Red and White Lesions
In day-to-day clinical practice oral physicians often encounter a wide spectrum of oromucosal lesions. These lesions range from harmless mucosal alterations like change in the color and texture of the oral mucosa, needing simple therapeutic remedies and patient counseling to lesions of a life-threatening nature. Red and white colored alterations of the oral mucosa are commonly seen in dental practice. Recognizing and differentiating these mucosal alterations from normal anatomic variations is imperative for the effective management of these lesions.
As the oral mucosa is translucent, it reflects the contents of the underlying connective tissues. Normal color of the oral mucosa is pink, the intensity being varied in different parts of the oral cavity and depends upon various factors like,
White lesion is a non-specific term used to describe any abnormal area of the oral mucosa that on clinical examination appears whiter than the surrounding tissue. It is usually slightly raised, roughened or of different texture from the adjacent normal mucosa (e.g. linea alba buccalis, frictional keratosis, leukoplakia, chronic hyperplastic candidiasis etc).
This normal color of the mucosa may turn into white due to the increased thickness of the epithelium with increased production of keratin (hyperkeratosis) and production of abnormal keratins and imbibition of fluid by the upper layers of the mucosa. In situations like coagulation of tissue surface (occurs in burns), results in the formation of white pseudomembrane, which remains attached to the mucosa but can be scraped off easily. Generally white lesions result from various factors like, trauma, infections, immunologic injury to the mucosa or other genetically determined factors.
Red lesion refers to an area of reddened mucosa that may appear smooth and atrophic or exhibits a granular, velvety texture (e.g. erythroplakia, median rhomboid glossitis, erythematous candidiasis, etc). These lesions may occur alone or in combination with a white lesion. Such lesions may be termed as a mixed lesion or a red and white lesion (e.g. speckled leukoplakia, erosive lichen planus, etc). Individual variations in the color of the oral mucosa are probably an expression of one or more genetically controlled factors.
Healthy masticatory mucosa (gingiva, palate, dorsal surface of the tongue) is light pink in color. The lining mucosa (mucosa over the vestibule, cheeks, lips, floor of the mouth, and ventral surface of the tongue) is reddish pink in color. Palatoglossal arch region is dusky red in color due to increased vascularity and often misdiagnosed as sore throat.
Intraoral skin grafts (people of Afro-Asian origin) will not generally exhibit a white coloration of the skin graft. The graft will appear black or brown depending on the extent of melanin pigmentation (Figure 1).
White lesions of the oral cavity can be categorized clinically as keratotic (non-scrapable) or non-keratotic (scrapable) lesions. Table 1 gives a list of scrapable and non-scrapable lesions.
|Keratotic lesions (non-scrapable)||Non-keratotic lesions (scrapable)|
|Linea alba buccalis||Chemical burn/thermal burn|
|Frictional/traumatic keratosis||Pseudomembranous candidiasis|
|Homogeneous leukoplakia||Syphilitic mucous patch|
|Reticular lichen planus||Diphtheritic patch|
|Chronic hyperplastic candidiasis|
|White sponge nevus|
Frictional keratosis is defined a white patch with a rough surface which is clearly related to a source of mechanical irritation and that will disappear over a period of time with the removal of the stimuli. Lesions belonging to this category include linea alba buccalis, and cheek, lip or tongue biting or chewing.
Linea alba buccalis is a non-scrapable white line that is present on the buccal mucosa usually along the plane of occlusion (Figure 2). It may either be seen unilaterally or bilaterally. Linea alba occurs due to the constant friction or irritation of the buccal mucosa by the facial surfaces of teeth. It is more pronounced with respect to the posterior teeth and may have a scalloped architecture. It is asymptomatic and usually does not require any form of management.
Chronic cheek, lip, tongue chewing usually presents as thickened and shredded whitish areas. Habitual oral mucosa chewing can sometimes lead to areas of localized erosion and ulceration. The lesions may present bilaterally or unilaterally.
Individuals with chronic cheek biting (morsicatio buccarum) have either a habit of sucking the cheeks frequently or push the cheek in between teeth with their finger. Similarly individuals with chronic lip chewing habit (morsicatio labiorum) and chronic tongue nibbling habit (morsicatio linguarum) present with macerated appearance of the labial mucosa and lateral surface of the tongue respectively. The lower labial mucosa is usually affected in lip chewers (Figure 3A, B).
