As of 2005, leukoplakia is defined by the World Health Organization as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.”7 The term leukoplakia literally means “white patch,”5, 7 and is considered the most common pre-malignant lesion of the oral cavity.3 Clinicians further define these lesions as those that cannot easily be rubbed off, ruling out epidermal slough, lichen planus, and candida infections. Leukoplakia is not a histological classification; instead, the term characterizes a clinical condition or finding. In order to verify a diagnosis, a biopsy and histopathological classification of the lesion must be performed.
CLASSIFICATION OF LEUKOPLAKIA
There are two clinical variants of leukoplakia: homogenous and non-homogenous. Homogenous lesions exhibit a uniform appearance and in general, are consistently textured. Homogenous lesions can be further classified into four sub-types: flat, corrugated, wrinkled, or pumice. 2 Non-homogenous lesions have irregular textures and can appear flat, nodular, or exophytic and also have four sub-types: verrucous, nodular (speckled), ulcerated, or erthyroleukoplakia.2
RISK FACTORS FOR DEVELOPMENT OF LEUKOPLAKIA
Mixed tobacco habits (chewing and smoking) have repeatedly been proven to dramatically increase incidence of oral leukoplakia.2 Indeed, the most effective treatment for patients with leukoplakia who smoke is smoking cessation. Multiple studies have shown 43-97.5% resolution of lesion with as little as six weeks of cessation of smoking tobacco.4 There are conflicting reports on whether gender, age, and site in oral cavity increases risk for developing leukoplakia and it has been suggested that geographical location and societal habits largely affect this data. For example, in India it is more socially acceptable for men to use tobacco. Accordingly, incidence of oral leukoplakias are higher in men than women, which may be associated with societal chewing tobacco and smoking habits versus a strict sex predilection.2 Geographically, public health initiatives for smoking cessation campaigns have been in place for 20-30 years in the North America and northern Europe, but not eastern or southern Europe. Recent WHO statistics show Poland, Greece, and Hungary with a much higher smoking prevalence and associated high incidence of oral cancer and leukoplakia.4
MALIGNANT TRANSFORMATION POTENTIAL
The clinical significance of leukoplakia lies in its potential for malignant transformation. Identifying the variant and subtype of lesion can provide clues as to the likelihood the lesion will develop into dysplasia or carcinoma.
Idiopathic leukoplakia (leukoplakia in non-smokers) and non-homogenous types have the greatest potential for malignant transformation.2, 6 Other risk factors that show statistical significance for malignant transformation are female gender8 (which may be the result of a generally higher prevalence of epithelial dysplasia in women2), long duration of lesion, location on the tongue or floor of mouth, size (greater than 200mm2), presence of C. albicans, and presence of epithelial dysplasia.2 Although smoking tobacco has been consistently shown to increase incidence of leukoplakia, a direct association between smoking and malignant transformation has not always been shown.2 However, smoking is the strongest risk factor associated with leukoplakia and smoking cessation is known to resolve leukoplakia lesions, and because increased duration of lesion is associated with increased potential for malignant transformation, it can be reasonably argued that smoking tobacco is in the very least indirectly associated with malignant transformation. Chronic ethanol abuse has also long been suspected to be causative, or in the very least additive with smoking tobacco, although a Chinese study showed no association between malignant potential and ethanol intake alone. 10
The implication of human papilloma virus (HPV) in cervical/uterine cancer has long been known, leading to extensive studies attempting to link HPV infection with the development of oral cancer. To date, there is no research that confirms a correlation of HPV to development of leukoplakia. An extreme range in reporting of HPV found in oral precancerous lesions (0-100%) may at least partially be accounted for by varying detection techniques performed by the researchers.7 In some studies the investigators used PCR techniques without also qualifying viral load . Because PCR techniques can detect a tiny fragment of DNA, this data may represent either contamination or clinically insignificant infection. 7 Further, it may simply represent as superinfection when present.3 Epstein-Barr virus (EBV) is also suspected to play a role in the etiology of oral cancers, but at present there is no conclusive evidence to support this notion.3
There are many defined clinical-histological pathologies that may appear in a differential diagnosis list. The following is an incomplete list of pathology that may be considered when evaluating leukoplakia: leukoedema, nicotine stomatitis, lichen planus, candidiasis, SCC, verrucous carcinoma, linea alba, secondary syphilis, and white sponge nevus.
