Leukoplakia

§ overviewOverview

WHO 2005: 'A white plaque of questionable risk having excluded other known diseases or disorders that carry no increased risk for cancer.'

§ icdICD Classification

ICD-10 K13.21

§ etiologyEtiology

• 01Tobacco (smoking and smokeless)
• 02Areca nut / pan / gutka
• 03Alcohol (synergistic)
• 04Candida albicans (co-factor in nodular type)
• 05HPV 16/18 (subset)
• 06Chronic mechanical / galvanic irritation (contested)
• 07Idiopathic (~10–30%)

§ riskRisk Factors

• 01Male, age > 40
• 02Heavy tobacco or areca use
• 03Immunosuppression
• 04Prior head-and-neck malignancy
• 05Nutritional deficiency (Fe, folate, vit A/B12)

§ geneticsGenetics & Molecular Biology

• 01Loss of heterozygosity at 3p, 9p21 (CDKN2A), 17p (TP53) predicts progression
• 02Aneuploidy on DNA image cytometry — strong risk marker
• 03TP53 mutation in dysplastic epithelium

§ epidemiologyEpidemiology

Global point prevalence ≈ 2% (range 0.5–3.5%); South Asia up to 5–10%. Male:female ≈ 2:1. Peak 50–70 y. Malignant transformation rate ≈ 1% per year overall.

§ pathogenesisPathogenesis

Chronic exposure of basal keratinocytes to carcinogens (tobacco nitrosamines, areca alkaloids) → oxidative DNA damage → clonal expansion of altered keratinocytes with hyperkeratosis and progressive dysplasia. Field cancerisation explains multifocal disease and PVL.

§ clinicalClinical Features

• 01Homogeneous — thin, flat, uniform white plaque with sharp margins
• 02Non-homogeneous — nodular, verrucous, speckled (erythroleukoplakia) — significantly higher malignant risk
• 03Proliferative verrucous leukoplakia (PVL) — multifocal, persistent, recurrent, elderly women, gingiva
• 04Cannot be scraped off (differentiates from candidiasis)
• 05Common sites: buccal mucosa, lateral/ventral tongue, floor of mouth, retromolar area

§ signsSigns & Symptoms

• 01Usually asymptomatic — discovered on routine exam
• 02Roughness or altered taste
• 03Pain, induration or bleeding suggest malignant change

§ differentialDifferential Diagnosis

• 01Frictional keratosis
• 02Lichen planus (reticular)
• 03White sponge nevus
• 04Pseudomembranous candidiasis
• 05Leukoedema
• 06Nicotinic stomatitis
• 07Hairy leukoplakia (EBV, HIV)

§ criteriaDiagnostic Criteria

• 01Diagnosis of exclusion — clinically white plaque not attributable to another known disease
• 02Biopsy from most suspicious (red, nodular, indurated) area is mandatory to grade dysplasia

§ histopathHistopathology

• 01Hyperkeratosis (ortho- or para-) ± acanthosis
• 02Epithelial dysplasia graded mild / moderate / severe / carcinoma in situ (WHO 2022 — low vs high grade binary system now preferred)
• 03Dysplastic features: basal cell hyperplasia, drop-shaped rete ridges, nuclear pleomorphism, hyperchromatism, increased/abnormal mitoses, individual cell keratinisation, loss of polarity
• 04Basement membrane intact — distinguishes from invasive SCC
• 05PVL: verrucous surface, minimal dysplasia early, progressive verrucous or squamous cell carcinoma

§ investigationsInvestigations

• 01Toluidine blue vital staining (adjunct, false positives)
• 02Autofluorescence (VELscope) screening
• 03Brush cytology + DNA image cytometry
• 04Incisional biopsy of most suspicious area — GOLD STANDARD
• 05Molecular markers: LOH panel, TP53 IHC in research settings

§ ihcIHC / Special Stains

• 01p53 — suprabasal / diffuse staining suggests dysplasia
• 02Ki-67 — suprabasal proliferation indicates dysplasia
• 03Podoplanin — over-expression associated with progression

§ whoWHO Classification

WHO 2022 Head & Neck Tumours: classified under Oral Potentially Malignant Disorders (OPMDs). Dysplasia grading recommended as two-tier (low-grade / high-grade) alongside traditional three-tier system.

