Precancers of the Head & Neck

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Proliferative Verruc. Leukoplakia
Smokeless Tobacco Keratosis
Lichen  Planus
Submucous Fibrosis
Recurring Melanotic Macule

Proliferative verrucous leukoplakia under tongue has areas of erythroleukoplakia, thin, thick and granular
(verruciform) leukoplakia.

An Overview of Precancers

Today a variety of oral precancers are successfully evaluated and managed as a routine facet of oral health care, despite the inevitable controversies and differing definitions. Each of these has its own level of risk (Table 1) and because of the potentially fatal consequences it is extremely important for each clinician to remain knowledgeable and updated on the diagnostic and prognostic features of all premalignancies of the head and neck region. It is especially important to remember that a premalignancy is not guaranteed to eventually transform into cancer, as was believed in the not too distant past. Many, in fact, only do so in a small proportion of cases. This means that the clinician may have to make some very real choices relative to the management of such lesions as leukoplakia, erythroplakia, smokeless tobacco keratosis and lichen planus, and it means that the best choice may not be complete surgical removal, but rather a good, rational follow-up protocol.

A logical review of any controversial issue must begin with a number of definitions. Fortunately, the World Health Organization (WHO) has provided simple but workable definitions of oral precancerous conditions and lesions. The following variations of the WHO definitions are recommended for use with oral precancers:

Precancerous Lesion (Precancer, Premalignancy) -- A benign, morphologically altered tissue which has a greater than normal risk of containing a microscopic focus of cancer at diagnosis or of transforming into a malignancy after diagnosis.

Precancerous Condition -- A disease or patient habit which does not necessarily alter the clinical appearance of local tissue but is known to have a greater than normal risk of precancer or cancer development.

Malignant Potential -- The risk of cancer being present in a precancerous lesion or condition, either at the time of initial diagnosis or at a future date. The potential for mucosa without precancerous lesions or conditions is termed "normal".

Leukoplakia -- A chronic white mucosal macule which cannot be scraped off, cannot be given another specific diagnostic name, and does not typically disappear with removal of known etiologic factors.

Erythroplakia -- A chronic red mucosal macule which cannot be given another specific diagnostic name and cannot be attributed to traumatic, vascular or inflammatory causes.

Smokeless Tobacco Keratosis -- A chronic white or gray/translucent mucosal macule, in an area of smokeless tobacco (ST) contact, which cannot be scraped off and disappears with cessation of the ST habit.

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Oral leukoplakia is well established as one of the very best examples of premalignancy in man and the management of such lesions is now a routine facet of the practice of dentistry.  The precancerous nature of leukoplakia was initially suspected because a large number were found in close proximity to mucosal carcinomas, especially in arsenic-treated syphilis patients. Later investigation found dysplastic and/or microinvasive epithelium in 17-25% of leukoplakia biopsy samples. But true premalignancy was not proven until large numbers of leukoplakias were followed for long periods of time. For half a century now rates of malignant transformation have been available from numerous follow-up studies.

Such studies have not only proven premalignancy, but have helped us to recognize that certain clinical features of leukoplakia can be strong predictors of future risk, stronger predictors than much more sophisticated contemporary laboratory tests. Inconsistencies in the design and reporting of clinical investigations have, unfortunately, resulted in such a wide variance in transformation rates that it is difficult to know which to accept. Basic disease characteristics such as lesion size, duration, multiplicity, etiologic factors, etc. have been largely ignored, and only recently has a precancer staging system been proposed which can assure uniformity between future follow-up investigations. Until such a system is in effect, however, it is inappropriate to do more than suggest a range of malignant transformation rates. Table 1 indicates that this range varies from 3-20%, but specific leukoplakia subtypes, to be mentioned later, have been associated with rates as high as 40%.

It should be emphasized that leukoplakia is not only the most common oral precancer, representing 85% of such lesions, but it is also the most common of all chronic lesions of the oral mucosa, affecting 3% of white adults. As only one leukoplakia in four is ever biopsied, as biopsy sites are determined by clinical evaluation, and as follow-up consists predominantly of clinical examination, it is incumbent upon every dental practitioner to be familiar with its clinical features.

The World Health Organization has provided a clinical definition which is now generally accepted for oral leukoplakia: a keratotic white plaque that cannot be scraped off, cannot be given another specific diagnostic name and has no known etiology except tobacco use.  Leukoplakia, then, is a clinical diagnosis which has the unusual attribute of being dependent not so much on definable appearances as on the exclusion of other lesions which present as oral white plaques. Such lesions as lichen planus, chronic cheek bite, frictional keratosis, tobacco pouch keratosis, nicotine palatinus, leukoedema, white sponge nevus, etc. must be ruled out before a diagnosis of leukoplakia can be made.

