This is a white patch adhering to oral mucosa that cannot be removed by rubbing. It is usually a diagnosis of exclusion. The term should be exclusively reserved for idiopathic lesions when investigations fail to reveal any cause. The term carries no histological association.

Aetiology

It is considered a pre-malignant lesion. The transformation rate in various studies and locations ranging from 0.6 to 20%.¹
Factors most frequently blamed for the development of idiopathic leukoplakia include tobacco use, alcohol consumption, chronic irritation, candidiasis, vitamin A or Vitamin B deficiency and endocrine disturbances.
It may also be associated with other conditions such as:

• Lichen planus
• Ill-fitting dentures
• Secondary syphilis
• Human papilloma virus infection

Epidemiology

• Prevalence - occurs in fewer than 1% of individuals.
• Most cases of leukoplakia occur at age 50-70 years. Approximately 80% of patients are older than 40.
• Leukoplakia is more common in men than in women, with a male-to-female ratio of 2:1.

Presentation

• Occurs on mucous membranes in the mouth.
• Most commonly found on the tongue.²
• It is seen as patches that are bright white and sharply defined.
• The surfaces of the patches are slightly raised above the surrounding mucosa.
• Individuals are not symptomatic.

1. The earliest lesion is non-palpable, faintly translucent, and has white discolouration.
2. Next, localised or diffuse, slightly elevated plaques with an irregular outline develop. These lesions are opaque white and may have a fine, granular texture.
3. In some instances, the lesions progress to thickened, white lesions, showing induration, fissuring and ulcer formation.

Five clinical criteria demonstrate a particularly high risk of malignant change:

1. The verrucous (speckled) type is considered high-risk.
2. Erosion or ulceration within the lesion is highly suggestive of malignancy.
3. The presence of a nodule indicates malignant potential.
4. A lesion that is hard in its periphery is predictive of malignant change.
5. Leukoplakia of the anterior floor of the mouth and undersurface of the tongue is strongly associated with malignant potential.

In all cases, the relative risk of malignant potential is determined by the presence of epithelial dysplasia upon histological examination.
Biomarkers of gene instability, such as aneuploidy and allelic imbalance, can also accurately measure the cancer risk of oral premalignant lesions or intra-epithelial neoplasia.³

Investigations

Any suspicious areas should be referred urgently for biopsy.

Management

General measures

The patient should abstain from alcohol and tobacco.

Pharmacological

• Systemic retinoids may be effective; however, they have toxic effects.
  • Studies investigating the use of a high-dose induction followed by low-dose systemic isotretinoin report stabilisation of the majority of lesions, a more effective response than beta-carotene in preventing malignant changes, and no toxicity.⁴
• Studies have reported that beta-carotene produced sustained remissions in patients with leukoplakia, with a durable response for at least 1 year.⁵
• Oral lycopene (a carotenoid) appeared, from a small RCT conducted over 5 months, to be effective in the treatment and management of oral leukoplakia.⁶ Further evaluation is required.
• Low-dose fenretinide, a synthetic retinoid, has recently been found to be clinically active in a 3-month trial in patients with resistance or relapse with natural retinoids.⁷ It produced a small increase in apoptosis.

Surgical

• Surgical excision of leukoplakia may be considered.
• Frequent clinical observation accompanied by photographic records is recommended. Because of the unpredictable behaviour of dysplastic lesions, immediately obtain a biopsy on any areas that are suggestive, or that change in appearance.
• Cryotherapy ablation and carbon dioxide laser ablation are also used:
  • The area heals rapidly, and apparently healthy mucosa is left behind.
  • However, uncertainty remains regarding the risk of invasive carcinomas subsequently arising in sites previously treated.
  • However a study from Japan showed only 1.2% malignant transformation, where the cases had non-keritinised epithelia, i.e. the tongue and buccal mucosa.⁸

