Oral Leukoplakia

Back

Background

Oral leukoplakia (OL) is a white patch or plaque that cannot be rubbed off, cannot be characterized clinically or histologically as any other condition, and is not associated with any physical or chemical causative agent except tobacco. Therefore, a process of exclusion establishes the diagnosis of the disease. In general, the term leukoplakia implies only the clinical feature of a persistent, adherent white plaque; therefore, reserve the term for idiopathic lesions when investigations fail to reveal any cause. The term carries absolutely no histologic connotation, although, inevitably, some form of disturbance of the surface epithelium is characteristic.

Follow-up studies suggest that cancer is more likely to occur in individuals with idiopathic leukoplakia than in individuals who do not have this condition. Thus, idiopathic leukoplakia is considered a premalignant lesion.[1, 2]

Pathophysiology

The etiology of most cases of OL is unknown (idiopathic). In other cases, the initiation of the condition may depend on extrinsic local factors and/or intrinsic predisposing factors. Factors most frequently blamed for the development of idiopathic leukoplakia include tobacco use, alcohol consumption, chronic irritation, candidiasis, vitamin deficiency, endocrine disturbances, and possibly a virus.

Epidemiology

Frequency

International

OL occurs in fewer than 1% of individuals.

Mortality/Morbidity

OL is considered to be potentially malignant, with a transformation rate in various studies and locations that range from 0.6 to 20%.

A long-term follow-up study by Fan et al indicated that oral leukoplakia can increase the risk of esophageal squamous cell carcinoma (ESCC). The study, in which nearly 29,584 healthy adults were enrolled, found that 2924 persons in the study developed ESCC over a 28-year follow-up period; in adults aged 52 years or younger at baseline, the hazard ratio for the disease in those with leukoplakia was 1.31.[3]

Sex

OL is more common in men than in women, with a male-to-female ratio of 2:1.

Age

Most cases of OL occur in persons in their fifth to seventh decade of life. Approximately 80% of patients are older than 40 years.

History

See the list below:

Physical

 

The following three stages of OL have been described:

Clinically, OL falls into one of the following two main groups:

The following five clinical criteria demonstrate a particularly high risk of malignant change:

A literature review by Lyu et al focused on Chinese patients indicated that other risk factors for malignant transformation of OL include female gender, age over 50 years, and nonhomogeneity of OL.[4]

In all cases, the relative risk of malignant potential is determined by the presence of epithelial dysplasia upon histological examination.

Causes

See the list below:

Laboratory Studies

Idiopathic lesions and dysplastic lesions do not have any specific clinical appearance. Therefore, in any case, the clinical appearance is not a guide to the underlying microscopic characteristics. A definitive diagnosis of oral leukoplakia is made when any etiological cause other than tobacco/areca nut use has been excluded and histopathology has not confirmed any other specific disorder.[5]

Procedures

Biopsy obtainment, repeated as necessary, is essential.

Histologic Findings

The plaque may show hyperorthokeratosis or hyperparakeratosis. The granular layer is often thickened and extremely prominent in cases of hyperorthokeratosis, but it is seldom observed in even severe cases of hyperparakeratosis. Acanthosis, which refers to the abnormal thickening of the prickle cell layer, may also be observed. Epithelial changes suggestive of premalignancy include the following:

Yang et al analyzed the relationship between clinical features of OL using endoscopy with narrow-band imaging histopathology. They concluded that flexible endoscopy can be a successful tool for examining OL.[6]

Molecular markers that may indicate an increased likelihood of malignant transformation are (1) Mutations in the p53 gene, (2) Inappropriate expression of oncogenes (eg, cyclin D1), keratins, blood-group antigens and other cell-surface carbohydrates, and (3) DNA aneuploidy (when the amount of DNA is not an exact multiple of the diploid number). The latter emerges as one of the most promising prognostic indicators since oral cancer with poor survival consistently developed in human subjects with aneuploid dysplastic OL.[7, 8]

A study by Sakata et al indicated that a combination of low expression of the tumor suppressor SMAD4 and high stromal lymphocyte infiltration is predictive for the malignant transformation of OL.[9]

A study by von Zeidler et al suggested that reductions in the amount of epithelial cadherin (E-cadherin), a cellular adhesion protein, signal an increased risk of malignant transformation by OL. The investigators found that the amount of E-cadherin expressed in tissue differed between normal oral mucosa and low-risk OL, between low-risk and high-risk OL, and between high-risk OL and squamous cell carcinoma of the oral cavity with cervical lymph node metastasis.[10]

A study by Habiba et al indicated that expression of aldehyde dehydrogenase 1 and the transmembrane protein podoplanin are associated with a 3.02- and 2.62-fold increase, respectively, in the likelihood that OL will progress to oral cancer.[11]  In addition, a report by Grochau et al indicated that expression of podoplanin in OL correlates with the leukoplakia’s degree of dysplasia (as indicated by the lesion’s squamous intraepithelial neoplasia classification).[12] A study by Gissi et al also found evidence of a relationship between podoplanin expression and dysplasia in OL.[13]

Medical Care

Surgical excision of oral leukoplakia (OL) may be considered. Frequent clinical observation accompanied by photographic records is recommended. Because of the unpredictable behavior of dysplastic lesions, immediately obtain a biopsy on any areas that are suggestive or that change in appearance.[14] Cryotherapy ablation and carbon dioxide laser ablation are also used.[15] 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.

Consultations

Consult an oral medicine specialist to evaluate etiologic factors and to determine the individualized treatment.

Diet

Discontinue the use of alcohol.

Activity

Physical activity is not restricted.

