Search

Hairy leukoplakia was first described as an oral marker of human immunodeficiency virus infection in 1984. The clinical significance of this lesion in an otherwise healthy, high-risk symptom-free person is that it can be an early manifestation of human immunodeficiency virus infection. Because of its benign nature and the lack of clinical evidence that treatment of the lesion improves the prognosis of human immunodeficiency virus-infected patients, systemic therapy with antiviral drugs does not seem warranted at this time. Topical retinoids (Retin-A sol) and systemic antivirals such as acyclovir have been previously tried; however, lesions tend to recur a few days after treatment is discontinued. Nine patients with oral hairy leukoplakia seen at the Oral Medicine Clinic, University of California San Francisco were offered treatment with podophyllum resin 25% sol. All patients had a complete remission of their condition within 1 week (5 patients) or after the second application a week later (4 patients). Side effects were transient and reversible. These remissions of oral hairy leukoplakia lasted from 2 to 28 weeks, which suggests that podophyllum may be a relatively safe and cost-effective treatment of this otherwise symptom-free lesion.

Findings from a research program in oral cancer at Regional Cancer Centre, Trivandrum, Kerala, India are reviewed. There is evidence of immune impairment in oral cancer patients. Plant lectins are being investigated for specific binding characteristics in various oral precancers and different histological subtypes of oral cancer. Tobacco and alcohol have been identified as the major risk factors for oral cancer. The chemopreventive potential of carotenoids and retinoids have been evaluated in oral leucoplakias. Beta-carotene and vitamin A in heavier doses induced remission of oral leukoplakias in 25%-50% of trial participants who continued with their tobacco and alcohol habits during the trial. The remission could be maintained with lower doses. Less than 20% of our patients with oral cancer were initially seen in localized stages. Various community-oriented programs for prevention of primary and secondary oral cancers are being evaluated. These include antitobacco health education, oral self-examination, and oral examination by trained volunteers. The results of radical radiotherapy and surgical salvage of radiation failure are also discussed. The 5-year disease-free survival rate of 34% is a reflection of the advanced stages of the disease when initially seen. Salvage rates with surgery for radiation failures were encouraging.

There are only a small number of specialized centres that cater for the dental care of the steadily increasing number of HIV-infected individuals. The responsibility will, therefore, be increasingly shared with the dental practitioner who should be knowledgeable on the basic oral management protocols involved in treating these individuals. This article summarizes some essentials of oral health care in HIV-infected individuals.

Over the past few years, beta-carotene has progressively gained ground as a drug chosen in the treatment of oral leukoplakias, thus making it possible to reduce the use of 13-cis-retinoic acid, which was shown by many studies to be highly toxic while beta-carotene has proved to have no significant side effects and hence to be much more suitable in oral premalignancy. In 1989, a phase II study of patients showing oral leukoplakias and treated with beta-carotene (90 mg/day) was begun. A total of 23 patients (aged between 17 and 85) were included in the study and 18 (8 male and 10 female) were evaluated. Eight patients (44.4%) had objective responses (6 complete, 2 partial). Four CR and a PR appeared unexpectedly within 2-7 months after the end of the therapy. The lesions were macroscopically and histologically examined at entry; in the evaluated patients, two types of alterations were found: atypical hyperplasia (16 patients) and dysplasia (2 patients). No signs of significant toxicity were detected; only in 1 patient treatment had to be interrupted for 1 week. The results of this study show the fair efficacy of beta-carotene against oral leukoplakias, but further confirmations through controlled clinical studies are needed.

Leukoplakia is the only important precancerous lesion of the mouth. The epidemiology of oral leukoplakia has been well established in white adults in the United States. There is a hole in the epidemiologic literature, however, on leukoplakia in American minority populations. Recent literature has begun to address the issue of the pathophysiology of leukoplakia, its causes and treatment, and predicting its malignant transformation. Computerized image analysis, retinoid compounds, beta-carotene, and laser surgery are contributing to advances in these lines of research. Though leukoplakia is often seen in patients who use smokeless tobacco products, it is usually benign and reversible if use of the tobacco product is discontinued. The direction of current research in leukoplakia studies eventually should lead to an understanding of the nature and cure of this ubiquitous lesion.