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. The average duration at diagnosis is 2.4 years. Carcinomas arising from leukoplakias usually occur 2-4 years after the onset of the white plaque, but may occur decades later. Transformation does not appear to be dependent on the age of the affected patient.

Leukoplakias begin as thin gray or gray/white plaques which may appear somewhat translucent, are sometimes fissured or wrinkled, and are typically soft and flat. They usually have sharply demarcated borders but occasionally blend gradually into normal mucosa. This early stage is sometimes referred to as preleukoplakia, but is preferably designated thin leukoplakia. Thin leukoplakia may disappear or continue unchanged, but as time progresses as many as 2/3 of such plaques extend slowly laterally and acquire a distinctly white appearance from a thickening keratin layer.  They may become leathery to palpation and fissures may deepen, but there should be only a few, if any, localized nodules or surface projections if they are to be given the next most "severe" diagnosis: homogeneous or thick, smooth, perhaps fissured leukoplakia. Most of these lesions remain indefinitely in this phase but some, perhaps as many as one-third, regress or disappear and a few become even more severe.

The latter lesions begin to develop surface irregularities of a nodular or granular nature, hence are referred to as granular or nodular leukoplakia. Occasionally, pointed projections develop on the surface and may be so numerous that the resulting lesions are called verruciform leukoplakia. Both types have a similar prognosis. It should be mentioned, furthermore, that hairy leukoplakia, seen on the lateral tongues and buccal commissures of HIV infected patients, is a distinctive, rapid-onset, nonpremalignant keratosis with similarities to verruciform leukoplakia, but is not a true leukoplakia. It is, rather, a keratin hyperplasia presumably induced by the Epstein-Barr virus and is perhaps better termed "oral HIV keratosis."

The thick or homogeneous leukoplakias may become dysplastic, even invasive, with no change whatsoever in the clinical appearance.  An additional surface change can occur over time, however. Multiple circular or oval patches of nonblanching redness or erythroplakia begin appearing in scattered areas. Such areas presumably represent sites in which epithelial cells are so immature that they are no longer able to produce keratin. These intermixed red-and-white lesions, called erythroleukoplakia, speckled leukoplakia, or nonhomogeneous leukoplakia, are the most worrisome form of the disease and carry an extremely high risk of malignant transformation. Their multiplicity, moreover, is strong support for the multicentric-origin theory of cancer, a theory which originated from studies of oral carcinomas. It has been demonstrated, incidentally, that oral cancers associated with leukoplakia have a better prognosis than those which arise without juxtapositioned leukoplakia, regardless of the clinical type at the time of diagnosis.

Oral leukoplakia is a predominantly male disease, except in regional populations in which women use tobacco products more than men. In the United States a slight decrease has been noted in this male predilection: 74% of affected persons were males in 1935, compared to 69% in 1988. This decrease is a welcome change, as leukoplakias in males have a much higher risk of dysplasia or malignant transformation than similar lesions in females. Overall, the disease is more frequently diagnosed now than in 1935, but this is probably because of enhanced awareness rather than because of a real increase in incidence.

This precancer usually affects persons over 40 years of age. Prevalence increases rapidly with age, especially for males. While fewer than 1% of males prior to 30 years of age have lesions, an alarming 8% of males beyond 70 years of age are affected. This may have grave implications for the practice of dentistry as the U.S. population ages. The average age of affected persons, 60 years, is similar to the average age for oral cancer patients, although some studies have found it to occur about five years earlier than cancer.

The etiology of leukoplakia remains unknown. Many physical agents have been proposed, including tobacco, alcohol, chronic friction, electrogalvanic reaction between unlike restorative metals, and ultraviolet radiation. Tobacco smoking is by far the most accepted factor, although obvious smoke-related keratotic changes such as nicotine palatinus (smoker's palate) are legitimately excluded from the diagnosis of leukoplakia. The cancer risk in nicotine palatinus is so low, surprisingly, that it appears to be nonexistent and most authorities no longer consider it to be a precancerous lesion except in persons who practice reverse-smoking (smoking with the lit end of a cigar or cigarette in the mouth). Clinical changes in this lesion appear to be largely related to thermal irritation and disappear within a few weeks of habit cessation.

The evidence for a tobacco smoking etiology for leukoplakia, however, is quite strong. Not only do 70-90% of leukoplakia patients have such a habit, but 78% of lesions either completely disappear (58%) or regress within 12 months after smoking cessation. Ironically, leukoplakias remaining after habit cessation or in persons who have never smoked may have a higher risk of malignant transformation than leukoplakias in smokers.

Ultraviolet radiation is another accepted etiologic factor for leukoplakia but only for those associated with actinic cheilitis or "farmer's lip." Significantly, two-thirds of all lip vermilion carcinomas are associated with leukoplakia. This is the strongest association for any cancer of the upper aerodigestive tract. Chronic mechanical irritation is no longer considered important to the production of precancerous leukoplakia. Such obvious traumatic lesions as linea alba and chronic cheek bite have never been reported to have transformed into malignancies. White lesions produced by mechanical irritation are best considered as frictional keratoses, which have no potential for malignant transformation.