Medication Summary

Topical retinoids are ineffective. Systemic retinoids may be effective, but they have toxic effects. Studies that investigated the use of a high-dose induction followed by low-dose systemic isotretinoin report stabilization of the majority of lesions, a more effective response than beta-carotene in preventing malignant changes, and no toxicity.[16] Recently, studies report that beta-carotene produced sustained remissions in patients with oral leukoplakia (OL), with a durable response for at least 1 year.[17] Both of these drugs have been used in experimental trials and must be investigated in more depth.

Further Outpatient Care

Care includes monitoring the efficacy of surgical or systemic treatment with clinical observation.

Further Inpatient Care

Oral leukoplakia (OL) is managed exclusively in an outpatient setting.

Deterrence/Prevention

If etiologic factors can be determined, avoidance of these factors is recommended.

Prognosis

Approximately 10% of patients who develop OL have invasive carcinoma in the lesion (6%) or will develop carcinoma (4%).[18] Despite excision, small dysplastic lesions can be followed by multiple carcinomas and a fatal outcome. In addition, some dysplastic OL lesions may have a worse prognosis than isolated carcinomas without leukoplakia. However, the fact that many dysplastic OL lesions can regress spontaneously shows that the behavior of dysplastic lesions is unpredictable and that no reliable management protocol has been determined. Prolonged and close follow-up care is essential, but the prognosis may still be poor.

Patient Education

See the list below:

Author

Christopher M Harris, MD, DMD, Residency Program Director, Department of Oral and Maxillofacial Surgery, Maxillofacial Tumor and Reconstruction, Naval Medical Center Portsmouth

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nader Sadeghi, MD, FRCSC, Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, McGill University Faculty of Medicine; Chief Otolaryngologist, MUHC; Director, McGill Head and Neck Cancer Program, Royal Victoria Hospital, Canada

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .

Additional Contributors

David J Terris, MD, FACS, Porubsky Professor and Chairman, Department of Otolaryngology, Medical College of Georgia, Georgia Regents University

Disclosure: Nothing to disclose.

References

  1. Liu W, Shi LJ, Wu L, Feng JQ, Yang X, Li J, et al. Oral cancer development in patients with leukoplakia--clinicopathological factors affecting outcome. PLoS One. 2012. 7(4):e34773. [View Abstract]
  2. Brouns E, Baart J, Karagozoglu K, Aartman I, Bloemena E, van der Waal I. Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis. 2013 Mar 6. [View Abstract]
  3. Fan JH, Wang JB, Qu CX, et al. Association between oral leukoplakia and upper gastrointestinal cancers: a 28-year follow-up study in the Linxian General Population Trial. Oral Oncol. 2014 Oct. 50(10):971-5. [View Abstract]
  4. Lyu MY, Guo YS, Li S, Yang D, Hua H. Hospital-based epidemiological and clinical characterisation of the malignant transformation of oral leukoplakia in a Chinese population. Int Dent J. 2017 Mar 9. [View Abstract]
  5. Pathology & Genetics. Head and Neck Tumours. World Health Organization. World Health Organization of Tumours. In: Barnes L, Eveson JW, Reichart P, Sidransky D, eds. Lyon: International Agency for Research of Cancer (IARC) IARC Press; 2005. 177-179.
  6. Yang SW, Lee YS, Chang LC, Hwang CC, Luo CM, Chen TA. Use of endoscopy with narrow-band imaging system in evaluating oral leukoplakia. Head Neck. 2011 Nov 3. [View Abstract]
  7. Greenspan D, Jordan RC. The white lesion that kills--aneuploid dysplastic oral leukoplakia. N Engl J Med. 2004 Apr 1. 350(14):1382-4. [View Abstract]
  8. Sudbø J, Lippman SM, Lee JJ, Mao L, Kildal W, Sudbø A. The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med. 2004 Apr 1. 350(14):1405-13. [View Abstract]
  9. Sakata J, Yoshida R, Matsuoka Y, et al. Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia. Cancer Med. 2017 Mar 3. [View Abstract]
  10. von Zeidler SV, de Souza Botelho T, Mendonca EF, et al. E-cadherin as a potential biomarker of malignant transformation in oral leukoplakia: a retrospective cohort study. BMC Cancer. 2014 Dec 17. 14:972. [View Abstract]
  11. Habiba U, Hida K, Kitamura T, et al. ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia. Oncol Lett. 2017 Jan. 13 (1):321-8. [View Abstract]
  12. Grochau KJ, Safi AF, Drebber U, Grandoch A, Zöller JE, Kreppel M. Podoplanin expression in oral leukoplakia─a prospective study. J Craniomaxillofac Surg. 2019 Mar. 47 (3):505-9. [View Abstract]
  13. Gissi DB, Gabusi A, Tarsitano A, Luccarini L, Morandi L, Montebugnoli L. Podoplanin expression as a predictive marker of dysplasia in oral leukoplakia. J Craniomaxillofac Surg. 2018 May. 46 (5):759-64. [View Abstract]
  14. Jeong WJ, Paik JH, Cho SW, Sung MW, Kim KH, Ahn SH. Excisional biopsy for management of lateral tongue leukoplakia. J Oral Pathol Med. 2011 Nov 12. [View Abstract]
  15. Lin HP, Chen HM, Cheng SJ, Yu CH, Chiang CP. Cryogun cryotherapy for oral leukoplakia. Head Neck. 2011 Nov 15. [View Abstract]
  16. Lippman SM, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin JW. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med. 1993 Jan 7. 328(1):15-20. [View Abstract]
  17. Garewal HS, Katz RV, Meyskens F, Pitcock J, Morse D, Friedman S. 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. [View Abstract]
  18. Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer. 1967 Dec. 20(12):2189-93. [View Abstract]