Deficiency of vitamin A and/or its precursors has been associated with increased cancer risk in animals and humans. Therapeutic trials of vitamin A and related compounds have demonstrated activity in several cancerous and precancerous conditions. The authors measured the effects of a retinoid, 13-cis-retinoic acid, and a carotenoid, beta-carotene, on the human immune system in vivo in conjunction with their use in ongoing clinical trials. Immune cell subpopulations were analyzed by quantifying the expression of markers using flow cytometric study. Both compounds produced significant effects on immune cell populations. 13-cis-Retinoic acid resulted in an increase in the percentage of peripheral blood lymphoid cells expressing surface markers for T-helper cells with only minimal effect on natural killer cell marker expression. In contrast, beta-carotene produced an increase in the percentage of cells expressing natural killer cell markers with smaller effect on T-helper markers. Modest increases in the percentage of cells expressing Ia antigen, transferrin, and interleukin-2 receptors were produced by both drugs. These results suggest that retinoids and carotenoids can produce major changes in immune cellular marker expression in vivo in humans at doses relevant to their potential clinical use.

Participants in the intervention trials were fishermen (Kerala, India), who chewed tobacco-containing betel quids daily before and throughout the study period. Frequency of oral leukoplakia, micronuclei in oral mucosal cells, and alterations in nuclear textures were used as endpoints. Administration of vitamin A (60 mg/wk) for 6-mo resulted in complete remission of leukoplakias in 57% and a reduction of micronucleated cells in 96% of tobacco-chewers. beta-carotene (2.2 mmol/wk) induced remission of leukoplakia in 14.8% and reduction of micronucleated cells in 98%. Vitamin A completely suppressed and beta-carotene suppressed by 50% formation of new leukoplakia within the 6-mo trial period. After withdrawal of vitamin A or beta-carotene treatment, oral leukoplakias reappeared, frequency of micronuclei in oral mucosa increased, and nuclear textures reverted to those present before the administration of chemo-preventive agents. The protective effect of the original treatment could be maintained for at least 8 additional months by administration of lower doses of vitamin A or beta-carotene.

Mucosal dysplasia in the head and neck region is recognized to be a precancerous lesion. Between January 1983 and December 1987, a pilot study was conducted at the Manitoba Cancer Treatment and Research Foundation to determine the effects of beta-carotene and cis-retinoic acid on mucosal dysplasias. Eighteen patients were treated with a "cross-over" regimen. The overall response to treatment was 61%, with 33.3% complete responses. Patients who smoked had a significantly better response than nonsmokers. The response rate for 9 of 11 smokers was 81.2%, and 2 of 7 nonsmokers or 28.6% responded to this protocol. The beneficial effect of these drugs should be established by prospective, randomized trial in high risk populations.

The therapy of choice for oral hairy leucoplakia in HIV-infected patients is treatment with acyclovir. During treatment the replication of Epstein-Barr Virus (EBV) in cells scraped from the epithelium of hairy leucoplakia was investigated using filter-in-situ hybridization. On the 2nd day of treatment a slight and on the 5th day a marked reduction of the replication was observed, and on the 8th day of treatment replication of EBV could hardly be detected. At that time a marked regression of leucoplakia was seen. Within another 7 days the lesions had completely disappeared. These findings demonstrate the relationship between treatment with acyclovir and inhibition of EBV replication in hairy leucoplakia and the relationship between inhibition of EBV replication and remission of hairy leucoplakia.

