Oral epithelial dysplasia (OED) is characterized by abnormal cellular growth and loss of normal maturation and stratification. It is a premalignant condition caused by chemical, biologic, or radiation insults. Leukoplakia is the most common clinical presentation of OED. Risk factors for malignant transformation of OED include female gender, duration of leukoplakia over 3 years, location on tongue or floor of mouth, non-homogenous or speckled/erosive appearance, and size over 200mm2. Molecular markers like p16 and p53 show promise in predicting cancer risk but have not been conclusively shown to improve treatment decisions. Treatment options range from monitoring mild dysplasia

1. ORAL EPITHELIAL
DYSPLASIA: AN UPDATE
MATT JACKS, DDS, FACS

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%

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).

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

9. OTHER FACTORS
• QOL MEDICATIONS
• Biologic Modifiers (monoclonal anti-bodies, anti-tumor necrosing factors)
• Humira, Enbrel, Remicade
• Methotrexate
• CellCept, Tacrolimus, Sirolimus
• Glucocorticoids
• Vaping e-cigarettes

10. CASES
• Hyperplasia/keratosis
• Dysplasia
• Mild
• Medium
• Severe
• Carcinoma

12. • Frictional Keratosis
• BARK
• Noted parakaretin layer

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

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

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

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

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

33. CHEMOPREVENTION
• Antimutagens
• N-acetyl-L-cysteine
• Topical Bleomycin
• Bowman-Birk Inhibitor
• Polyphenols
• Green Tea Extract
• Antiproliferatives
• Retinoids
• Carotinoids

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