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January 14, 2005

Premalignant Oral Lesions

Leukoplakia, erythroplakia and erythroleukoplakia are the chief clinical entities recognized as oral premalignant lesions.

Outline

A. Definition of terminology
1. Leukoplakia
2. Erythroplakia
3. Erythroplasia
4. Dysplasia

B. Predisposing factors related to oral premalignant lesions

C. Clinical appearance of oral premalignant lesions
1. White Lesions
2. Red Lesions

D. Histologic changes which are related to premalignant lesions

E. Other clinical factors related to premalignant lesions
1. Age
2. Sex
3. Race

F. Early detection and diagnosis

G. Treatment

H. Conditions which mimic oral premalignant lesions

Premalignant Oral Lesions
Leukoplakia, erythroplakia and erythroleukoplakia are the chief clinical entities recognized as oral premalignant lesions.

LEUKOPLAKIA

Leukoplakiais a clinical term indicating a white patch or plaque of oral mucosa that cannot be rubbed off and cannot be characterized clinically as any other disease. In part it is a diagnosis of exclusion just as the definition excludes lesions that may be clinically diagnostic, such as lichen planus, candidiasis, leukoedema, and white sponge nevus. Leukoplakias may have similar clinical appearances but have a considerable degree of microscopic variation. The absence of any specific histologic connotation for leukoplakia is an important concept intended to eliminate some of the former confusion which was prevalent before the late 1970s. Because leukoplakias may range microscopically from benign hyperkeratosis to invasive squamous cell carcinomas, biopsy is mandatory to establish a definitive diagnosis. It is also important to note that premalignant lesions are not always white and that persistent leukoplakias are usually not premalignant or malignant.

Etiology and Pathogenesis. Leukoplakia, in many cases, has been etiologically related to the use of tobacco (smoked or smokeless) and has been shown to regress after discontinuation of tobacco use. The point of irreversibility, however, cannot be defined in terms of duration of tobacco use, forms of tobacco used, or clinical presentation. Other factors, such as alcohol abuse, trauma, and Candida albicans infection, may have a role in the etiology of leukoplakia. Additionally, nutritional factors have also been cited as important, particularly those relative to iron deficiency anemia and development of sideropenic dysphagia (Plummer-Vinson or Paterson-Kelly syndrome).

There is no doubt that some leukoplakias develop into oral squamous cell carcinoma. Rates of transformation vary considerably from study to study. Geographic differences in transformation rate as well as prevalence and location of oral leukoplakias are likely related to these differences in tobacco habits in various parts of the world. In studies of U.S.A. populations, the majority of oral leukoplakias are benign and probably never become malignant. Studies indicate that malignant transformation of leukoplakia occurs over a range from about 1% to as high as 17%, averaging approximately 4.5%. There are wide ranges of risk of transformation from one anatomic site to another.

Clinical Features. Leukoplakia is associated with a middle-aged and older adults, with the vast majority of cases occurring in persons over the age of 40 years. Trends in the use of smokeless tobacco by middle-school and high-school students may ultimately result in a shift of this age toward a younger population. Over time there has also been a shift in gender predilection, with near parity in incidence of leukoplakia due apparently to the change in the smoking habits of women. In some rural southern localities, where women use smokeless tobacco with some frequency, a female predilection, or at least parity between the sexes, can also be noted.

Site predilection has also changed through the years. At one time, the tongue was the most common site for leukoplakia, although this area has given way to the mandibular mucosa and the buccal mucosa, which account for almost half of the leukoplakias today. The palate, maxillary ridge, and lower lip are somewhat less frequently involved, and the floor of the mouth and retromolar sites are involved comparatively infrequently. However, from this list of sites of occurrence, one can see that any site can be involved on occasion.

The relative risk of neoplastic transformation varies from one oral region to another. Although the floor of the mouth accounts for a relatively small percentage (10%) of leukoplakias, a large percentage are dysplastic, carcinoma in situ, or invasive lesions when examined microscopically (Table 1). Leukoplakia of the lips and tongue also exhibits a relatively high percentage of dysplastic or neoplastic change. In contrast to these sites, the retromolar area exhibits these changes in only about 10% of cases.

On visual examination, leukoplakia may vary from a barely evident, vague whiteness on a base of uninflamed, normal-appearing tissue to a definitive white, thickened, leathery, fissured, verrucous or wart-like lesion. Red zones may also be seen in some leukoplakias, prompting use of the term speckled leukoplakia. On palpation, some lesions may be soft, smooth, or finely granular in texture. Other lesions may be roughened, nodular, or indurated.