Oral hairy leukoplakia is a new clinicopathological entity. Little is known about its etiology, pathogenesis and natural history. It is considered a specific marker of HIV infection, although it has been also reported in HIV-negative patients. The etiology appears related to Epstein-Barr virus. Hairy leukoplakia has a characteristic clinical and histopathological aspect, but it is not specific. Because hairy leukoplakia may be easily confused with other lesions of the tongue, the dentist should be very careful in making the final diagnosis. Hairy leukoplakia is usually asymptomatic and treatment is not necessary. In cases of extensive lesions or psychological intolerance of the patient, useful drugs are acyclovir and vitamin A derivatives.

Psoriasis is a chronic inflammatory skin disease which very rarely affects the oral mucosa. In the present article, an interesting case of psoriasis with exclusive oral involvement is described. The patient's history, clinical, microscopic features, and HLA typing were consistent with a diagnosis of psoriasis. A review of the 68 reported cases of oral psoriasis is presented in table form.

Nuclear textures of oral mucosal cells were quantitated by image analysis, and their suitability as markers in a chemopreventive trial explored. Subjects were chewers of tobacco-containing betel quids with well established oral leukoplakias. Treatment consisted of a weekly oral administration of vitamin A (200,000 IU/week) for six months. Leukoplakias regressed in 57.1% of the 21 trial participants. The original leukoplakias did not redevelop within four months after termination of treatment. For image analysis, biopsies were taken from leukoplakias of five chewers before administration of vitamin A, at the end of the administration, and four months after termination of treatment. Sections of paraffin-embedded biopsies were stained with the Feulgen reaction and submitted to quantitative image analysis of two parameters: variance of intensity and entropy. Both these parameters were significantly reduced in all five trial participants as a result of the six-month vitamin A treatment. During the post-treatment period, nuclei with condensed chromatin, as measured by the variance of intensity, reappeared in the mucosa of four of the five chewers examined, although no leukoplakias were detectable on visual examination of the oral cavity. The results indicate that the quantitation of nuclear textures in a small subpopulation of a chemopreventive trial could conceivably be a simple marker with a predictive value.

The efficacy of desciclovir, an analog of acyclovir, in eliminating lesions of oral hairy leukoplakia (HL) and suppressing Epstein-Barr virus (EBV) infection was evaluated in a double-blind, placebo-controlled study of 14 patients. Patients were randomized to receive either the active drug, 250 mg three times a day for 14 days, or placebo. In all eight patients receiving desciclovir, lesions of HL were either completely resolved or significantly reduced during the treatment period, whereas lesions in patients receiving placebo showed no change. The histological features of HL were significantly diminished in patients on desciclovir, and cytochemical, in situ hybridization, and ultrastructural studies showed that EBV infection was eliminated or dramatically reduced in the desciclovir group only. Four patients on desciclovir reported side effects, but none required withdrawal from the study. The reappearance of HL in all eight subjects on desciclovir within 1-4 months after therapy was discontinued suggests the need for additional study.

Although epidemiological studies suggest the presence of anticarcinogenic agents in the diet, it is difficult to obtain actual proof for the activity of such agents in humans. One approach is to develop and validate potential quantifiable indicators of antigenotoxic/anticarcinogenic agents which can be used in humans belonging to populations at elevated risk for cancer. This paper provides evidence that the exfoliated cell micronucleus test (MEC test) can be used (i) to provide a quantifiable marker for the amount of chromosomal breakage occurring in target tissues of carcinogen-exposed populations; (ii) to indicate the capacity of beta-carotene, alone or in combination with vitamin A, to prevent such damage; and (iii) to predict the response of other biological indicators of cancer risk, such as oral leukoplakias, in individuals receiving oral supplementation with beta-carotene/vitamin A (although the dose and time to response may differ for these endpoints). Future extensions of this approach include establishing the levels of beta-carotene required for antigenotoxic activity in a carcinogen's target tissue by concurrently measuring MEC frequencies and beta-carotene levels in exfoliated cells. In summary, early indications are that the MEC assay is an effective indicator for antigenotoxic agents in carcinogen-exposed individuals and that beta-carotene and vitamin A can suppress such genotoxic activity in at least some populations.