Figure 3 (A) Whitish macerated appearance of the upper labial mucosa. (B) Whitish thickened and shredded area on the lower labial mucosa. Courtesy: Department of Oral Medicine and Radiology, MCODS, Mangalore
Habitual chewing may be associated with individuals under stress. However most of the individuals are unaware of the parafunctional habit. The management of these conditions should be targeted at educating the patient regarding the ill-effects of the parafunctional habit.
Chemical burn usually results from the patient applying analgesics like aspirin or acetaminophen or home remedies such as clove oil to the mucosa adjacent to a decayed tooth to alleviate pain. Chemical substances like phenol, silver nitrate, concentrated hydrogen peroxide, root canal medicaments can also produce an area of necrosis.
The clinical appearance of these burns in most cases depends upon the severity of the tissue damage. Chronic mild burn usually produces keratotic white lesion whereas intermediate burn causes localized mucositis and the more severe burns coagulates the surface of the tissue and produces a diffuse white lesion. In such cases the tissue can be scraped off, leaving a raw bleeding painful surface (Figure 5).
Thoma in 1941 was the first to use the term stomatitis nicotine because he noticed this lesion to almost exclusively occur in individuals who had the habit of smoking tobacco. This lesion is a reactive hyperplasia to the heat generated by the tobacco smoke that acts as a chronic irritating agent. These mucosal changes are mostly seen in reverse cigarette/chutta and pipe smokers and relatively lesser in cigar, cigarette and beedi smokers.
Smoker’s palate is usually seen in males. However, in the Indian subcontinent women who have the habit of reverse chutta smoking also exhibit these mucosal changes. It is generally asymptomatic. The palatal mucosa appears as a diffuse grayish white surface or flat topped nodules may be seen with red pinpoint areas situated in the center of each nodule (Figure 6A, B). These red pinpoint areas correspond to the inflamed orifice of the minor salivary gland ducts.
Oral leukoplakia (OL) is the most common precancerous lesion of the oral mucosa. The term leukoplakia was first used by Schwimmer in 1877 to describe a white lesion on the dorsum of the tongue, which probably represented syphilitic glossitis. He proposed the term ‘leukoplakia’ for a diffuse patch on the dorsum of tongue. Since then it has evolved as a clinicopathologic concept over many years; sometimes representing an innocent hyperkeratosis and sometimes dysplastic features.
The requirement for a clear definition for oral white lesions has long been recognized. Similar requirements also apply to red lesions or the red component of preponderantly white lesions. The definition of leukoplakia has often been confusing and controversial. Currently the WHO definition and definition given by Axell are widely used. Auluck et al conducted a survey in 10 different dental colleges in India among 153 specialists including oral surgeons, oral physicians and oral pathologists to check the prevalence of confusion regarding the definition of leukoplakia and its application. It was found that 33.33% of the specialists preferred to follow WHO definition (1978), while 65.35% preferred to follow Axell (1984) definition. The authors described the current ambiguity regarding the accepted definition of oral leukoplakia and emphasized the need for an international collaboration to reach a consensus on the use of the term leukoplakia.
Leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease. The definition indicates that the term leukoplakia does not carry a histologic connotation and should be used only in descriptive clinical context.
Leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease and not associated with any physical or chemical causative agent except the use of tobacco.
Leukoplakia as a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion; some oral leukoplakia will transform into cancer. This definition is most widely accepted in the western world.
The frequency of leukoplakia is highly variable among geographical areas and demographic groups. The prevalence in the general population varies from less than 1 to more than 5%. The prevalence of leukoplakia increases to 8% in men over the age of 70 and the prevalence in women past the age of 70 is approximately 2%.
Mehta et al (1961) reported the prevalence of 3.5% in 4,734 Indian population. Manghi et al (1965) reported a prevalence of 6.5% among 2,004 persons. Smith et al (1975) reported a prevalence of 11.7% among 57,518 persons. Yang et al (2001) reported the prevalence of leukoplakia as 24.4% among the aborigines in southern Taiwan. Chang et al (2005) reported the prevalence of 7.44%. In a 10-year follow-up study, a random sample of 30,000 villagers in three areas in India, the annual incidence rates varied from 1.1 to 2.4 per 1,000 men and 0.03 to 1.3 per 1,000 women.