Microorganisms have been implicated in leukoplakia etiology for more than a century, beginning with the classic dorsal leukoplakia of syphilitic glossitis. Today tertiary syphilis is rare, but a fungus, Candida albicans, is ubiquitous and is so often found in thick or homogeneous lesions that the terms candida epithelial hyperplasia and candida leukoplakia are commonly used to describe them. It is not known whether this yeast produces dysplasia or secondarily infects previously altered epithelium, but some leukoplakias have disappeared or become altered to a lower risk level after topical antifungal therapy.

Recently developed molecular biology and virology techniques have allowed investigators, for the first time, to identify human papillomavirus in leukoplakia and oral cancer.  Detection rates are similar to normal oral epithelium, however, and such techniques have not yet been applied to large numbers of followed patients. It is, nevertheless, very significant that HPV type 16, a type demonstrated in oral leukoplakias and carcinomas, has been shown to induce dysplasia in squamous epithelium in an otherwise sterile in vitro environment.

Conservative surgical excision remains the treatment of choice for small leukoplakias. Electrocautery, cryosurgery and laser ablation appear to be equally effective, although thermal excision tends to hinder a pathologist's ability to evaluate extension and degree of dysplasia. The key is long-term follow-up after removal, because recurrences are frequent and additional leukoplakias occur. Clinical evaluation every six months is recommended, every 2-3 months for high risk lesions. Treatment sites remaining disease free for three years need no longer be followed, but any patient with residual leukoplakia should be followed for a lifetime. Multiple biopsies of high risk areas of large, multiple, or recurrent lesions are essential and should be followed by removal of all dysplastic tissue identified. Even moderate epithelial dysplasias should be removed, as recent research from laryngeal keratosis has identified a significant risk of malignant transformation.

More Detail about Leukoplakia Top of This Page

 Proliferative Verrucous Leukoplakia

Proliferative verrucous leukoplakia (PVL) is a very special form of oral precancer. First described under that title in 1985, it is a white mucosal plaque or discoloration which virtually always develops nodular, papillary or verruciform surface projections and which gradually, sometimes rapidly, spreads laterally to encompass a large mucosal area. On an average, 2.6 mucosal sites are affected. Four of every five affected patients are female and the mean age at diagnosis is 62 years (range: 22-89 years). The usual site of female involvement is the buccal mucosa (63% of cases), while the tongue is most frequently affected in men (82% of cases).

Etiologic factors are elusive. Two-thirds of patients do not have a tobacco habit, but there are especially strong associations with human papillomavirus (89%) and candida albicans (50%), a feature which is discussed below in the microbiology section of this paper.

At initial diagnosis, almost half of PVL samples will demonstrate epithelial dysplasia, and few cases are spared this change eventually. More than 70% of affected patients will develop an oral carcinoma during the decade following PVL diagnosis. Thus far no better treatment has been identified than aggressive and frequent surgical interventions and very close follow-up.

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Erythroplakia is a clinical term for a chronic red mucosal macule which, like leukoplakia, cannot be given another specific diagnostic name and cannot be attributed to traumatic, vascular or inflammatory causes. Such lesions are less common than white precancers but very careful observation will reveal erythroplakia in association with a many early invasive oral carcinomas. Erythroplakia may also be associated with leukoplakia (erythroleukoplakia), and in mixed red and white lesions it is the red portion that is more worrisome than the white. Most cases of erythroplakia are diagnosed on the mucosa of the lateral and ventral tongue, the oral floor and the soft palate.

This lesion has been called "the dangerous oral mucosa" because it typically presents as carcinoma in situ, severe epithelial dysplasia or superficially invasive carcinoma under the microscope. In very high risk settings, such as oral floor lesions in heavy smokers and alcohol abusers, 80% of these red patches already may contain focal areas of microinvasive cancer at the time of initial biopsy.

Follow-up studies are not available for erythroplakia, but its usual microscopic counterpart, carcinoma in situ, has been shown to transform into invasive carcinoma in approximately one of every four cases. This malignant transformation occurs despite the fact that carcinoma in situ lesions are routinely treated by conservative surgical removal or laser ablation. One head and neck site, the larynx, has several investigations which followed untreated carcinoma in situ lesions (see Follow-up web page). Without therapy this disease transforms into invasive carcinoma in 60-90% of the cases within 5-10 years after initial diagnosis.