Vitamin A acid (VAS) has proved itself an effective local therapeutic agent for intra-oral leucoplakia. Clinical remission characterized by a decrease in horny lumps and the eosinophilic index and an increase in intermediary cells was achieved in 32 out of 50 cases. In the course of maintenance therapy development towards an exfoliocytologically healthy mucosa proceeds via increasing parakeratosis. VAS therapy is essentially thought of as symptomatic therapy.

This two phase study was designed to observe the toxicity and effectiveness of retinoids on oral leukoplakia. The study design included patients who had visible and measurable oral leukoplakia without history of synchronous oral cancer or oral cancer within the previous 2 years. Documentation of the lesion by direct measurement and photography, as well as a biopsy at the beginning and at the end of the study (for verification of the histologic appearance of the lesion), were performed in each patient. Sixteen patients with oral leukoplakia were treated with 13-cis-retinoic acid formulated in a troche in the strength of 1 mg. Three patients received 3 mg/day, 8 patients received 5 mg/day, and 5 patients received 10 mg/day. The initial visible responding event appeared to be a thinning of the leukoplakia with reduction in the whitish surface leaving a reddish, velvety epithelium. If resolution occurred, the velvety area became pink, assuming the color and texture of the normal adjacent mucosa. Toxicity of the drug appeared to be acceptable among the evaluable patients. Of the 11 patients, 3 demonstrated complete response and 6 demonstrated partial response after 6 months of treatment with the drug under study. Recurrences developed in two of the three patients with complete response, and neither of the two showed complete histologic and cytologic regression. One of the patients with partial response went on to complete response after cessation of treatment. Under the condition of our study, a treatment effect was observed with small amounts of topical 13-cis-retinoic acid and that the level of toxicity was acceptable.

Oral hairy leukoplakia (HL) is a remarkable lesion associated with Epstein-Barr virus (EBV) found in persons infected with the human immunodeficiency virus. The clinical and histologic features of HL are characteristic and distinctive. However, none of these features are entirely specific for HL, and we consider that the presence of EBV is required for diagnosis in questionable cases. EBV can be demonstrated by means of electron microscopy, immunocytochemistry, or molecular biologic techniques. Therapy directed toward the HL lesion is sometimes indicated; acyclovir is the current drug of preference in such cases.

First clinical experiences with the anti-androgenic drug cyproterone-acetate in treatment of pachydermia laryngis are reported in eleven male and female patients. This endocrine therapy led to complete healing in four and to marked improvement in six patients. One did not respond. Evaluation of the endocrine state of these patients showed imbalance in the androgen/estrogen equilibrium. As the larynx constitutes a secondary sex characteristic and an endocrine target organ, the significance of endocrine factors for pathogenesis and therapy of epithelial changes on the vocal cords is discussed.

Six patients with oral leukoplakia were treated by the daily application of a 0.5 per cent (w/v) solution of bleomycin sulphate in dimethyl sulphoxide. After 12 to 15 applications, the white patch peeled off and the resultant raw surface epithelialised over the following 14 days. Repeat biopsies showed a significant improvement in the histology, with reduced dysplasia and keratinisation.

Activity of acid hydrolases, alkaline phosphatase and leucine aminopeptidase was studied in leukocytes of patients with leukoplakia of mouth mucosa before and after the treatment involving antioxidant drugs. The enzymatic activity studied was increased in leukoplakia. Cryotherapy combined with antioxidants and the treatment with antioxidants only contributed to a decrease in these enzymes activity.

Patients with chronic snuff-induced keratosis associated with mucosal ulcerations were treated with topically applied vitamin A acid. In each case, after a marked, local inflammatory response initially, topical vitamin A acid showed a definite beneficial effect in promoting healing and involution of the precancerous snuff-induced leukoplakic keratosis. In one patient there was distinct involution of the oral lesions with complete healing and restoration of a normal-appearing mucosa within five weeks after beginning of treatment. In four patients there was healing of superficial ulcerations and regression in the size of the luekoplakic lesions.

