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Leukoplakia, Oral

- 70 " “90% of oral leukoplakia is related to tobacco, particularly smokeless tobacco or areca/betel nut use. - Alcohol increases risk 1.5-fold - Repeated or chronic mechanical trauma from dental appliances or cheek biting - Chemical irritation to oral regions - Diabetes - Age - Socioeconomic status - 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 - Nonhomogenous type - Presence of epithelial dysplasia

- Appearance - Varies from homogeneous, nonpalpable, faintly translucent white areas to thick, fissured, papillomatous, indurated plaques - May feel rough or leathery - Lesions can become exophytic or verruciform. - Color may be white, gray, yellowish white, or brownish gray. - Cannot be wiped or scraped off

- World Health Organization classification (1) - Homogeneous refers to color - Flat, corrugated, wrinkled, or pumice

- White oral lesions that can be wiped away: acute pseudomembranous candidiasis - White oral lesions that cannot be rubbed off (1) - Morsicatio buccarum (habitual cheek-biting), generally benign (4)[C] - Chemical injury - Acute pseudomembranous candidiasis - Traumatic or frictional keratosis (e.g., linea alba) - Leukoedema (benign milky opaque lesions that disappear with stretching) - Aspirin burn (from holding aspirin in cheek) - Lichen planus (bilateral fairly symmetric lesions, reticular pattern of slightly raised gray-white lines) - Lichenoid reaction - Verrucous carcinoma - Discoid lupus erythematosus - Skin graft (known history) - Squamous cell carcinoma - Oral hairy leukoplakia, commonly on the lateral border of the tongue with a bilateral distribution (in HIV patients with Epstein-Barr virus infection) - Smoker 's palate (leukokeratosis nicotina palati) - White sponge nevus (congenital benign spongy lesions) - Syphilitic oral lesion - Dyskeratosis congenita (a rare inherited multisystem disorder)

para>Malignant transformation to carcinoma is more common in older patients. ‚

ETIOLOGY AND PATHOPHYSIOLOGY

Hyperkeratosis or dyskeratosis of the oral squamous epithelium ‚

  • Tobacco use in any form
  • Alcohol consumption/alcoholism
  • Oral infections
  • Candida albicans infection may induce dysplasia and increase malignant transformation (2)[B].
  • Human papillomavirus, types 11 and 15
  • Sunlight
  • Vitamin deficiency
  • Syphilis
  • Dental restorations/prosthetic appliances
  • Estrogen therapy
  • Chronic trauma or irritation
  • Epstein-Barr virus (oral hairy leukoplakia)
  • Areca nut/betel (Asian populations)
  • Mouthwash preparations and toothpaste containing the herbal root extract sanguinaria

Genetics

  • Dyskeratosis congenital and epidermolysis bullosa increase the likelihood of oral malignancy (1)[B].
  • P53 overexpression correlates with leukoplakia and particularly squamous cell carcinoma (3)[B].

RISK FACTORS

  • 70 " “90% of oral leukoplakia is related to tobacco, particularly smokeless tobacco or areca/betel nut use.
  • Alcohol increases risk 1.5-fold
  • Repeated or chronic mechanical trauma from dental appliances or cheek biting
  • Chemical irritation to oral regions
  • Diabetes
  • Age
  • Socioeconomic status
  • Risk factors for malignant transformation of leukoplakiaFemaleLong duration of leukoplakiaNonsmoker (idiopathic leukoplakia)Located on tongue or floor of mouthSize >200 mm2Nonhomogenous typePresence of epithelial dysplasia

GENERAL PREVENTION

  • Avoid tobacco of any kind, alcohol, habitual cheek biting, tongue chewing.
  • Use well-fitting dental prosthesis.
  • 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, " ť or erythroleukoplakia is a marker for underlying dysplasia.

DIAGNOSIS

Leukoplakia is an asymptomatic white patch on the oral mucosa. ‚

HISTORY

  • Usually asymptomatic
  • History of tobacco or alcohol use or oral exposure to irritants

PHYSICAL EXAM

  • Location50% on tongue, mandibular alveolar ridge, and buccal mucosaAlso seen on maxillary alveolar ridge, palate, and lower lipInfrequently seen on floor of the mouth and retromolar areasFloor of mouth, ventrolateral tongue, and soft palate complex are more likely to have dysplastic lesions.
  • AppearanceVaries from homogeneous, nonpalpable, faintly translucent white areas to thick, fissured, papillomatous, indurated plaquesMay feel rough or leatheryLesions can become exophytic or verruciform.Color may be white, gray, yellowish white, or brownish gray.Cannot be wiped or scraped off
  • World Health Organization classification (1)Homogeneous refers to colorFlat, corrugated, wrinkled, or pumiceNonhomogeneous refers to color and texture (more likely to be dysplastic or malignant).Erythroleukoplakia (mixture of red and white)Exophytic: papillary or verrucous texture

