eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Head & Neck Surgery

Oral Leukoplakia, Idiopathic

Nikos Soukos, DDS, PhD, Director of the Applied Molecular Photomedicine Laboratory, Assistant Member of the Staff, The Forsyth Institute, Clinical Collaborative, Massachusetts General Hospital

Updated: Feb 7, 2008

Introduction

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.

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.

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%.

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.

Clinical

History

Oral leukoplakia (OL) manifests as patches that are bright white and sharply defined. The surfaces of the patches are slightly raised above the surrounding mucosa.
Individuals with OL are not symptomatic.

Physical

Three stages of OL have been described.
- The earliest lesion is nonpalpable, faintly translucent, and has white discoloration.
- Next, localized or diffuse, slightly elevated plaques with an irregular outline develop. These lesions are opaque white and may have a fine, granular texture.
- In some instances, the lesions progress to thickened, white lesions, showing induration, fissuring, and ulcer formation.
Clinically, OL falls into 1 of 2 main groups.
- The most common are uniformly white plaques (homogenous OL) prevalent in the buccal mucosa, which usually have low premalignant potential.
- Far more serious is speckled or verrucous leukoplakia, which has a stronger malignant potential than homogenous leukoplakia. Speckled leukoplakia consists of white flecks or fine nodules on an atrophic erythematous base. These lesions can be regarded as a combination of or a transition between leukoplakia and erythroplasia, which is flat or depressed below the level of the surrounding mucosal red patch, is uncommon in the mouth, and carries the highest risk of malignant transformation.
Five clinical criteria demonstrate a particularly high risk of malignant change.
- The verrucous type is considered high risk.
- Erosion or ulceration within the lesion is highly suggestive of malignancy.
- The presence of a nodule indicates malignant potential.
- A lesion that is hard in its periphery is predictive of malignant change.
- OL 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.

Causes

In persons who smoke, the combustion end-products brought about by burning tobacco and heat (eg, tobacco tars and resins) are irritating substances capable of producing leukoplakic alterations of the oral mucosa. Years of heavy pipe, cigar, and cigarette smoking can lead to a characteristic type of benign keratosis in the hard palate, called stomatitis nicotina. Many investigators regard this lesion as simply an anatomic variant of leukoplakia. Numerous red dots due to the inflamed and dilated orifices of salivary gland ducts are apparent throughout the whitened palatal mucosa. Later, the mucosa becomes pale because of a slight increase in keratinization. In advanced cases, the palatal tissue is keratinized more heavily, and nodules appear that are related to hyperplasia of the underlying glands, retention of saliva, and fibrosis.
The use of alcohol has been suggested as a possible etiology because alcohol may irritate the mucosa. Persons who habitually consume considerable quantities of alcohol usually also smoke inveterately; therefore, establishing the effects of alcohol alone is difficult.
Malocclusion; chronic cheek biting; ill-fitting dentures; and sharp, broken-down teeth that constantly irritate the mucosa are considered extremely important in the etiology of OL.
Patients who have had syphilitic glossitis have a higher prevalence of OL than individuals with a nonsyphilitic background.
The presence of Candida albicans, a relatively common oral fungus, has been reported to be very frequently associated with OL.
Deficiency of vitamins A and B has been suggested as an inciting factor in the development of OL.

Differential Diagnoses

Workup

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.¹

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:

Nuclear hyperchromatism
Loss of polarity
Increased number of mitotic figures
Nuclear pleomorphism
Altered nuclear-to-cytoplasmic ratio
Deep cell keratinization
Loss of differentiation
Loss of intercellular adherence

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.^2,3

Treatment

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. 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.

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

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.⁴ Recently, studies report that beta-carotene produced sustained remissions in patients with oral leukoplakia (OL), with a durable response for at least 1 year.⁵ Both of these drugs have been used in experimental trials and must be investigated in more depth.

Follow-up

Further Inpatient Care

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

Further Outpatient Care

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

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%).⁶ 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

Patients must be aware that lesions may recur. They should be able to monitor the lesions and report any changes. They should maintain excellent oral hygiene.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Cancer of the Mouth and Throat.

