Leukoplakia

Clinical and Pathologic Features

Causes and Risk Factors

• Smoking and chewing tobacco: the leading risk factor, present in more than 80% of patients. Heat and toxic chemicals in tobacco smoke (polycyclic aromatic hydrocarbons, nitrosamines) damage the DNA of mucosal keratinocytes.
• Betel quid / areca nut chewing: very common in Southeast Asia, including Vietnam. The areca nut alkaloid arecoline causes submucosal fibrosis and promotes genetic mutations in the epithelium.
• Heavy alcohol use: alcohol acts as a solvent that makes the mucosa more permeable to tobacco carcinogens, so the two risks multiply each other.
• Chronic mechanical irritation: long-term rubbing from sharp or broken teeth, decayed teeth or ill-fitting dentures.
• Candida co-infection: Candida albicans (especially in its hyphal form) produces N-nitrosobenzylmethylamine, which promotes mutations in keratinocytes.
• HPV: high-risk HPV types (HPV-16, 18) are present in some particular forms of leukoplakia.

Clinical Types and Risk of Malignancy

• Homogeneous leukoplakia:
  • A uniformly white, thin or thick, well-defined patch with a flat, slightly wrinkled or shallowly fissured ("cracked mud") surface.
  • Usually painless, with a low risk of malignant change (1–5%).
• Non-homogeneous leukoplakia:
  • The risk of malignant change is 4–7 times higher than with the homogeneous type (20–30%). Forms include:
    • Erythroleukoplakia (speckled leukoplakia): white areas mixed with red, inflamed or ulcerated areas.
    • Nodular / granular leukoplakia: an irregular surface studded with small red and white granules.
    • Verrucous leukoplakia: a raised, rough, bumpy, wart-like or cauliflower-like surface.
• Proliferative verrucous leukoplakia (PVL):
  • A rare and particularly dangerous variant. It starts as a single patch but gradually spreads to many sites, progressing slowly and stubbornly and resisting all standard treatments.
  • Very high rate of malignant change (>60–80%), progressing to verrucous carcinoma or invasive OSCC. Notably, PVL typically affects older women, many of whom have never smoked or drunk alcohol.

Histopathology

The pathology report on leukoplakia covers two things: changes in the keratin layer and whether epithelial dysplasia is present.

• Hyperkeratosis: orthokeratosis or parakeratosis, with thickening of the spinous layer (acanthosis).
• Epithelial dysplasia: the single most important predictor of cancer risk. WHO grading:
  • Mild dysplasia: atypical cells confined to the lower third of the epithelium.
  • Moderate dysplasia: atypical cells extend into the lower two-thirds.
  • Severe dysplasia / carcinoma in situ (CIS): atypical cells occupy more than two-thirds or the full thickness of the epithelium, but the basement membrane is still intact.
  • Cytologic features of atypia: large hyperchromatic nuclei, a raised nuclear-to-cytoplasmic ratio, loss of basal cell polarity, abnormal mitoses high in the epithelium, basophilic cytoplasm and premature keratinization of single cells within the epithelium (dyskeratosis).

Differential Diagnosis and Immunohistochemistry (IHC)

Our Approach to Treating Leukoplakia

Our leukoplakia protocols rest on two principles: other diagnoses must always be ruled out, and cancer risk must be actively managed:

• Biopsy is required: leukoplakia is not diagnosed by eye alone. A biopsy shows precisely whether dysplasia is present and rules out a hidden focus of microinvasive cancer.
• Removing all external irritants: patients must stop smoking, betel chewing and drinking alcohol, and any dental sources of mechanical injury must be corrected, before or alongside medical treatment.
• Treatment guided by dysplasia grade: lesions without dysplasia or with mild dysplasia can be closely monitored or treated gently with laser; moderate to severe dysplasia or non-homogeneous lesions must be completely removed surgically or by laser.

How We Diagnose Leukoplakia at Haute-Derma

• Fluorescence-guided mucosal examination (VELscope system): blue light (400–460 nm) is shone on the mucosa. Healthy tissue glows green, while dysplastic or cancerous areas lose their fluorescence and look dark (fluorescence visualization loss, FVL).
• Toluidine blue (tolonium chloride) vital staining: a 1% toluidine blue solution is applied. Areas with increased DNA content and abnormal cell division stain dark blue (positive staining), pinpointing the highest-risk spot for biopsy.
• Wipe test: the white patch is rubbed firmly with gauze. If it comes off, Candida is suspected; if it does not, leukoplakia or lichen planus is more likely.
• Targeted punch or incisional biopsy: the whole lesion, or the most suspicious representative area (red, ulcerated, granular or FVL-positive), is sampled.
• Immunohistochemistry and genetic testing (p53, Ki-67): assessing the proliferation index and TP53 mutation status to estimate the long-term risk of cancer.

Specialized Treatments at Haute-Derma

• UltraPulse CO2 laser ablation / excision:
  • Laser excision: our first choice for dysplastic leukoplakia. The CO2 laser cuts precisely around the lesion and seals blood vessels and nerve endings as it goes, so there is little bleeding or pain, and healing is soft with minimal tightening of the mouth.
  • Laser ablation: for large patches in areas that are hard to operate on.
• Conventional surgical excision: for leukoplakia with severe dysplasia or carcinoma in situ. A safety margin of 3–5 mm beyond the visible edge is recommended.
• Photodynamic therapy (PDT): the photosensitizer 5-ALA is applied to the area, followed by red laser light (630 nm). It works well for leukoplakia spread across many sites in the mouth, where surgical removal would be badly disfiguring.
• Supportive medical treatment and prevention of recurrence:
  • Systemic or topical retinoids (isotretinoin / acitretin): normalize epithelial differentiation and help the patch regress.
  • Combined antifungal treatment: topical or oral fluconazole, or nystatin, if there is Candida co-infection.