Multifocal verrucous leukoplakia with a changing erythematous focus
A 63-year-old woman, a lifelong non-smoker and non-drinker, is referred for white patches in the mouth present for 3 years. She has no pain. Examination shows multifocal adherent white plaques on the left buccal mucosa, the right alveolar gingiva and the hard palate. One 2 x 2 cm area on the gingiva is verrucous, with a 5 mm erythematous, slightly indurated zone at its edge. An incisional biopsy of a buccal plaque 18 months ago showed hyperkeratosis with mild epithelial dysplasia, and that area was excised but has recurred. She takes amlodipine and has no skin lesions; HIV testing is negative. There is no cervical lymphadenopathy.
1. What is the most likely diagnosis, and why is a single biopsy insufficient to exclude malignancy here?
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The picture is that of proliferative verrucous leukoplakia (PVL): multifocal, persistent, progressive white plaques in an older non-smoking woman, involving gingiva and alveolar mucosa, becoming verrucous, recurring after excision.
A single biopsy cannot exclude malignancy because PVL is a field-change disease with marked histological heterogeneity. Mild dysplasia in one buccal plaque says nothing about the indurated erythematous gingival margin, which may already harbour verrucous carcinoma or conventional squamous cell carcinoma. Sampling error runs in both directions: a superficial or non-representative specimen can miss invasion, and a verrucous surface can conceal a focus of conventional carcinoma beneath.
Differential to consider: chronic hyperplastic candidiasis (would respond to antifungal therapy and show hyphae), oral lichen planus (usually bilateral reticular striae, not verrucous multifocal plaques), frictional keratosis (unilateral, related to a cause, does not recur after removal), and verrucous carcinoma.
Next step: repeat incisional biopsy, deliberately including the erythematous indurated edge and the deepest verrucous area, with enough depth to assess the basement membrane. I would also take a separate specimen from a second site, send a candidal smear, and record the full extent with photographs and a map.
2. Outline your management and follow-up plan for this patient.
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Immediate: biopsy the suspicious gingival focus and any other non-homogeneous area; treat candidiasis if present, though a partial response must not be mistaken for resolution of PVL.
Definitive management: PVL has no single curative treatment; management is staged excision of suspicious or symptomatic areas with scalpel or CO2 laser, with histological verification of the excised specimen and clearance of any carcinoma. I would avoid mutilating wide resection based on mild dysplasia alone in a multifocal disease, and equally avoid 'watch and wait' on an indurated ulcerated or erythroplakic change. Where carcinoma is confirmed, refer to the head and neck oncology team for staging imaging and neck assessment.
Follow-up: review every 2-3 months for the first year, then 3-6 monthly lifelong, with clinical photographs, measurement of lesions and a lesion map. Any new area should be biopsied rather than observed indefinitely.
Communication: explain that this is a chronic condition with a real risk of malignant change, that it can recur after every excision, and that tobacco and alcohol avoidance, good oral hygiene and denture adjustment (if applicable) reduce additional risk. Document the discussion.
3. Which clinical and histological features would raise your suspicion of transformation, and what is the approximate magnitude of risk?
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Magnitude: published series put malignant transformation in PVL at roughly 40-50% over prolonged follow-up, sometimes higher, with transformation often years after the first presentation. This is why the diagnosis changes management even when the first biopsy is only mildly dysplastic.
Clinical red flags:
- A change from homogeneous white to verrucous, speckled or erythroplakic surface - erythroplakia is the strongest clinical warning.
- Induration, ulceration, pain, bleeding or fixation to underlying tissue.
- Rapid enlargement or a new nodular component.
- Gingival/alveolar and palatal sites, which in PVL carry higher risk than buccal mucosa.
- Cervical lymphadenopathy or trismus.
- Recurrence after excision, which indicates field change rather than incomplete removal.
Histological red flags: increasing grades of dysplasia, verrucous architecture with broad pushing rete ridges, loss of basement membrane integrity, and any invasive islands. HPV-negative status does not lower the risk.
Practical consequence: mild dysplasia in a single sample does not downgrade the diagnosis - the clinical behaviour defines PVL. Any red flag means re-biopsy without delay, and a negative biopsy in the presence of a suspicious lesion should prompt a second, deeper sample rather than reassurance.