Prognosis

A 2.9% annual malignant transformation rate was found in a hospital-based study. The median follow-up period was 29 months. Parameters associated with an increased risk of malignant transformation were female gender, absence of smoking habits in women and a non-homogeneous clinical aspect.⁹

Another (more recent) study showed higher rates, with the highest frequency of malignant development (15%) seen in non-homogeneous leukoplakias, this figure being 3% for homogeneous leukoplakias.¹⁰

Despite excision, small dysplastic lesions can be followed by multiple carcinomas and a fatal outcome. In addition, some dysplastic lesions may have a worse prognosis than isolated carcinomas without leukoplakia.
However, dysplastic lesions can regress spontaneously. Therefore the behaviour of dysplastic lesions is unpredictable. There is currently no reliable management protocol.
Prolonged and close follow-up care is essential but the prognosis may still be poor.

'Hairy' leukoplakia

This is associated with Epstein-Barr virus (EBV) and occurs mostly in people with HIV, both immunocompromised and immunocompetent.¹¹ It can affect patients who are HIV negative and many cases have been reported in heart, kidney and bone marrow transplant recipients and in patients with haematological malignancies.

Management of hairy leukoplakia

As a benign lesion with low morbidity, hairy leukoplakia does not require specific treatment in every case. Indications for treatment include symptoms attributable to the lesion, or a patient's desire to eliminate the lesion for cosmetic reasons. The variable natural history of the lesion and its tendency toward spontaneous resolution should be considered in any management decision.
Options include:

• Systemic antiviral therapy, which usually achieves resolution of the lesion within 1-2 weeks of therapy.
• Topical therapy with podophyllin resin 25% solution, which usually achieves resolution after 1-2 treatment applications.
• Topical therapy with retinoic acid (tretinoin), which has been reported to resolve hairy leukoplakia.
• Ablative therapy, which can also be considered for small hairy leukoplakia lesions. Cryotherapy has been reported as successful but is not widely used.

Document references

1. Soukos N, White WM; Oral Leukoplakia, Idiopathic; eMedicine: February 2008
2. Gosselin EJ, Malignant Tumors of the Mobile Tongue, eMedicine (2009)
3. Sudbo J; Novel management of oral cancer: a paradigm of predictive oncology.; Clin Med Res. 2004 Nov;2(4):233-42. [abstract]
4. Lippman SM, Batsakis JG, Toth BB, et al; Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis.; N Engl J Med. 1993 Jan 7;328(1):15-20. [abstract]
5. Garewal HS, Katz RV, Meyskens F, et al; Beta-carotene produces sustained remissions in patients with oral leukoplakia: results of a multicenter prospective trial.; Arch Otolaryngol Head Neck Surg. 1999 Dec;125(12):1305-10. [abstract]
6. Zakrzewska JM; Oral lycopene--an efficacious treatment for oral leukoplakia?; Evid Based Dent. 2005;6(1):17-8. [abstract]
7. Lippman SM, Lee JJ, Martin JW, et al; Fenretinide activity in retinoid-resistant oral leukoplakia.; Clin Cancer Res. 2006 May 15;12(10):3109-14. [abstract]
8. Ishii J, Fujita K, Munemoto S, et al; Management of oral leukoplakia by laser surgery: relation between recurrence and malignant transformation and clinicopathological features.; J Clin Laser Med Surg. 2004 Feb;22(1):27-33. [abstract]
9. Schepman KP, van der Meij EH, Smeele LE, et al; Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol. 1998 Jul;34(4):270-5. [abstract]
10. Holmstrup P, Vedtofte P, Reibel J, et al; Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006 May;42(5):461-74. Epub 2005 Nov 28. [abstract]
11. Kozyreva O, May SK, Bleibel SK; Hairy Leukoplakia. eMedicine, 2007.

Internet and further reading

• SIGN; Diagnosis and Mangement of Head and Neck Cancer, Quick Reference Guide, 2006
• American Family Physician; Photo Quiz: Common Lesions on the Floor of the Mouth

Acknowledgements