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 Smokeless Tobacco Keratosis

Smokeless tobacco keratosis (snuff pouch, snuff dipper's lesion, tobacco pouch) is a chronic white or gray/translucent mucosal macule localized in areas of direct contact with smokeless tobacco. The lesion cannot be scraped off, disappears with cessation of the tobacco habit, and is poorly demarcated from surrounding mucosa. Typically there is a soft, velvety feel to the altered mucosa and further palpation of a tobacco chewer's cheek will usually reveal a distinct "pouch" caused by flaccidity in the chronically stretched muscles in the area of tobacco placement. As tobacco is not in the mouth during a clinical examination the usually stretched mucosa appears folded or fissured. Induration, ulceration and pain are not associated with this lesion but occasional inflammatory erythema may be noted.

It usually takes 5-10 years of tobacco habit for smokeless tobacco keratosis to become apparent, but it may be present after less than a year. Once it occurs, it typically remains unchanged indefinitely unless the daily smokeless tobacco contact time increases, in which case it will gradually become thickened to the point of appearing as a distinctly white, leathery or nodular plaque. In the latter case lesions may become clinically indistinguishable from leukoplakia.

The development of smokeless tobacco keratosis in users is very much dependent on the type of habit popular in a society. Snuff appears to produce more keratoses, for example, than chewing tobacco, and persons who keep their quid in one site are more prone to keratoses than those using multiple sites. Other factors leading to high risk of keratosis include the specific brand of tobacco used, an extended duration of the habit, an excessive daily contact-hours of tobacco on oral mucous membranes, an increased amount of tobacco consumed daily, and a deficiency of beta-keratin or vitamin A.

The malignant transformation potential of smokeless tobacco keratosis has not been determined, but the tobacco habit itself is said to carry a risk four times greater than normal mucosa, based on case-control studies of oral cancer patients. Investigations using large numbers of tobacco chewers have found few if any keratotic lesions with serious dysplasias, although older and smaller investigations have concluded that as many as 16% of biopsied cases show at least mildly dysplastic cells.

Some authorities have attempted to provide a clinical grading scale for smokeless tobacco keratoses according to intensity of whiteness, erythema and fissuring. Unfortunately, none of these grading systems has successfully correlated severe or high-grade lesions with an increased risk of malignancy.

 More Detail about Smokeless Tobacco Keratosis Top of This Page

Lichen Planus

The estimated risk of malignant transformation, if real, is less than 2% over a 10 year period. Lichen sclerosus et atrophicus of the mouth carries no malignant potential, as it does in the genital region.

Note: To be completed.  For more information click below or the "Lichen Planus" link at the top of this page.

More Detail about Lichen Planus Top of This Page

Oral Submucous Fibrosis

This irreversible precancerous condition is strongly associated with the habit of chewing areca nuts. Affected users experience a burning sensation of the oral mucosa, occasional mucosal ulceration, a peculiar marble-like blanching of the mucosa, and palpable fibrous bands of the buccal mucosa, soft palate and lips. Leukoplakic lesions are commonly seen and oral carcinoma development has been shown to occur in 5% of users during a 15 year period of follow-up. Whether or not these cancers develop more from the leukoplakias than from the nonleukoplakic mucosa is as yet unknown, but presumably the leukoplakias behave in the same precancerous fashion as leukoplakias in persons without submucous fibrosis. It should be emphasized that the increased risk of oral cancer in betel quid chewers is only relevant to those who include tobacco in the quid; without the addition of tobacco the relative risk is insignificant, although all other features of the disease remain the same.

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Recurring Oral Melanotic Macule

Oral melanoma is a rare cancer, but it has been estimated that one-third are preceded by an apparently innocuous mucosal melanosis. A recent example of recurring oral melanotic macule has been reported to have eventuated after seven years in melanoma of the affected mucosa. Not one of the six early biopsies demonstrated histopathologic characteristics of melanoma, they were classic examples of oral melanotic macule. DNA flow cytometry, however, showed obvious aneuploidy of cells in the early biopsies, as well as in the final melanoma. This suggests that histologically benign-appearing oral melanoses may actually be the radial growth phase of oral melanoma in some instances. It certainly adds a new perspective to melanotic mucosal discolorations.

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Table 1: Precancerous lesions of the oral, pharyngeal and laryngeal mucosa, clinical terms only (modified from Speight PM, Farthing PM, Bouquot JE. Curr Diag Path 1996; 3:165-177).   
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Disease Name

Malignant Transformation Potential      
Proliferative verrucous leukoplakia (PVC) ******
Nicotine palatinus in reverse smokers # *****
Erythroplakia *****
Oral submucous fibrosis *****
Erythroleukoplakia ****
Granular leukoplakia ****
Laryngeal keratosis ***
Actinic cheilosis ***
Smooth, thick leukoplakia **
Lichen planus (erosive forms) **
Smooth, red tongue of Plummer-Vinson disease **
Smokeless tobacco keratosis *
Smooth, thin leukoplakia +/-

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      # reverse smoking: smoking with the lit end of the cigarette in one's mouth