DIFFERENTIAL DIAGNOSIS

  • White oral lesions that can be wiped away: acute pseudomembranous candidiasis
  • White oral lesions that cannot be rubbed off (1)Morsicatio buccarum (habitual cheek-biting), generally benign (4)[C]Chemical injuryAcute pseudomembranous candidiasisTraumatic or frictional keratosis (e.g., linea alba)Leukoedema (benign milky opaque lesions that disappear with stretching)Aspirin burn (from holding aspirin in cheek)Lichen planus (bilateral fairly symmetric lesions, reticular pattern of slightly raised gray-white lines)Lichenoid reactionVerrucous carcinomaDiscoid lupus erythematosusSkin graft (known history)Squamous cell carcinomaOral hairy leukoplakia, commonly on the lateral border of the tongue with a bilateral distribution (in HIV patients with Epstein-Barr virus infection)Smoker 's palate (leukokeratosis nicotina palati)White sponge nevus (congenital benign spongy lesions)Syphilitic oral lesionDyskeratosis congenita (a rare inherited multisystem disorder)

DIAGNOSTIC TESTS & INTERPRETATION

Biopsy to rule out carcinoma if lesion is persistent, changing, or unexplained ‚

Initial Tests (lab, imaging)

  • Laboratory tests generally are not indicatedConsider saliva culture if C. albicans infection is suspected.
  • No imaging is indicated.

Follow-Up Tests & Special Considerations

  • Biopsy is necessary to rule out carcinoma if lesion is persistent, changing, or unexplained (1).
  • Consider CBC, rapid plasma reagin (RPR).

Diagnostic Procedures/Other

  • Oral cytology is superior to conventional oral examination (5)[A].
  • Computer-assisted cytology or liquid-based cytology is not superior to oral cytology (5)[A].
  • Noninvasive brush biopsy and analysis of cells with DNA " “image cytometry constitute a sensitive and specific screening method.
  • Patients with dysplastic or malignant cells on brush biopsy should undergo more formal excisional biopsy (1).
  • Excisional biopsy is definitive procedure.

Test Interpretation

  • Biopsy specimens range from hyperkeratosis to invasive carcinoma.
  • At initial biopsy, 6% are invasive carcinoma.
  • 0.13 " “6% subsequently undergo malignant transformation
  • Location is important: 60% on floor of mouth or lateral border of tongue are cancerous; buccal mucosal lesions are generally not malignant but require biopsy if not resolving.

TREATMENT

  • All oral leukoplakias should be treated.
  • Treatment may include the following:For 2 to 3 circumscribed lesions, surgical excisionFor multiple or large lesions where surgery would cause unacceptable deformity, consider cryosurgery or laser surgery (6)[C].Removal of predisposing habits (alcohol and tobacco)
  • Complete excision is standard treatment for dysplasia or malignancy.
  • After treatment, up to 30% of leukoplakia recurs, and some leukoplakia still transforms to squamous cell carcinoma (6)[B].
  • Oral hairy leukoplakia may be treated with podophyllin with acyclovir cream (7)[A].

GENERAL MEASURES

  • Eliminate habitual lip biting.
  • Correct ill-fitting dental appliances, bad restorations, or sharp teeth.
  • Stop smoking and using alcohol.
  • Some small lesions may respond to cryosurgery.
  • Ž ˛-carotene, lycopene, retinoids, and cyclooxygenase 2 (COX-2) inhibitors may cause partial regression.
  • For hairy tongue: tongue brushing

MEDICATION

Carotenoids, vitamins A, C, and K, bleomycin, and photodynamic therapy ineffective to prevent malignant transformation and recurrence (8)[A] ‚

ISSUES FOR REFERRAL

Consider otolaryngologist or oral surgery referral for extensive disease ‚

SURGERY/OTHER PROCEDURES

  • Scalpel excision, laser ablation, electrocautery, or cryoablation
  • Cryotherapy slightly less effective than photodynamic therapy response (73% vs. 90%) and recurrence (27% vs. 24%) (9)[A]
  • CO2 laser had 20% recurrence and 10% malignant transformation within 5 years (10)[B].

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization

  • Eliminate etiologic factors.
  • Reevaluate in 7 to 14 days.
  • Biopsy if lesion is persistent.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Regular, close follow-up, even after successful treatment
  • Biopsy as needed

DIET

Regular ‚

PATIENT EDUCATION

  • If biopsy is negative, stress importance of periodic and careful follow-up.
  • Initiate a dental referral to eliminate dental factors.
  • Stress importance of stopping tobacco and alcohol use.
  • Encourage participation in smoking cessation program.