Viral infections, predominantly those of the herpes virus family, account for up to 16% of all clinically significant infections in AIDS patients. Acyclovir has provided successful treatment in AIDS patients suffering from severe herpes simplex and herpes zoster virus infections. Preliminary results are presented on newly developed acyclovir analogues. Desciclovir, an oral prodrug of acyclovir which is metabolized to acyclovir in vivo, allows treatment of virus infections per os, where high serum levels are needed, e.g. in Epstein-Barr virus infections. BW B759U, another analogue of acyclovir, has been used for the treatment of life-threatening or sight-threatening cytomegalovirus infections in AIDS patients. More than 80% of the patients treated for retinitis experienced stabilization or clinical improvement. Antiviral efficacy was demonstrated in 73% of the patients. Azidothymidine, a nucleoside analogue of thymidine, has been developed specifically to treat the HIV infection. Its antiviral activity is based on inhibition of reverse transcriptase. Phase I studies have demonstrated that azidothymidine is well tolerated. Its ability to cross the blood brain barrier makes it an attractive candidate for treatment of HIV. Trials to determine efficacy are in progress.

Leukoplakia is a clinical diagnosis with the potential for malignant transformation. This pilot study tested the use of bleomycin a as topical agent for the treatment of leukoplakia. Twelve patients were enrolled in this study, each for 2 weeks of daily topical application of bleomycin in dimethylsulphoxide (DMSO) painted over the lesion. Two patients were excluded from analysis due to excessive dilution of the medication by local saliva production. Five patients were treated with a 0.5% solution that caused a decrease in the thickness of all of the lesions clinically. One lesion also had a sharp decrease in size. Five patients were treated with a 1.0% solution that caused a complete resolution of the lesions in three patients. Two lesions demonstrated maturation of parakeratosis to keratosis only. All patients tolerated the treatments well. Topical bleomycin may play a role in the treatment of leukoplakia and warrants further investigation.

Research on retinoid treatment of neoplastic lesions will ultimately determine the long-term effect of these substances on cancer development. However, until specific indications are firmly established through clinical trials, retinoid compounds cannot be routinely recommended.

This report presents a case of oral hairy leukoplakia that has completely disappeared during treatment with azidothymidine. The reason for the resolution of the lesions in this case is not certain, but the outcome may be due to the action of the drug on the agent or agents causing the lesion.

Oral hairy leukoplakia was treated in six patients with (a) acyclovir (i.v. or p.o.), (b) 0.1% vitamin-A acid solution or (c) human beta-interferon-gel (10(5) I.E./g) in a total of 23 therapeutic courses. In 5/6 patients, acyclovir (7.5 mg/kg every 8 h i.v. or 5 x 400 mg p.o. over 5-10 days) led to partial (n = 1) or complete (n = 4) remission. After 1-6 months, however, the leukoplakia recurred in all cases. Vitamin-A acid solution (n = 3) led to remission in one and to improvement in the others. Human beta-interferon gel (n = 3) had no visible effect. The efficacy of acyclovir is further evidence of the concept that the Epstein-Barr virus is a major cause of oral hairy leukoplakia.

Among 11 patients with oral cancer that disappeared after combined treatment with bleomycin and radiotherapy without surgery, one had an early recurrence and three had recurrences after 2 years or more. These late occurring recurrences were microcancers on mucous membranes that were thought to have been cured. Two of the three patients whose tumors recurred and another patient were found to have epithelial dysplasia at 1 year and 2 months, 4 years and 2 months, and 1 year and 3 months later, respectively. Among 59 patients who underwent surgery after the combined treatment, no viable cancer cells were found in the resected specimens of 20 patients, but moderate or severe epithelial dysplasia was noted in ten of the 20 patients. The present findings imply that patients in whom an apparent cure has been brought about by conservative treatment may harbor latent malignancy.