOWMAN-BIRK INHIBITOR
• Serine Protease Inhibitor
• Soybeans
• Trypsin and chymotrypsin inhibitory activity
• Premalignant human tissues may have elevated
levels of proteolytic activity
• Success in phase I trial - oral troche for oral
leukoplakia
• Single study Armstrong, 2013
• 132 subjects, randomized, placebo controlled
• Effective: 28% (BBI) vs 30% (Placebo)
• No statistical differences
37. POLYPHENOLS
• Green Tea extract
• Arrests cells in the G0/G1 phase
• Between synthesis (dividing) and maturation
• Regulates apoptosis
• Block angiogenesis via phosphorylation of
(VEGFR) and inhibition of VEGF secretion in
tumor cells
• Complete resolution or oral lesions in higher
doses (1000mg PO QD)
• At doses 750 -1000mg
• Insomnia, diarrhea, oral/neck pain, nervousness
• 41% return of lesions upon cessation
38. RETINOIDS
• Natural and synthetic derivatives of vitamin A
• Modulators of epithelial-cell differentiation
• Suppress carcinogenesis
• 50mg/daily maintenance
• 0.2% isotretinoin rinse BID. 1-minute duration
• Skin dryness, cheilitis, hypertriglyceridemia,
conjunctivitis, dizziness, headaches
• Complete resolution with 25% recurrence upon
cessation
39. CAROTINOIDS
• Converts to vitamin A and retinoids
• Scavengers free-radical species
• Positive influence on the activity of carcinogen
detoxification enzymes
• Humans can ONLY OBTAIN from diet
• Absorbed better from heat-processed food
sources and lipid-rich diets than from raw food
• Benefits reported in observational diet studies -
10 mg/day
• Good resolution of lesions
• 54% recurrence upon cessation
• Carotenodermia
40. SUMMARY
• What we do know
• Leukoplakia still represents the
prevailing form of dysplasia
• Oral epithelial dysplasia is a continuum
that has a significant likelihood to
convert to cancer based on:
• Insult/exposure
• Time
• Immunocompetence
• High risk factors
• P16 HPV is predictable
• Treatability
• What we don’t know
• What causes idiopathic OED
• How long it takes to develop
• (we suspect > 2-5 years)
• Efficacy of P53 and other markers
• Efficacy of non-invasive treatment
• Predictability