PROGNOSIS

  • Most leukoplakia is benign.
  • Leukoplakia may regress, remain stable, or progress.
  • 0.13 " “6% of initially benign lesions subsequently develop into cancer.
  • More likely to be cancerous if on floor of mouth or lateral border of tongue

COMPLICATIONS

  • New lesions may develop after treatment.
  • Risk of malignant transformation to squamous cell carcinoma is approximately 5 " “17% (11)[B].
  • Larger lesions and nonhomogeneous leukoplakia are associated with higher rates of malignant transformation.

REFERENCES

11 Warnakulasuriya ‚ S, Johnson ‚ NW, van der Waal ‚ I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36(10):575 " “580.22 Cao ‚ J, Liu ‚ HW, Jin ‚ JQ. The effect of oral candida to development of oral leukoplakia into cancer [in Chinese]. Zhonghua Yu Fang Yi Xue Za Zhi. 2007;41(Suppl):90 " “93.33 Duarte ‚ EC, Ribeiro ‚ DC, Gomez ‚ MV, et al. Genetic polymorphisms of carcinogen metabolizing enzymes are associated with oral leukoplakia development and p53 overexpression. Anticancer Res. 2008;28(2A):1101 " “1106.44 Cam ‚ K, Santoro ‚ A, Lee ‚ JB. Oral frictional hyperkeratosis (morsicatio buccarum): an entity to be considered in the differential diagnosis of white oral mucosal lesions. Skinmed. 2012;10(2):114 " “115.55 Fuller ‚ C, Camilon ‚ R, Nguyen ‚ S, et al. Adjunctive diagnostic techniques for oral lesions of unknown malignant potential: systematic review with meta-analysis. Head Neck. 2015;37(5):755 " “762. doi:10.1002/hed.23667.66 Feller ‚ L, Lemmer ‚ J. Oral leukoplakia as it relates to HPV infection: a review. Int J Dent. 2012;2012:540561.77 Moura ‚ MD, Haddad ‚ JP, Senna ‚ MI, et al. A new topical treatment protocol for oral hairy leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110(5):611 " “617.88 Ribeiro ‚ AS, Salles ‚ PR, da Silva ‚ TA, et al. A review of the nonsurgical treatment of oral leukoplakia. Int J Dent. 2010;2010:186018.99 Kawczyk-Krupka ‚ A, Wa … ›kowska ‚ J, Raczkowska-Siostrzonek ‚ A, et al. Comparison of cryotherapy and photodynamic therapy in treatment of oral leukoplakia. Photodiagnosis Photodyn Ther. 2012;9(2):148 " “155.1010 Jerjes ‚ W, Upile ‚ T, Hamdoon ‚ Z, et al. CO2 laser of oral dysplasia: clinicopathological features of recurrence and malignant transformation. Lasers Med Sci. 2012;27(1):169 " “179.1111 Rhodus ‚ NL, Kerr ‚ AR, Patel ‚ K. Oral cancer: leukoplakia, premalignancy, and squamous cell carcinoma. Dent Clin North Am. 2014;58(2):315 " “340.

ADDITIONAL READING

  • Nair ‚ DR, Pruthy ‚ R, Pawar ‚ U, et al. Oral cancer: premalignant conditions and screening " ”an update. J Cancer Res Ther. 2012;8(Suppl 1):S57 " “S66.
  • Reamy ‚ BV, Derby ‚ R, Bunt ‚ CW. Common tongue conditions in primary care. Am Fam Physician. 2010;81(5):627 " “634.
  • Warnakulasuriya ‚ S, Dietrich ‚ T, Bornstein ‚ MM, et al. Oral health risks of tobacco use and effects of cessation. Int Dent J. 2010;60(1):7 " “30.
  • Yardimci ‚ G, Kutlubay ‚ Z, Engin ‚ B, et al. Precancerous lesions of oral mucosa. World J Clin Cases. 2014;2(12):866 " “872.

SEE ALSO

Infectious Mononucleosis, Epstein-Barr Virus Infections; HIV/AIDS ‚

CODES

ICD10

  • K13.21 Leukoplakia of oral mucosa, including tongue
  • K13.3 Hairy leukoplakia

ICD9

528.6 Leukoplakia of oral mucosa, including tongue ‚

SNOMED

  • 414603003 Leukoplakia of oral mucosa
  • 414952002 oral hairy leukoplakia (disorder)

CLINICAL PEARLS

  • Excisional biopsy is indicated for any undiagnosed leukoplakia.
  • After treatment, up to 30% of leukoplakia recurs, and some leukoplakia still transforms to squamous cell carcinoma; thus, long-term surveillance is essential.
  • To lessen risk of malignant transformation, encourage tobacco and alcohol cessation and consider C. albicans eradication.