§ classificationClassification

• 01Homogeneous
• 02Non-homogeneous: nodular, verrucous, speckled (erythroleukoplakia)
• 03Proliferative Verrucous Leukoplakia (PVL)
• 04By site: idiopathic vs tobacco-associated

§ planTreatment Planning

• 01Confirm diagnosis histologically
• 02Assess dysplasia grade and size
• 03Stop all habits before definitive therapy
• 04Multidisciplinary review for PVL and severe dysplasia

§ treatmentTreatment

• 01Habit cessation (tobacco, areca, alcohol) — MANDATORY first step
• 02Small homogeneous, no dysplasia: observation + 3-monthly review
• 03Dysplastic or non-homogeneous: complete excision
• 04Topical/systemic retinoids, β-carotene, lycopene — adjuncts only, high recurrence on withdrawal

§ medicalMedical Management

• 01Vitamin A / retinoids (13-cis retinoic acid) — reduces size, does not prevent transformation
• 02β-carotene, lycopene supplementation
• 03Topical bleomycin (severe dysplasia, off-label)

§ surgicalSurgical Management

• 01Cold-knife excision with 5 mm margin for dysplastic lesions
• 02CO2 laser ablation / excision — good haemostasis, minimal scarring, but no specimen if ablation
• 03Cryosurgery — limited use
• 04Photodynamic therapy (5-ALA) for large field lesions

§ complicationsComplications

• 01Malignant transformation to SCC
• 02Recurrence after excision (10–35%)
• 03Post-surgical scarring, restricted mouth opening
• 04Missed dysplasia if inadequate biopsy site

§ recurrenceRecurrence Rate

10–35% after surgical excision; higher for PVL (up to 70%). Lifelong surveillance required.

§ followupFollow-up Protocol

• 013-monthly for first year
• 026-monthly for years 2–5
• 03Annually thereafter, lifelong for PVL / high-grade dysplasia
• 04Re-biopsy any change in colour, texture, symptoms

§ prognosisPrognosis

Overall malignant transformation ≈ 1% per year (range 0.1–17%). Risk factors: non-homogeneous type, size > 200 mm², floor of mouth / ventral tongue, high-grade dysplasia, female non-smoker, PVL (up to 70% lifetime).

§ preventionPrevention

• 01Tobacco and areca cessation counselling
• 02Alcohol moderation
• 03Regular oral cancer screening in high-risk groups
• 04Public health education, ban on smokeless tobacco

§ examKey Examination Points

• 01Site, size, colour (uniform vs mixed), surface (smooth, nodular, verrucous)
• 02Consistency and induration
• 03Wipes off? (excludes candidiasis)
• 04Cervical lymphadenopathy
• 05Habit history duration and frequency

§ revisionQuick Revision Summary

• 01Diagnosis of exclusion — clinical + histological
• 02Non-homogeneous >> homogeneous risk
• 03Habit cessation is treatment step 1
• 04Biopsy is mandatory
• 05Lifelong follow-up for high-risk lesions

§ vivaBDS Viva Questions

• 01Define leukoplakia per WHO 2005.
• 02Which type has the highest malignant transformation rate?
• 03How do you biopsy a large heterogeneous leukoplakia?
• 04What is PVL and why is it dangerous?
• 05Name three histological features of epithelial dysplasia.
• 06How does leukoplakia differ from candidiasis clinically?
• 07What are the WHO 2022 changes to dysplasia grading?
• 08Enumerate treatment options.
• 09What is field cancerisation?
• 10Name molecular markers predicting transformation.

§ bdsBDS Professional Examination

• 01Define leukoplakia. Classify and describe clinical features, histopathology and management of oral leukoplakia (10 marks).
• 02Short note: Proliferative verrucous leukoplakia.

§ fcpsFCPS Residency Questions

• 01Discuss the concept of oral potentially malignant disorders, molecular basis of malignant transformation in leukoplakia, and evidence for chemoprevention.
• 02Critically evaluate CO2 laser vs cold-knife excision for dysplastic leukoplakia.

§ pearlsClinical Pearls

• 01Any leukoplakia that fails to regress 2–4 weeks after removing irritants must be biopsied.
• 02Red > white — a speckled lesion is more ominous than a homogeneous plaque.
• 03PVL is a clinical, not histological, diagnosis — established retrospectively.

§ mnemonicsMnemonics

• 01Non-homogeneous = Nasty (higher risk)
• 02PVL — Persistent, Verrucous, Lethal

§ readingSuggested Reading

• 01Warnakulasuriya S. Oral potentially malignant disorders. Oral Oncol 2020.
• 02van der Waal I. Oral leukoplakia — a proposal for uniform reporting. Oral Oncol 2000.
• 03WHO Head & Neck Tumours 5e (2022).

§ differentialDifferential Comparison

§ mcqsMCQs — Assessment (8)

§ relatedRelated Diseases

References

1. Neville BW et al. Oral & Maxillofacial Pathology, 4e
2. Warnakulasuriya S, Kujan O et al. J Oral Pathol Med 2021 — nomenclature and classification of OPMDs
3. WHO Classification of Head and Neck Tumours, 5e (2022)