INTRODUCTION
Leukoplakia is defined as a whitish patch which cannot be characterized pathologically or clinically as any other lesion or disease.[1] Leukoplakia in the oral cavity is considered as a premalignant or potentially malignant lesion. The term “leukoplakia” is a clinical term rather than histological. It often presents as single or multiple lesions [Figure 1] found in the mucosa of the oral cavity. This whitish patch of the oral mucosa [Figure 2] cannot be defined as any other lesion.[1] It can transfer into oral cancer. It accounts for approximately 80% of potentially malignant oral lesions.[2] The exact etiology of oral leukoplakia is idiopathic and often associated with tobacco use.[3] Worldwide, there is increasing habit of using tobacco in both smokeless and smoking form which enhancing the chance of oral leukoplakia. The malignant transformation in leukoplakia occurs in 0.3%–25% cases, and the presence of the dysplasia increases the chance of malignancy by 30%.[4] The prevalence of this lesion increases with age, and it is more common in elderly persons. The prevalence of oral cavity leukoplakia is approximately <1% in persons younger than 30 years old, and its prevalence increases to approximately 8% in male patients older than 70 years of age, and approximately 2% in female patients of more than 70 years of age.[5] The treatment of oral leukoplakia in early stage can reduce the incidence of the oral carcinoma. There are the several modalities of treatment for leukoplakia such as use of the antioxidants such as Vitamin A, Vitamin C, and Vitamin E, analogs of Vitamin A and beta-carotenes, surgical excision of the leukoplakia, electrocautery, cryosurgery, and laser ablation have been used. However, there has been search for nonsurgical or noninvasive treatment of the oral leukoplakia. In this review article, we discuss the details of the nonsurgical treatment modalities of the oral leukoplakia.
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Figure 1: Multiple whitish patches in the lateral surface of the tongue
Figure 2: Leukoplakia in buccal mucosa
METHODS FOR LITERATURE SEARCH
For searching the published articles, we conducted an electronic search of the Google Scholar, Medline, Scopus, and PubMed databases. The search term in the database included oral cavity, leukoplakia, nonsurgical treatment of the leukoplakia, premalignant lesions of the oral cavity, and whitish patch in the oral cavity. The abstracts of the published articles are identified by this search method, and other articles identified manually from the citations. This review article reviews the nonsurgical treatment of the oral cavity leukoplakia. This review article presents a baseline from where further prospective trials can be designed and help as a spur for further research in this commonly encountered clinical entity where not many studies are done.
TREATMENT OPTIONS FOR ORAL CAVITY LEUKOPLAKIA
There are surgical and nonsurgical treatment options available for oral cavity leukoplakia. The surgical treatment includes conventional surgical excision, electrocoagulation, cryosurgery, and laser surgery. Surgical methods are often treatment of choice in oral cavity leukoplakia with histologically diagnosed dysplasia.[6] The surgical excision of the oral cavity leukoplakia rarely prevents the transformation of the oral cavity leukoplakia to oral squamous cell carcinoma provided the resection margins are thicker and free of the epithelial abnormalities. However, surgical intervention does not prevent oral cavity leukoplakia from leading to recurrence. Malignant transformation of the oral cavity leukoplakia is independent of laser therapy or drug treatment.[7]
NONSURGICAL TREATMENT
There certain nonsurgical or conservative treatments are done in oral cavity leukoplakia such as chemopreventive agents such as vitamins (Vitamin A, C, and E), carotenoids (beta-carotene and lycopene), fenretinide (Vitamin A analog), bleomycin, protease inhibitor, anti-inflammatory drugs, green tea, and curcuma.[8] Chemoprevention is defined as natural or synthetic chemicals which reverse or suppress the malignant potential lesions, so reduce the morbidity and mortality associated with it. The photodynamic therapy (PDT) is also considered as a nonsurgical treatment. Proper follow-up and routine observation of the leukoplakia are often considered as appropriate measures in conjunction with avoidance of the risk-associated addiction or habits.
