Description

• Leukoplakia is defined by the World Health Organization (WHO) as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.”
• System(s) affected: gastrointestinal (GI)
• Hyperplasia of squamous epithelium

Epidemiology

Most common in individuals who use tobacco (smoking and especially smokeless), heavy alcohol use, and areca nuts (Asian populations).

Incidence
250,000 annual cases worldwide

Prevalence

• Age of onset is >40 years old with peak in the 60s (1).
• Males 3 times more likely to be affected than females (1)
• Smokers 6 times more likely to be affected than nonsmokers (1)

Geriatric Considerations
Malignant transformation to carcinoma is more common in older patients.

Etiology and Pathophysiology

Hyperkeratosis or dyskeratosis of the oral squamous epithelium. Tissue cell exposure to carcinogens spurs adaptive changes including hyperplasia. Continued irritant exposure can lead to cellular degeneration of the epithelium and eventually apoptosis or malignant transformation.

• Tobacco use in any form
• Alcohol consumption
• Dental restorations/prosthetic appliances/periodontitis
• Candida albicans infection
• Human papillomavirus, types 16 and 18
• Vitamin and combined micronutrient deficiencies
• Syphilis
• Chronic trauma or irritation
• Epstein-Barr virus (oral hairy leukoplakia)
• Areca nut/betel (Asian populations)
• Mouthwash/toothpaste containing the herbal root extract sanguinaria
• Hormonal disturbances/estrogen therapy
• Ultraviolet exposure (2)

Genetics

• Dyskeratosis congenital and epidermolysis bullosa increase the likelihood of oral malignancy.
• P53 overexpression, PTEN allelic loss correlates with leukoplakia and particularly squamous cell carcinoma.
• Changes in expression of p53, p16INK4a and 3p, 9p, and 17 (especially TP53) gene mutations can have greater cancer risk (2). Decreased expression of E-cadherin, hMLH1, and CD1a.
• Biomarkers: IL-6, IL-8, and TNF-α have been detected in leukoplakia, and there is new research showing possible use of Hsp27 and PTHRP/PTHLH as biomarkers (2).

Risk Factors

• 70–90% of oral leukoplakia is related to tobacco, particularly smokeless tobacco or areca/betel nut use.
• Alcohol increases risk by 1.5-fold.
• Repeated or chronic mechanical trauma from dental appliances or cheek biting
• Chemical irritation to oral regions
• Diabetes
• Risk factors for malignant transformation of leukoplakia
  • Female
  • Long duration of leukoplakia
  • Nonsmoker (idiopathic leukoplakia)
  • Located on tongue or floor of mouth
  • Size >200 mm²
  • Nonhomogeneous type
  • Presence of epithelial dysplasia
  • Presence of C. albicans
  • Possible shift of oral microbiome in those with malignant transformation (3)

General Prevention

• Avoid tobacco of any kind, alcohol, habitual cheek biting, tongue chewing, and betel nut ingestion.
• Use well-fitting dental equipment.
• Regular dental check-ups to avoid bad restorations
• Diet rich in fresh fruits and vegetables may help to prevent cancer.
• HPV vaccination may be preventive.

Commonly Associated Conditions

• HIV infection is closely associated with hairy leukoplakia.
• Erythroplakia in association with leukoplakia, “speckled leukoplakia,” or erythroleukoplakia is a marker for underlying dysplasia.