An entity now known as proliferative verrucous leukoplakia has been segregated from other leukoplakias. This type of leukoplakia begins as simple keratosis and eventually becomes verrucous in nature. Some lesions can become clinically aggressive. It is persistent, becomes multifocal, and is recurrent. The cause is unknown, although some may be associated with human papillomavirus and some with tobacco usage. The diagnosis is determined clinicopathologically and is usually made retrospectively. Malignant transformation to verrucous or squamous cell carcinoma is seen in as many as 15% of cases.

Histopathology. Histologic changes for leukoplakia range from hyperkeratosis, acanthosis, dysplasia, and carcinoma in situ to invasive squamous cell carcinoma (Fig. 1). By definition, the term dysplasia refers to disordered growth whereas the term atypia refers to abnormal cellular features. Various degrees of dysplasia may be described in which the epithelial pattern shows mild, moderate, or severe change. This is a subjective determination, and it indicates that the changes do not appear abnormal enough to qualify as neoplastic. Specific microscopic characteristics of dysplasia include (1) drop-shaped epithelial ridges, (2) basal layer hyperplasia, (3) irregular stratification, (4) increased and abnormal mitotic figures, (5) individual or cell-group keratinization (epithelial pearl formation) within the spinous layer, (6) cellular pleomorphism, (7) nuclear hyperchromatism, (8) reversal of the nuclear cytoplasmic ratio, (9) enlarge nucleoli, (10) loss of basal cell polarity and "streaming" of spinous layer cells, and (11) diminished or loss of intercellular adherence.

When the entire thickness of epithelium is involved with these changes in the so-called top-to-bottom effect, the term carcinoma in situ may be used. Carcinoma in situ may also be identified when cellular atypia is particularly severe, even though the changes may not be evident from basement membrane to surface.

Progression of dysplasia to carcinoma is difficult to document. However, it is generally accepted that the more severe the change, the more likely a lesion is to evolve to cancer. Also, some lesions can persist for indefinite periods without changing microscopically, and a few others apparently revert to normal. Carcinoma in situ is not regarded as a reversible lesion, although it may take many years for invasion to occur. It has been shown that a majority of squamous cell carcinomas of the upper aerodigestive tract, including the oral cavity, were preceded by severe dysplasia. Conceptually, invasive carcinoma begins when a microfocus of epithelial cell invades the lamina propria 1 to 2 mm beyond the basal lamina. At this early stage, the risk of regional metastasis is low.

About 5% of leukoplakias are invasive squamous cell carcinoma. There is, however, considerable variation in this figure because of variances in study design and population. The overall malignant transformation of benign leukoplakias accounts for approximately another 5% of the lesions.

Differential Diagnosis. The first step in developing a differential diagnosis for a white patch (leukoplakia) in the oral mucosa is determining whether the lesion can be eliminated with a gauze square or tongue blade. If the lesion can be removed, it represents a pseudomembrane, fungus colony, or debris. If there is evidence of bilateral buccal mucosa disease, hereditary conditions, cheek chewing, lichen planus, and lupus erythematosus (LE) should be included in the differential. Concomitant cutaneous lesions would give weight to the latter two. If either chronic trauma or tobacco use is elicited in the patient's history, frictional or tobacco-associated hyperkeratosis should be considered. Elimination of suspected cause should result in some clinical improvement. Also included in a differential for tongue leukoplakia would be hairy leukoplakia and geographic tongue.

If the lesion in question is not removable and is not clinically diagnostic, it can then be generally classified as idiopathic, and biopsy becomes mandatory. In extensive lesions, multiple biopsies may be necessary to avoid sample error. The clinically most suspicious areas (red, ulcerated, or indurated areas) should be included in the biopsy plan.

Treatment and Prognosis. In the absence of dysplastic or atypical epithelial changes, periodic examinations and rebiopsy of new suspicious areas would be appropriate. If the lesion is mildly dysplastic, some clinical judgment should be exercised in patient management. Potential etiologic factors would be considered. Removal of mildly dysplastic lesions would be in a patient's best interest if there is no apparent causative factor and the lesion is small. If considerable morbidity would result because of lesion size or location, follow-up surveillance would be desirable.

If leukoplakia is diagnosed as moderate to severe dysplasia, removal becomes obligatory. Various surgical methods such as scalpel excision, cryosurgery, electrosurgery, and laser surgery seem to be equally effective in ablating these lesions. In cases of extensive lesions, grafting procedures may be necessary after surgery. It is important to note that some idiopathic leukoplakias may recur after complete removal. It is impossible to predict which lesions will return and which will not.


