CHAPTER III LEUKOPLAKIA 3.

1 Risk Factor Leukoplakia is a white lesion that, unlike oral candidiasis, cannot be removed by rubbing the mucosal surface. The areas of leukoplakia are usually small but may be several centimeters in diameter. Histologically, they are often hyperkeratoses occurring in response to chronic irritation (e.g., from tobacco and dentures); about 2-6%, however, represent either dysplasia or early invasive squamous cell carcinoma.4 There are some risk factors that contribute to the occurrence of leukoplakia: a. Age Those with age older than 65 have increased risk of having leukoplakia. b. Sex More men than women get leukoplakia. In women, the condition more often develops into cancer. c. Lifestyle Tobacco (especially smokeless tobacco) and long-time alcohol use increase the vulnerability of getting leukoplakia.
d. Conditions

Incidence of leukoplakia increase in those with diminished immune system, such as in HIV-positive patients. 3.2 Etiology and Epidemiology No etiologic factor can be identified for most persistent oral leukoplakias (idiopathic leukoplakia). Known causes of leukoplakia include the following:5

Trauma (eg, chronic trauma from a sharp or broken tooth or from mastication may cause keratosis) Tobacco use: Chewing tobacco is probably worse than smoking. Alcohol

Infections (eg, candidosis, syphilis, Epstein-Barr virus infection): EpsteinBarr virus infection causes a separate and distinct nonpremalignant lesion termed hairy leukoplakia.

Chemicals (eg, sanguinaria) Immune defects: Leukoplakias appear to be more common in transplant patients.

3.3

Pathogenesis and Pathophysiology No etiologic factor can be identified for most persistent oral white plaques (ie, idiopathic leukoplakia). The histopathologic features are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and severe dysplasia. Patients with idiopathic leukoplakia have the highest risk of developing cancer. In studies of these patients, 4-17% had malignant transformation of the lesions in less than 20 years. The risk of developing malignancies at lesion sites is 5 times greater in patients with leukoplakia than in patients without leukoplakia.5 Dysplastic lesions do not have any specific clinical appearance; however, where erythroplakia is present, dysplasia is likely. Dysplasia is evident in 1725% of biopsy samples of leukoplakias. Erythroleukoplakias, verrucous leukoplakias, and nodular leukoplakias show an increasing frequency of dysplastic histologic changes or aneuploidy. 5 Leukoplakias that are speckled, or erythroleukoplakic, are usually dysplastic or frank carcinomas. Nodular or verrucous lesions are also sinister, but homogenous leukoplakias are far less likely to be potentially malignant. 5 Most idiopathic leukoplakias are homogenous leukoplakias and show little evidence of dysplastic histologic changes or aneuploidy. However, studies have revealed carcinoma or severe dysplasia in the excision specimens of approximately 5% of leukoplakias excised when the diagnostic biopsy specimens had revealed no dysplasia. 5 Carcinoma in situ is a controversial term used for severe dysplasia in which the abnormalities extend throughout the thickness of the epithelium. All the

cellular abnormalities characteristic of malignancy may be present; only invasion of the underlying connective tissue is absent. Top-to-bottom epithelial dysplasia, like other dysplastic lesions, has no characteristic clinical appearance, although erythroplasia often proves to be carcinoma in situ or early invasive carcinoma. 5 3.4 Clinical Manifestation Leukoplakia has a varied clinical appearance and its appearance frequently changes over time. Change or progression over time accounts for yet another unique aspect of leukoplakia, it is one of the few diseases in which long duration is not evidence of harmless future behavior. Lesions of long duration have a greater risk of malignant transformation than those of short duration, and the older a leukoplakia the worse is its prognosis.4 Leukoplakias are white lesions that cannot be removed with a gauze swab. Most leukoplakias are smooth, white plaques (homogeneous leukoplakias), occur on the lip, the buccal mucosae, or the gingivae. Some leukoplakias are white and warty (verrucous leukoplakia), some are mixed white and red lesions (erythroleukoplakias or speckled leukoplakias). Dysplastic lesions do not have any specific clinical appearance; however, where erythroplasia is present, dysplasia, carcinoma in situ, and frank carcinomas are more likely to be seen. The site of the lesion is relevant; leukoplakias on the floor of the mouth or on the ventrum of the tongue and the lip are sinister. The size of the lesion appears to be irrelevant. Even small dysplastic lesions may lead to multiple carcinomas and a fatal outcome.5 3.5 Diagnosis and Management The first diagnostic method should be performed is physical examination. A systematic intraoral examination including the lateral tongue, floor of the mouth, gingiva, buccal area, palate, and tonsillar fossae and palpation of the neck for enlarged lymph nodes should be part of any general physical examination, especially in patients over the age of 45 who smoke tobacco or drink immoderately.4