Table 2 gives the overall impression of the prevalence of oral leukoplakia with a geographic emphasis.
Van der Waal (2000) designed and proposed the classification and staging system. The present classification and staging system is primarily designed for the purpose of uniform reporting of treatment or management results and requires the availability of a biopsy report. It also could serve as means for epidemiological studies.
|Stage III||L3P0 or L1L2P1|
1. If there is doubt concerning the correct L or P category to which a particular case should be allotted, then the lower (i.e. less advanced) category should be chosen. This will also be reflected in the stage grouping.
Some leukoplakias have a white verrucous texture being referred to as verrucous leukoplakia. In the majority of these cases no epithelial dysplasia is present. Yet, such lesions may easily recur (‘proliferative verrucous leukoplakia’) after conservative treatment and may finally lead to the development of a squamous cell carcinoma.
Use of tobacco in the form of factory-made cigarettes, beedi, cigars and cheroots and powdered tobacco in pipes or rolled into hand-made cigarettes, are the main etiological agents in the causation of leukoplakia.
Much of the tobacco in the world is consumed in the form of smokeless tobacco and it is placed in contact with the mucous membrane. In south-east Asian countries tobacco is mostly consumed mixed with other ingredients like areca nut, betel leaf, slaked lime, catechu and condiments.
Smokeless tobacco use is practiced in many forms. Chewing of tobacco containing products or snuff dipping habits vary greatly from one part of the world to another. It is of great importance to quantify the degree of exposure.
Over 300 carcinogens have been identified in tobacco smoke or in its water-soluble components which can be expected to leach into saliva. The major and most studied among them include aromatic hydrocarbons, benzopyrene and the tobacco specific nitrosamines, N-nitrosonornicotine (NNN), nitrosopyrrolidine (NYPR), nitrosodimethylamine (NDMA) and 4-(methylnitrosamine)-1-(3-pyridyl)-1-buta-none (NNK). Benzopyrene is a powerful carcinogen and is found in amounts of 20–40 mg per cigarette. The mainstream smokes of a cigarette contain 310 mg of NNN and 150 ng of NNK. These agents act locally on keratinocytes, stem cells, and are absorbed and act in many other tissues in the body.
Cigarettes can be classified as low or medium, if the tar yield is below 22 mg and as high if tar yield above 22 mg compared with non-smokers the risk of oral cancer and OL for smokers using low to medium tar cigarettes is 8.5%.
A case control study from Brazil also found an increased risk among cigarette or pipe smokers with a strong doseresponse relationship between the number of years smoked and oral cancer risk (Franco et al, 1989).
Snuff involves placing moistened, powdered tobacco, treated with natron (sodium sesquicarbonate) in the lower labial, buccal sulcus or the floor of the mouth against the lingual side of the mandible. Snuff has been shown to contain carcinogens such as N-nitrosamines which are derived from tobacco.
Alcohol has also been emerged as a significant risk factor for OL. In Germany, Wilsch et al (1978) found that alcohol consumption was greater among people with leukoplakia as compared to control. In India Gupta et al (1984) studied alcohol habits of over 7,000 individuals with tobacco habits and found that 31% consumed alcohol regularly, 25% occasionally and 44% did not consume alcohol at all. The prevalence of OL was higher among regular and occasional (3.9%) alcohol drinkers than among non-drinkers (2.9%).
Although alcohol by itself not an important risk factor for leukoplakia, it might produce synergetic effects when combined with the habit of chewing tobacco or smoking. Alcohol causes dehydration of the oral mucosa and increases the ambient temperature of the oral cavity thereby making the oral mucosa more vulnerable to the carcinogenic effects of tobacco. Alcohol by itself contains known carcinogens such as hydrocarbons and nitrosamines. It also causes liver induced cellular changes in target tissues (increased acetaldehyde content).
The possible implication of human papilloma virus in the etiology and potential for malignant transformation of oral premalignant lesion has been studied extensively and it was reported that the likelihood of detecting HPV was 2–3 times higher in precancerous oral mucosa and 4–5 times higher in oral squamous cell carcinoma than in normal oral epithelium.
