Proliferative Verrucous Leukoplakia

Proliferative verrucous leukoplakia is a rare, progressive form of oral leukoplakia that spreads to several mucosal sites, becomes thicker and verrucous over time, and carries the highest rate of malignant transformation of any oral potentially malignant disorder.

It affects women more than men, mostly in the sixth to eighth decades, and a large share of patients have never smoked. The gingiva, alveolar ridge, buccal mucosa, tongue and palate are the usual sites.

Pathophysiology. The cause is unknown, and no consistent link to human papillomavirus or Epstein-Barr virus has been established. Field cancerisation of the whole oral mucosa with accumulating genomic change is the accepted model.

Lesions begin as flat white keratosis, then progress through exophytic verrucous hyperplasia and verrucous carcinoma to invasive squamous cell carcinoma, often at several sites over time.

Persistent white plaques on more than one site, commonly adjacent to or involving the gingiva, with a corrugated or papillary surface and a tendency to spread despite treatment and removal. Lesions recur after excision. Many patients are asymptomatic, and some report roughness, soreness or a lump.

Progression to a red or ulcerated area, a firm base, bleeding, or a fixed lymph node signals carcinoma. A lesion that has been followed without change for years can still transform.

• Diagnosis is clinical and retrospective: multifocal leukoplakia that progresses, with biopsies showing hyperkeratosis, then verrucous hyperplasia, verrucous carcinoma or invasive carcinoma.
• Incisional biopsies of the thickest, reddest or most irregular areas at more than one site. A single negative biopsy does not exclude disease at other sites, so re-biopsy any area that changes.
• Clinical photographs and mapping of lesions at every visit for comparison.
• Imaging of the neck by ultrasound, CT or MRI when a node is palpable or carcinoma is found.
• Exclusion of other causes of white lesions (candidiasis, lichen planus, frictional keratosis, chemical injury).

Differential diagnosis.

• Homogeneous or non-homogeneous leukoplakia
• Verrucous carcinoma
• Oral squamous cell carcinoma
• Oral lichen planus or lichenoid reaction
• Hyperplastic candidiasis
• White sponge naevus
• Smokeless tobacco lesion

• No treatment halts progression or lowers the transformation rate with certainty. Reported transformation is high, roughly 60 to 100% over 5 to 10 years in published series, and these figures are less certain.
• Stop tobacco, areca nut and alcohol. Treat Candida when present.
• Excision, with histological margins, of discrete thickened, red or dysplastic areas, preferably by scalpel or laser with preserved tissue for pathology. Recurrence is frequent, so repeated excision may be needed.
• Photodynamic therapy and laser ablation are options for extensive disease with limited response, with variable results and no proven effect on cancer rate.
• Systemic retinoids, topical agents and other chemoprevention have not been shown to prevent cancer and are not advised for this purpose.
• Early squamous cell carcinoma is treated by wide excision with neck assessment, and advanced disease by combined surgery with adjuvant radiotherapy or chemoradiotherapy, directed by tumour stage.

Monitoring. Examination every 3 months at first, and at least every 6 months when stable, for life. Biopsy any area that thickens, ulcerates or changes colour. Annual neck examination and imaging as indicated.

Referral and escalation. Refer to oral medicine or oral and maxillofacial surgery at diagnosis. Urgent referral within 2 weeks for ulceration, induration, rapid growth, a neck node or a histological diagnosis of dysplasia or carcinoma.