Carotenoids
Carotenoids are the group of highly hydrophobic chemicals useful to prevent the oral leukoplakia. The carotenoids include group of hydrophobic molecules with minimal or no solubility in water. Beta-carotene is Vitamin A precursor. Beta-carotene is a type of carotenoid which often found in vegetables such as spinach, sweet potato, carrots, mango, papaya, and oranges.[9] An important effect of the excess intake of the beta-carotene is yellowish coloration of the skin, also called as carotenodermy, which usually disappear after disruption of this for few weeks.[9] One study showed, supplementation of the beta-carotene can cause headache and muscle pain in few patients.[10] The beta-carotene is usually recommended for preventing the oral leukoplakia and possibly oral cavity cancer. The benefits and protective actions of the beta-carotene are related to its anti-oxidizing property.[11] This anticancer property is accomplished by a ligation of beta-carotene with oxygen, which makes an unstable molecule, thus reduce the damaging activity of the free radicals.[12] Diet supplemented with beta-carotene helps to prevent the changes in the oral cavity mucosa; specifically, among smokers those have low serum Vitamin-C and beta-carotene in comparison to the nonsmokers. Beta-carotene has a better therapeutic response for minimizing the oral cavity leukoplakia among smokers than nonsmokers.[13] Beta-carotene has better therapeutic response for preventing the oral leukoplakia in chronic smokers than in nonsmokers. One study documented that clinical resolution of the oral cavity leukoplakia ranging 4%–54% with dose ranges from 20 to 90 mg/day of the beta-carotene with time period of the 3–12 months.[8]
Lycopene
Lycopene is a fat soluble red color pigment seen in some vegetables and fruits. The major source of lycopene is tomatoes. It appears to be a promising antioxidant molecule for the treatment of the oral leukoplakia and prevent the cells against the injury/damage.[14] Along with antioxidant nature of the lycopene, it also has capacity to alter the intercellular exchange junctions and so play an important role for protecti on against the dysplasia by blocking the tumor cell proliferation. Lycopene helps to bring the histological alternation of a significant degree in patients of oral leukoplakia.[14] Lycopene may cause the suppression of carcinogen-induced phosphorylation of the proteins such as p53 and Rb anti-oncogene and block cell division at the Go-G 1 cell-cycle phase.[15]
Vitamin-C
Vitamin-C is also called as L-ascorbic acid (L-AA) and found in citrus fruits such as strawberries, papaya, kiwi, papaya, and mango.[16] It has antioxidant properties which react with the superoxide released during normal metabolic process. The inactivation of the superoxide inhibits to form nitrosamines during digestion of the protein and block to damage of the DNA and cellular proteins. The role of L-AA for maintaining healthy oral mucosa is little described. One study showed the presence of oral mucosal lesions in persons with low L-AA levels in the plasma in comparison to control groups with low plasma L-AA.[17] Vitamin C toxicity is not seen as this vitamin is water soluble, and the absorption efficiency decreased when the consumption exceeds 180 mg per day.[18] One study showed usefulness of the Vitamin C and beta carotene for the treatment of the oral cavity leukoplakia.[14]
Vitamin E
Vitamin E includes a family of chemical substances which are structurally related to the alpha-tocoferol. Alpha Tocoferol is the important constituent of the Vitamin E which has anti-proliferative nature as well as acts a free radical scavenger to prevent the lipid peroxidation of the polyunsaturated fatty acids.[19] This vitamin is found in green leaves, plant oil, and margarine. The daily limit of the Vitamin E is 10 mg per day in adult man and 8 mg per day in adult women. When the consumption is more than 30 mg per day, its absorption rate will be reduced. Addition of the alpha tocoferol in the food increases the antioxidant concentration in the plasma. One study showed improvement of the leukoplakia in the oral cavity clinically and histologically after taking the Vitamin E twice daily for 24 weeks.[19] The treatment of this oral cavity leukoplakia by Vitamin E was well tolerated without any toxicity and good compliance. High dose of the vitamin intake (more than 400 IU/d) may increase the chance of mortality, so high dose of the Vitamin E should be avoided.[19]
Vitamin A (retinoic acid)
Vitamin A is found in the human body as different inter-convertible molecules notably retinal (required for vision) and retinal which is the potent analog and important form of storage and transportation. Vitamin A is obtained from the carotene and certain foods such as milk, meat and eggs. The absorption is increased when ingested with food. The use of Vitamin A is not widely accepted because of its side effects such as hypervitaminosis, toxicity, and teratogenic effects.[20] The retinoid interact with the surface receptors at the cellular levels and penetrate into the cell. Then these are metabolized and transported into the nucleus by different proteins.