Table 1. Leukoplakia
Site
Dysplasia or Carcinoma (%)
Floor of mouth
Lateral and ventral tongue
Lower lip
Palate
Buccal mucosa
Maxillary/mandibular mucosa/sulcus
Retromolar

43
24
24
19
17
15
12

Normal


Hyperkeratosis


Dysplasia


Carcinoma in situ


( Represents possible reversible process)

Figure 1. Microscopic spectrum of idiopathic leukoplakia. Oral lesions may be found anywhere along this spectrum. Some may progress through the various stages over time, whereas others may apparently skip some or all stages to become invasive squamous cell carcinoma.

ERYTHROPLAKIA

Etiology. Erythroplakia is a clinical term that refers to a red patch on oral mucous membranes. It does not indicate a particular microscopic diagnosis, although after biopsy most are found to be severe dysplasia or carcinoma. The cause of this lesion is unknown. It is generally assumed, however, that the etiologic factors for erythroplakia are similar to those responsible for oral cancer. Therefore, tobacco probably has a significant role in the induction of many of these lesions. Alcohol, nutritional defects, chronic irritation, and other factors may also have contributing or modifying roles.

Clinical Features. Erythroplakia is seen much less frequently than its leukoplakia counterpart. It should, however, be viewed as a more serious lesion because of the significantly higher percentage of malignancies associated with it. The lesion appears as a red patch with fairly well-defined margins. High risks sites are the floor of the mouth, the tongue, and the retromolar mucosa. Individuals between 50 and 70 years of age are usually affected, and there appears to be no gender predilection. Focal white areas representing keratosis may also be seen in some lesions. Erythroplakia is usually supple to the touch, although some induration may be noted in invasive lesions.

Histopathology. On biopsy, approximately 90% of erythroplakias show at lease severe dysplastic change?about half are invasive squamous cell carcinomas, and 40% are severe dysplasias or in situ carcinomas. The remainder are mild to moderate dysplasias. A relative reduction in keratin production and a relative increase in vascularity accounts for the clinical color of these lesions. Products of keratinocyte terminal differentiation, such as keratin, involucrin, and filaggrin, are found in reduced or negligible amounts in these lesions when stained immunohistochemically.

A rare histologic subtype of carcinoma in situ, known as Bowen's disease, may be seen as a red (or white) patch in the oral mucosa. When this process occurs on the glans penis, it is known as erythroplasia of Queyrat. Microscopic features that separate this lesion from the usual carcinoma in situ include marked disordered growth, multinucleated keratinocytes, large hyperchromatic keratinocyte nuclei, and atypical individual cell keratinization.

Differential Diagnosis. The clinical features of erythroplakia may occasionally be shared by several other red lesions. Atrophic candidiasis results in a red mucosal lesion, but symptoms are usually present. An expanded differential diagnosis would include Kaposi's sarcoma, ecchymosis, contact allergic reaction, vascular malformation, and psoriasis. A careful clinical history and examination should distinguish most of these lesions. Biopsy provides a definitive answer.

Treatment. The treatment of choice for erythroplakia is surgical excision. It is generally more important to excise widely than deeply in dysplastic and in situ lesions, because of their superficial nature. However, because the epithelial changes may extend down the salivary gland excretory ducts in the area, the deep surgical margin should not be too shallow. Several histologic sections may be necessary to assess adequately the involvement of ducts.

It is generally accepted that severely dysplastic and in situ lesions eventually become invasive. The time required for this event can range from months to years. Follow-up examinations are critical for patients with these lesions, because of the potential field effect caused by etiologic agents.

ERYTHROLEUKOPLAKIA

This lesion represents a mixture of erythroplakia (red) and leukoplakia (white). The proportions and arrangements of the two colors will vary from lesion to lesion and also with the evolution of the same lesion. Lesions that have spots of white distributed over a red base are referred to as speckled erythroplakias or speckled leukoplakias respectively. Lesions with distinct patches of red and white are termed erythroleukoplakias. The red portion represents erythroplakia and as such carries a high suspicion index. The white regions represent excess surface keratin and generally suggest a less serious condition except for the neighboring areas of erythroplakia. Like erythroplakia, this lesion occurs most commonly in the high-risk oval and is painless. A working diagnosis of speckled erythroplakia/leukoplakia or erythroleukoplakia indicated a need for prompt biopsy and appropriate subsequent management.