High prevalence of HPV in PVL had been found by Maitland et al (1987) who found an overall rate of 42% using probes specific for HPV 16. The differences in detection of HPV may be accounted for different sensitiveness of methods used. D’costa et al (1998) in their study detected HPV 16 in 34% of the potentially malignant lesions and Mao et al (1996) in 36% of precancerous lesions. In oral cavity HPV 16 has been demonstrated in both homogeneous leukoplakia and in verrucous leukoplakia (Loning, 1985; De Villers, 1986; Milde, 1986; Syrjanen, 1988 and Kashima et al, 1990).
Studies by Nielsen et al (1996) in the prevalence of HPV in oral premalignant lesions found an overall rate of HPV positive lesions to be 40.8% of which five of them were HPV 16. Elamin et al (1998) suggested that the prevalence of HPV infection is higher in oral lesions from India. The high prevalence of HPV infection in oral premalignant cases indicates that HPV infection would be an early event in the process of malignant transformation of oral epithelial cells.
Albert et al (1992) reported an OL prevalence of 6.2% among diabetics as compared to 2.2% in a control group. However the analysis did not adjust for age and gender. Diabetes mellitus leads to a number of metabolic and immunologic changes that affect the oral mucosa and it is associated with a variety of oral conditions (Ponte et al, 2001). Thomas et al (2004) have found a significant association between diabetes mellitus and OL prevalence.
According to weighted model, diabetics were three times more likely to have OL than non-diabetics. However no association between diabetes and the incidence of oral squamous cell carcinoma has been described previously. Therefore the significance of the apparent association between diabetes and OL is unclear.
There is a longstanding discussion whether Candida infection is a cause of leukoplakia or if it is a superimposed infection in a pre-existing lesion. It has been shown that, upon treatment, non-homogeneous Candida-infected leukoplakias convert into a homogeneous lesion, and some lesions even regressed.
Ramaswamy et al (1996) have shown that serum vitamins A, B12, C, E, beta-carotene and foliate were decreased in leukoplakic patients as compared to controls. Many other studies supporting the protective effects of carotinoids and vitamin A, C and E have been reviewed by Enwon et al (1995) and Garewell et al (1999).
Only a very few studies have reported a positive association between estrogens and oral leukoplakia. Hashibe et al (2000) reported an inverse relationship between body mass index (BMI) and OL prevalence in a large population in India. The authors hypothesize that higher estrogen levels in people with higher BMI may explain this relationship. Kushlinskill et al (1988) have demonstrated estrogen receptors in oral squamous cell carcinoma and OL. Thomas et al (2004) recently have demonstrated a strong protective effect of estrogen use on OL prevalence in women. In their study there was no case of OL among women who were using estrogen.
1. Leukoplakia is seen most frequently in middle-aged and older individuals. Sex distribution is also variable. Men are more affected in some countries, while this is not the case in the western world. Less than 1% of men below the age of 30 have leukoplakia. The male-to-female ratio is reported to be about 3:1 to 6:1.
3. Leukoplakia may appear on any site of the oral cavity, the most common sites being: buccal mucosa, alveolar mucosa, floor of the mouth, lateral border of tongue, lips and palate, however the lesions in the floor of the mouth, lateral border of the tongue and lower lip are most likely to show dysplastic or malignant changes. By far the most affected oral sites are the commissures (Figure 7) and the buccal mucosa (Figure 8) showing 60–90% of the leukoplakia. Next are the lip (3.7%), the alveolar ridge (3.0%) (Figure 9), the tongue (1.4%), floor of the mouth (1.3%), vestibular mucosa (1.1%) (Figure 10) and the palate (0.9%).
4. Early or thin leukoplakia appears as a slightly elevated grayish-white plaque that may be either well defined or may gradually blend into the surrounding normal mucosa (Figure 11). As the lesion progresses, it becomes thicker and whiter, sometimes developing a leathery appearance with surface fissures. Some leukoplakias develop surface irregularities and are referred to as granular or nodular leukoplakias. Other lesions develop a papillary surface and are known as verrucous or verruciform leukoplakia.
Homogeneous leukoplakia is defined as a predominantly white lesion of uniform flat and thin appearance that may exhibit shallow cracks and that has a smooth, wrinkled or corrugated surface with a consistent texture throughout (Figure 12). This type is usually asymptomatic.