WHEN TO BIOPSY
Commonly, patients are recalled two weeks after the initial finding of a low-risk leukoplakia lesion to determine if the lesion has resolved. If it has not, either biopsy or referral for biopsy is indicated. Patients with high-risk lesions, especially non-homogenous or speckled leukoplakia, should be biopsied or referred for biopsy urgently. Communication with a laboratory on proper collection technique and tissue preservation is invaluable in obtaining a proper diagnosis. Also, it may be prudent to request a pathologist trained in examining tissues of the oral cavity.1
Martorell-Calatayed, et al. suggest different treatment modalities for leukoplakias designated “low-risk” (lacking dysplasia, mild dysplasia in low risk areas, homogenous lesions, or small lesions) versus those that are “high-risk” (large, dysplastic lesions in high risk areas - tongue or floor of the mouth, lesions with moderate to severe dysplasia, or verrucous dysplasias). Low-risk therapy options include regular follow-up or ‘watch and wait’, topical or systemic retinoids like isotretinoin, or nonsurgical ablation with CO2 laser or cryotherapy (CO2 laser has been shown to be more effective). If the lesion does not resolve after re-treatment with a low-risk modality, moving to a high-risk treatment is appropriate.
High risk lesion treatment starts with surgical decortication of the lesion. As long as the histology report rules out squamous cell carcinoma, the patient should be put on a regular recall schedule (every three months in the first year, every 6-12 months subsequently). If histological analysis shows any point of squamous cell carcinoma, radical excision with or without chemotherapy or radiotherapy is appropriate.
In cases where leukoplakia is diffuse or located in multiple regions of the oral cavity, more than one biopsy site should be chosen for histopathological analysis. Careful follow up for resolution and monitoring of the generalized lesion and/or multiple lesions is prudent.
It is important to note the most effective therapeutic option for treatment of low-risk leukoplakia in smokers is smoking cessation; therefore, the clinician should be diligent with these patients regarding education on the etiology and potential for development of oral cancer.
Oral leukoplakia is one of the most common precancerous lesions of the oral cavity and early detection and management of these lesions can prevent malignancy and the associated invasive treatment, loss of quality of life, and mortality.
1 Systemic Review of Randomized Trials for the Treatment of Oral Leukoplakia. Lodi, et al. Journal of Dental Education. Volume 66, No 8.
2 Oral premalignant lesions: from a clinical perspective. Amagasa et al. Int J Clin Oncol (2011) 16:5-14
3 Oral Leukoplakia: Clinical, Histopathologic, and Molecular Features and Therapeutic Approach. Martorell-Calatayud et al. Actas Dermosifiliogr. 2009; 100:669-84
4 Tobacco Use and Oral Leukoplakia. Banoczy et al. Journal of Dental Education, Volume 65, No 4.
5 Contemporary Oral and Maxillofacial Pathology, 2nd Edition. Sapp et al.
6 Scully, et a. Dermatologic Manifestations of Oral Leukoplakia. Medscape Reference. http://emedicine.medscape.com/article/1075448-overview#a0104
7 Feller, et al. Oral Leukoplakia as It Relates to HPV Infection: A Review. Int J Dent, 2012.2012:540561
8 Ribeiro, et al. A Review of the Nonsurgical Treatment of Oral Leukoplakia. Int J Dent 2010. 2010:186018
9 Wei Liu et al. Malignant transformation of of oral leukoplakia: a retrospective cohort study of 218 Chinese patients. BMC Cancer. 2010; 10: 685.
10 Management of the Medically Compromised Patient, 6th Ed. Little et al.