Bleomycin
The bleomycin is a glycopeptides derived antibiotic prepared from streptomyces.[21] The biochemical action of the bleomycin is explained through a sequence selective oxidative cleavage of the genetic materials such as DNA and RNA with the presence of the oxygen. It helps the oxidative degradation of cellular RNA and blockage of the DNA synthesis. Bleomycin is a cytotoxic antibiotic which was used for tumors of the penis and scrotum. Bleomycin is a cytotoxic drug used for squamous cell carcinoma of the head and neck area, skin, and esophagus.[21] The common adverse effects of bleomycin are mucocutaneous reactions which include alopecia, stomatitis, vesiculation erythema of the skin, eruptions, and pruritis erythema.[10] The use of topical bleomycin is also tried for leukoplakia. One study showed daily application of the 1% bleomycin for 2 weeks preventing the transformation of the leukoplakia to malignancy.[22] Topical application of the bleomycin will reduce the size of the leukoplakia with minimal side effects. It is helpful when used as adjunct with surgical excision of the lesions particularly in case of the extensive leukoplakia. This medication is useful to avoid grafting after excision of the lesions and prevent the dysplastic changes of this lesion.[14]
Photodynamic therapy
PDT is an effective treatment option for premalignant lesions such as oral cavity leukoplakia.[23] PDT is one of the recent treatment options for oral leukoplakia. It causes cellular and tissue damage in an oxygen-dependant method by the help of the nontoxic components such as light and photosensitizer. This treatment technique is based on the administration of an exogenous photosensitizer for making the sensitive of the tumor cells to light of a specific wavelength. The photosensitizers are usually inert and often selective affinity toward tumor cells. When the photosensitizer in tissue is activated with a specific wavelength light, it convert energy from light to the molecular oxygen, leading to the generation of the reactive-oxygen species (ROS). There are three methods by which PDT destroy the tumor cells. ROS finally kill the tumor cells directly. Second, PDT can kill the tumor-associated vessels, causing thrombus formation and lead to tumor infraction. Third, PDT activates an immune response against the tumor tissues.[23] This treatments functions on the basis of administration of an exogenous photo-sensitizer for making the tumor cells or tissue sensitive to the light of specific wavelength.
Green tea
Epigallocatechin gallate is present in green tea which possesses the antioxidant and chemopreventive properties. It has promising result for the treatment of the oral cavity leukoplakia. As per one study, the size of the oral cavity leukoplakia is deceased to almost 40% of the patients underwent treatment by green tea extract.[24]
Curcumin
Curcumin has been used in Indian Medicine since thousands of years. Curcumin has various pharmacological properties such as anti-inflammatory, antioxidant, antimicrobial, antifungal, anti-viral, and wound-healing activities. It has also the properties of suppress the tumor initiation, progression, and metastasis in case of the experimental model.[25] It has also anti-proliferative nature by blocking the cell cycle, inhibiting the mitotic spindle structures and induce the proptosis and micro-nucleation.[25] It is thought that curcumin act as a pleuripotent pharmacological agent and a new hope for minimizing the cancer and premalignant lesions.[26]
PREVENTIVE MEASURES
Any types of treatment for oral cavity leukoplakia should start with avoidance of risk factors such as tobacco use, chewing of the betel nut, alcohol abuse, and superimposed infection by Candida over the leukoplakia lesions. There is worldwide increased habit of tobacco use in both smoking and smokeless form. This is causing increased incidence of leukoplakia in the oral cavity. The cessation of the tobacco is a prior action for tobacco-associated leukoplakia in the oral cavity.[27] If tobacco use is completely stopped, the tobacco-associated leukoplakia will disappear in up to 60% of the cases, and the leukoplakia due to smokeless tobacco may resolve by stopping the tobacco use.[14] Proper counseling by clinicians and other professionals greatly help to quit the addiction toward the tobacco. A brief period (3 min) of counseling leads to quit the smoking by 5%–10% cases.[17] Candidal leukoplakia responds well to the antifungal medications and cessation of the smoking which may stop dysplasia. As the tobacco, alcohol, betel nut chewing, spicy diet are associated with formation leukoplakia in the oral cavity, so such types of addictions must be discouraged before treating the leukoplakia. Good diet and oral hygiene should be encouraged in these patients.
CONCLUSION
Leukoplakia is premalignant lesion found in the oral cavity, especially in male and middle aged. It is the most common potentially malignant lesion affect the oral cavity. It is more common among tobacco users than nonusers. Oxidative stress is considered as the important factor for contributing the risk toward cancer formation in oral leukoplakia. There are various surgical and nonsurgical treatment options are available, but presently, there is no universally accepted treatment in the clinical practice. The nonsurgical treatment, for example, retinoic acid and beta-carotene is effective for resolving the oral leukoplakia by blocking the oxidative stress. The nonsurgical treatment of oral cavity leukoplakia include easy application, minimal or no toxicity, or side effects and does not need treatment at a hospital set up and relatively low cost for the patients.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
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