Non-homogeneous leukoplakia has been defined as a predominant white or white-and-red lesion (erythroleukoplakia) (Figure 13) that may be either irregularly flat, nodular (speckled leukoplakia) or exophytic (exophytic or verrucous leukoplakia). These types of leukoplakia are often associated with mild complaints of localized pain or discomfort. Proliferative verrucous leukoplakia is an aggressive type of leukoplakia that almost invariably develops into malignancy. This type is characterized by widespread and multifocal appearance, often in patients without known risk factors. In general, non-homogeneous leukoplakia has a higher malignant transformation risk, but oral carcinoma can develop from any leukoplakia.
Leukoplakia is an example for precancerous lesion. The frequency of dysplastic or malignant alterations in oral leukoplakia has ranged from 15.6 to 39.2% in several studies. Although leukoplakia is more common in men than women, several studies have shown that women with leukoplakia have a higher risk of developing carcinoma.
A wide range of rates for the malignant transformation of leukoplakia has been reported from 0.13 to 19.8% but it is estimated that the annual transformation rate should not exceed 1%. Up to 10% of leukoplakia may be malignant at the time of initial examination. The potential for malignancy appears higher in certain risk sites like floor of the mouth and ventral surface of the tongue, where the lesion is associated with Candida species, or where the lesion is verrucous or mixed with red lesions (erythroleukoplakia or speckled leukoplakia).
Cawson (1966), Einhorn and Wersall (1967) and Banoczy (1977) inferred that certain features of leukoplakia have been reported to be associated with an increased risk of malignant transformation. These are:
In a study conducted by Gupta et al, 12,212 tobacco users were followed up annually to assess the malignant potential of precancerous lesions in Ernakulam district in Kerala, India. They observed that out of a total of 19 new oral cancers over period of 8 years, 15 (79%) originated from leukoplakia.
The location of oral leukoplakia has a significant correlation with the frequency of finding dysplastic or malignant changes at biopsy. In the study by Waldron and Shafer (1975), the floor of the mouth was the highest risk site, with 42.9% of leukoplakias showing some degree of epithelial dysplasia, carcinoma in situ, or unsuspected invasive squamous cell carcinoma. The tongue and lips were also identified as high risk sites, with dysplasia or carcinoma present in 24.2% and 24% respectively.
The study by Silverman and colleagues (1984) showed an overall malignant transformation of 17.5%. In their study only 6.5% of homogeneous leukoplakia underwent malignant change, however, 23.4% of speckled leukoplakia and 36.4% of leukoplakias with microscopic evidence of dysplastic changes transferred into cancer.
Among the different clinical varieties of leukoplakias, proliferative verrucous leukoplakia has got highest risk of malignancy. In a follow-up study of 54 cases of proliferative verrucous leukoplakia, Silverman and Gorsky found that 70.3% of the patients subsequently developed squamous cell carcinoma.
Holmstrup and Besserman (1983) and Silverman (1990) inferred that proper use of antifungal therapy might result in a shift from high risk nodular or speckled leukoplakia to low risk homogeneous leukoplakia. Hernandez et al (2003) have suggested that in patients who display oral premalignant conditions like leukoplakia, immunosuppression must be considered as an important risk factor for oral cancer.
Although an experienced oral physician may be able to diagnose and manage majority of the leukoplakias, it is always prudent to follow a systematic investigative protocol to diagnose leukoplakia. The investigative procedures includes the following:
Toluidine blue staining: Toluidine blue clinically stains malignant lesions, but not normal mucosa. In vivo, the dye may be taken up by the nuclei of malignant cells manifesting increased DNA synthesis. Toluidine blue also serves as a guide to biopsy by localizing tumor cells within the area of the lesion. Toluidine bluestaining uses a 1% aqueous solution of the dye that is decolorized with 1% acetic acid. The dye binds to dysplastic and malignant epithelial cells with a high degree of accuracy (Figure 14).
Cytobrush technique: This technique is more accurate than any other cytologic technique used in the oral cavity. The cytobrush technique uses a brush with firm bristles that obtains individual cells from the full thickness of the epithelium.
Biopsy: When a suspicious lesion is identified, an incisional biopsy using a scalpel or a biopsy forceps is recommended. When the lesion is very small excisional biopsy is performed as an investigative procedure and as a treatment modality.