Miscellaneous

Medicolegal Pitfalls

Failure to inform patients about the malignant potential of the disease before and after treatment
Failure to inform patients of the need for clinical follow-up care

References

Pathology & Genetics. Head and Neck Tumours. In: 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.
Greenspan D, Jordan RC. The white lesion that kills--aneuploid dysplastic oral leukoplakia. N Engl J Med. Apr 1 2004;350(14):1382-4. [Medline].
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. Apr 1 2004;350(14):1405-13. [Medline].
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. Jan 7 1993;328(1):15-20. [Medline].
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. Dec 1999;125(12):1305-10. [Medline].
Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer. Dec 1967;20(12):2189-93. [Medline].
Cawson RA, Odell EW. Essentials of Oral Pathology and Oral Medicine. 6th ed. New York, NY: Churchill Livingstone;1998.
Cawson RA, Speight P, Binnie WH, Wright J, eds. Luca's Pathology of Tumors of the Oral Tissues. 5th ed. New York, NY: Churchill Livingstone;1998.
Eveson JW. Oral premalignancy. Cancer Surv. 1983;2:403-424.
Haya-Fernández MC, Bagán JV, Murillo-Cortés J, Poveda-Roda R, Calabuig C. The prevalence of oral leukoplakia in 138 patients with oral squamous cell carcinoma. Oral Dis. Nov 2004;10(6):346-8. [Medline].
Kramer IR, El-Labban N, Lee KW. The clinical features and risk of malignant transformation in sublingual keratosis. Br Dent J. Mar 21 1978;144(6):171-80. [Medline].
Laskaris G. Color Atlas of Oral Diseases in Children and Adolescents. New York, NY: Thieme Medical;2000.
Mincer HH, Coleman SA, Hopkins KP. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. Oral Surg Oral Med Oral Pathol. Mar 1972;33(3):389-99. [Medline].
Pindborg JJ, Roed-Peterson B, Renstrup G. Role of smoking in floor of the mouth leukoplakias. J Oral Pathol. 1972;1(1):22-9. [Medline].
Shafer WG, Hine MK, Levy BM, eds. A Textbook of Oral Pathology. 4th ed. Philadelphia, Pa: WB Saunders;1983.
Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. Feb 1 1984;53(3):563-8. [Medline].
Silverman S, Bhargava K, Smith LW, Malaowalla AM. Malignant transformation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer. Oct 1976;38(4):1790-5. [Medline].
Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36:575-580.

Keywords

oral leukoplakia, OL, focal keratosis, hyperkeratosis, mouth cancer, leukoplakia, oral plaque, mouth plaque, idiopathic leukoplakia, idiopathic oral leukoplakia, premalignant oral lesion, premalignant mouth lesion, precancerous lesion, speckled leukoplakia, verrucous leukoplakia, homogenous leukoplakia, speckled OL, verrucous OL, homogenous OL

Contributor Information and Disclosures

Author

Nikos Soukos, DDS, PhD, Director of the Applied Molecular Photomedicine Laboratory, Assistant Member of the Staff, The Forsyth Institute, Clinical Collaborative, Massachusetts General Hospital
Disclosure: Nothing to disclose.

Medical Editor

David J Terris, MD, FACS, Porubsky Professor and Chairman, Department of Otolaryngology, Medical College of Georgia
David J Terris, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Association for the Advancement of Science, American Bronchoesophagological Association, American College of Surgeons, American Head and Neck Society, Federation of American Societies for Experimental Biology, International Association of Endocrine Surgeons, Phi Beta Kappa, Radiation Research Society, Society of University Otolaryngologists-Head and Neck Surgeons, and Triological Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nader Sadeghi, MD, FRCS(C), Associate Professor of Surgery, Director of Head and Neck Surgery, Department of Surgery, Division of Otolaryngology, George Washington University
Nader Sadeghi, MD, FRCS(C) is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society, Federation of Medical Specialists in Quebec, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Advanced Headache Intervention Consulting fee Consulting; Covidien Corp Consulting fee Consulting

Further Reading