Oral biopsy is performed to detect the dysplastic cells. Intraoral staining with 1% toluidine blue may aid in selection of the most suspicious biopsy site.4 The recently introduced, computer-assisted, oral brush biopsy is a detection tool providing evidence of cellular abnormalities in precancerous and cancerous lesions. With the aid of a highly specialized, neural, networkbased, image-processing system specifically designed to detect oral epithelial precancerous and cancerous cells, the pathologist can detect as few as 1 or 2 abnormal individual cells in several hundred thousand cells. The detection of 1 or 2 such abnormal cells is sufficient to warrant a histologic specimen obtained by scalpel biopsy.5 The histopathologic features are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and severe dysplasia. The histologic assessment of oral epithelial dysplasia is notoriously unreliable. Many studies show interpathologist and intrapathologist variation in diagnosing dysplasia. Besides the fact that the criteria for diagnosing dysplasia are ill defined, another serious problem exists. A tissue specimen from a biopsy may not be representative of the whole lesion. Latent carcinomas may be missed.5 Molecular and genetic analysis of premalignant and malignant tissue has produced increasing evidence of genetic instability (including microsatellite instability, cell cycle-regulatory gene P16 and P14 deletions and hypermethylation, and mutations in P53); and clonal alterations, such as loss of retinoic acid -receptor expression, occur during the early stage of aerodigestive tract carcinogenesis. These molecular and epidemiologic studies provide the foundation on which clinical trials have been designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the possible reduction in the 4-5% annual rate of second primary tumors.4 Once the diagnosis is established, thorough management should be done. The objective of care is to detect and to prevent malignant change. Several management regimens have been suggested; however, no large trials have shown a definitive, reliable treatment. Yet, possible courses of action include

medical therapies (eg, anti-inflammatory agents, vitamins, cytotoxic agents) and surgical removal

(eg, scalpel, laser, cryoprobe,

electrosurgery, photodynamic therapy).5

Patients should avoid any causal factor, such as use of tobacco and alcohol. Leukoplakias can regress under these circumstances. Any degree of dysplasia in a lesion at a high-risk site must be taken seriously and the lesion should be removed. Occasionally, patients are treated by photodynamic therapy or topical cytotoxic agents. Patients should be examined regularly, probably at 3- to 6-month intervals. A diet rich in fresh fruits and vegetables may help prevent cancer.5 A number of clinical trials have suggested a role for beta-carotene, vitamin E, and retinoids in producing regression of leukoplakia and reducing the incidence of recurrent SCCs. Retinoids suppress head and neck and lung carcinogenesis in animal models and inhibit carcinogenesis in individuals with premalignant lesions. They also seem to reduce the incidence of second primary cancers in head and neck and lung cancer patients previously treated for a primary.4 Retinoids appear to be very effective but can have severe adverse effects on liver function and may cause teratogenicity.5 3.6 Prognosis Some leukoplakias are potentially malignant. Dysplasia currently appears to be the best predictor of malignant potential. As many as 25% of leukoplakias are dysplastic at the first visit. Malignant change appears to be more frequent among nonsmokers than among smokers.5 Estimates of malignant transformation vary from 3-33% over a 10-year period. However, many innocuous leukoplakias are not always followed up in some centers, and the studies are often small. As many as 30% of leukoplakias can regress if habits are stopped. A poorer prognosis is noted in females, nonsmokers, moderate or severe epithelial dysplasia, and lesions in high-risk sites, such as the floor of the mouth.5