In homogeneous leukoplakia, the value of histological examination to some extent is questioned. The occurrence of epithelial dysplasia is rather low in this type as is the risk of future malignant transformation. However, even the experienced clinician will occasionally be surprised by the histopathological findings of a clinically innocent looking homogeneous leukoplakia. Therefore a biopsy should be performed in homogeneous leukoplakia. In non-homogeneous leukoplakia, i.e. usually symptomatic, epithelial dysplasia or even carcinoma in situ or early squamous cell carcinoma is rather common. The biopsy should be taken at the site of symptoms, if present, and or a site of redness or induration. Biopsies of exophytic, verrucous or papillary lesions should be taken deep enough to include a sufficient amount of underlying connective tissue, and preferably from the margins.
This lesion represents various degrees of epithelial dysplasias. Some lesions exhibit carcinoma in situ with top to bottom basilar hyperplasia, loss of polarity, increased mitosis, hyperchromatism, dyskaryosis and alteration in nuclear cytoplasmic ratio without any evidence of thickening of epithelial layer or without any evidence of disturbance of keratinization process (Figure 15).
The frequency of epithelial dysplasia in leukoplakia varies between less than 1% and more than 30%. The presence of epithelial dysplasia is generally accepted as one of the most important predictors of malignant development in premalignant lesions.
Markers of proliferation in leukoplakia: There are markers for determining future cancer development in oral premalignant lesions. These markers are divided into genomic markers and differentiation markers. The genomic markers include DNA aneuploidy, loss of heterozygosity and changes in expression of oncogenes and tumor suppressor genes (p53), whereas the proliferative markers include keratins and carbohydrate antigens.
As a standard rule all possible agents leading to white keratotic lesions should be eliminated such as sharp teeth, candidal infection, etc. so as to rule out other definable lesions. In persisting lesions or in the absence of possible causative factors, a biopsy should be taken to exclude histologically the presence of a definable lesion and to establish the degree of epithelial dysplasia, if present or even the presence of carcinoma or carcinoma in situ.
Up to 60% of leukoplakias regress or totally disappear if tobacco use is stopped. OL induced by smokeless tobacco may resolve if the habit is stopped. Some candidal leukoplakias respond, at least partially to antifungal drugs (smoking should also be stopped) and dysplasia may regress.
Some carotinoids have antioxidant or anticarcinogenic activities and can block genotoxic activity of oral carcinogens. Retinoids are the synthetic and natural analogs of vitamin A. There are naturally occurring retinoid, including retinol, retinal, retinoic acid and their metabolites.
Beta-carotene is a natural precursor of vitamin A. More recently etretinate 13-cis retinoic acid and other retinoid have been successfully used for the treatment of oral leukoplakia. Exactly how retinoids may act to inhibit carcinogenesis is unclear, although some retinoids may enhance anti-tumor immune responses. Retinoids have a pronounced and essential effect on cell differentiation. Retinoids may have an effect by their interaction with growth control mechanisms such as transforming growth factors and also possibly by acting on tumor suppressors either directly or via an interaction with transforming growth factors. Retinoids may inhibit the transformation mediated by papillomaviruses. Oral leukoplakias have been treated with a range of retinoids and carotinoids. Leukoplakias have been successfully treated with systemic 13-cis retinoic acid.
Mulay and Urbach (1958) was the first to use vitamin A therapy for topical therapy of oral leukoplakia. Smith (1962) administered 75,000–300,000 IU of vitamin A daily for a period of 3–18 months. Seventy two percent of hyperkeratosis lesions, 25% of massively keratotic and ulcerative forms of leukoplakia improved but the dyskeratotic forms were unresponsive. However signs of hypervitaminosis were not observed. Silverman et al (1965) reported that short-term large dose treatment with vitamin A (300,000–900,000 IU daily) leads to the improvement of leukoplakia.
13-cis retinoic acid (CRA) at 1.5 mg/kg per day for 3 months followed by 0.5 mg/kg daily for 9 months resulted in an initial 55% beneficial response followed by maintenance of effect in 92% of cases. Kaugars and Silverman (1995) in a study of 10 patients with leukoplakia using 50 mg of 13-CRA per day for 3 months showed a 50% reduction in the clinical size of the lesions in three patients. Treatment of three patients was discontinued because of elevated serum triglyceride levels or headache.
Many authors have proposed that beta-carotene supplementation can be used for the treatment of leukoplakia with minimal side effects. Beta-carotene alone in a dose of 30 mg daily for 3–6 months also produced a 71% response rate in 24 patients with oral leukoplakias, with no significant toxicity (Garewall et al, 1991). The same workers have used beta-carotene 60 mg daily for 6 months and report similar benefit (Garewall et al, 1992). Others have found beta-carotene 90 mg daily to produce benefit in 44% after three cycles of use of 3 months each.
Fenretinide (synthetic retinoid) 200 mg daily used for 1 year reduced the relapses and appearance of new oral leukoplakias, compared with controls, with few adverse effects in 39 patients having previously had leukoplakias surgically excised.
Vitamin E has synergistic inhibitory activity against carcinogenesis in animal models and may have some beneficial effect in man. Many studies, using vitamin E in oral leukoplakias showed a beneficial clinical response in 46% of 43 patients by 24 weeks, and a histo-logical response with no serious adverse effects. Another study showed a significant decrease in oral leukoplakia after combined treatment with vitamin E, retinol and (β-carotene (Zaridze et al, 1993). Vitamin E therefore shows promise in the control of leukoplakias.
A combined parenteral and locally applied treatment modality in the form of photodynamic therapy (PDT) using hematoporphyrins has been found to be effective in animal models and has been used to treat head and neck cancers and premalignant lesions in man. PDT was first used in 1990, when acridine and light were combined to kill paramecia and the first oncologic use of PDT was in 1903, when eosin and light were employed in the treatment of skin cancer. PDT involves using specific wavelength of laser light to activate a photosensitizing drug which is administered systemically and is retained selectively in the lesion and this triggers a cold photochemical reaction resulting in the generation of reactive products such as singlet oxygen that damages tissue. Advantages of this type of treatment as reported by Sciubba (1995) includes inactivation of clinically subtle or undetectable alteration, sparing of normal tissue, minimal morbidity and its use as an adjunctive tool to more traditional modalities. However it was pointed out that the major disadvantage of PDT is the cutaneous photosensitivity which can persist for several months after administration of the photosensitizer which can be a major problem in the Indian subcontinent, where oral cancer is most common.
Topical treatment of leukoplakia with podophyllin solution (Kovacs et al, 1962) or bleomycin (Hammersley et al, 1985; Malmstrom, 1988; Wong et al, 1989) has induced some regression or even total resolution of dysplasia and of clinical lesions. Hayasaki et al (1977) described the use of bleomycin with iontophoresis in the treatment of cancer, leukoplakia and papillomas of the head and neck region. Their results showed that this method of application was not effective for malignant lesions but was effective at removing leukoplakia of the oral mucosa.
Patients with head and neck cancer including oral cancer are more susceptible to chromosome damage when their cells are exposed to mutagens (Schantz et al, 1990) and there are a number of genetic changes now described in oral carcinoma (Scully et al, 1993). Synthetic antisense oligonucleotides complementary to the start codons of human papilloma virus (HPV) type 18 E6 and E7 genes can significantly inhibit growth in vitro of oral carcinoma cell lines (Steele et al, 1992, 1993).
Even though laboratory and animal data for the use of gene therapy is very incomplete, many investigators have begun clinical trials in human patients. Tests of several types of gene therapy have begun in various types of cancer, and for oral cancer; the trials include the testing of recombinant p53, the expression of suicide genes and the use of conditionally competent adenoviruses. Since the scientific basis for these trials is rather weak, it can hardly be expected that impressive results are imminent. There are as yet no trials in oral potentially malignant lesions aimed at correcting genetic changes or enhancing the immune response by gene therapy; indeed the whole field of gene therapy has been publicly criticized for its rush to clinical experiments, when the basic studies are still incomplete.
Tea, the dried leaves of the plant ‘Camellia sinensis’ is a popular beverage consumed worldwide. The pharmacological actions of green tea includes; antiinflammatory action, antioxidant action and anticancer action. Tea acts as an inhibitor of initiation of carcinogenesis in the following ways:
These reports strongly point toward antimutagenic activity of green tea. The gallated flavonoids (especially gallated EGCG and the aflavins) act Khafif et al (1998) reported that green tea extract has been shown to have a chemopreventive or inhibitory role in the treatment of oral leukoplak/>