Differential Diagnosis. The following list includes similar appearing lesions that must be considered in the differential diagnosis: single lesion of migratory glossitis, chronic traumatic lesions (cheek biting), nicotine stomatitis, erosive lichen planus, other lichenoid lesions, hyperplastic and atrophic candidiasis, chemical and thermal burns and lupus erythematosus.

Leukoplakia

Leukoplakia is a clinical term for a white plaque or patch on the oral mucosa that cannot be scraped off and cannot be classified as any other clinically diagnosable disease. Persons of any age may be affected, but most cases occur in men between the ages of 45 and 65 years. Recent incidence figures indicate that the male to female ration is decreasing; women are being affected almost as frequently as men.

Leukoplakia are protective reactions against chronic irritatants. Tobacco, alcohol, syphilis, vitamin deficiency, hormal imbalance, galvanism, chronic friction, and candidiasis have been implicated in the cause of these lesions. Leukooplakisa vary considerably in size, location, and clinical appearance. The preferntial sites for leukoplakia are the alteral and ventral tongue, floor of the mouth, alveolar mucosa, lip, soft palate- retromolar trigone, and mandibular attached gingiva. The lesional surface may appear smooth and homogeneous, thin and friable, fissured, corrugated, verrucoid, nodular, or speckled. The lesions can vary in color, form faintly translucent white to gray or brown-white.

A classification system offered by the World Health Organization recommends two divisions for oral leukoplakias: homogeneous and nonhomogeneous. Nonhomogeneous leukoplakias have been further subdivided into erythroleukoplakias, nodular, speckled, and verrucoid.

Most leukoplakias (80%) are benign, and the rest are dysplastic or cancerous. The clinical challenge lies in determining which leukoplakias are premalignant or malignant, especially because 4-6% of all leukoplakias progress to squamous cell carcinoma within 5 years. High risk sites of malignancy include the floor of the mouth, lateral and ventral tongue, uvulo-palatal complex and lips.

Leukoplakias with localized red areas also confer a high risk for carcinoma. For example, nonhomogeneous leukoplakias, particularly oral speckled leukoplakias, represent epithelial dysplasia in about half of the cases and have the highest rate of malignant transformation among intraoral leukoplakias. Candida albicans, a fungal organism often associated with oral speckled leukoplakias, may have a role in the dysplastic changes seen.

The initial step in the treatment of leukoplakia is to eliminate any irritating and causative factors and then observe for healing. The lesion may or may not disappear. When an unexplained oral leukoplakia is persistent, biopsy is mandatory. Several biopsy sites may be necessary for diffuse lesions. Nonhomogeneous or reddish areas of the lesion should always be selected for biopsy because they are associated with a higher risk for dysplasia and malignant transformaiton.

Cigarette Keratosis

Cigarette keratosis is a specific reaction evident in persons who smoke nonfiltered or marijuana cigarettes to a very shor length. The lesions, which approximate each other upon lip closure, involve the upper and lower lips at the location of cigarette placement. These keratotic patches are about 7 mm in diameter and invaariably are located lateral to the midline. Raised white papules are evident throughout the patch, producing a roughened texture and firmness to palpation. Cigarette keratoses may extend onto the labial mucosa, but the vermillion border is rarely involved. Elderly men are most commonly affected. Smoking cessation usually brings about resolution. The development of ulcer and crust formation should raise the suspicion of neoplastic transformation.

Snuff Dipper's Patch (Tobacco Chewer's Lesion, Snuff Keratosis)

A wrinkled yellow-white area on the gingival mucosal flexure and mandibular buccal or labial mucosa suggests intraoral use of unburned tobacco. The hard palate, floor of the mouth, and ventral tongue may also be affected if tabacco is placed in the maxillary vestibule or beneath the tongue. Smokeless tobacco has various forms (snuff, dip, plug, or quid) and leaves its characteristic mark at the preferential site of tabacco placement. Posterior sites are commonly used for dip, plug, or quid, whereas anterior sites are preferred for snuff. Persons whose introral sites vary have multiple, less prominent lesions. Male teenagers are most frequently affected, largely because of intensive marketing, peer and sports associations.

Early snuff dipper's patches are plae pink, and the surface appears corrugated and wrinkled. The color may progress to white, yello-white, and yellow-brown as hyperkeratosis and exogenous staining occur.

Long term use of smokeless tobacco is associated with periodontal alterations, caries, epidermal dysplastic changes, and verrucous carcinoma. To achieve resolution, cessation of use os recommended. If normal appearance does not return 14 days after cessation, biopsy is necessary.

Nicotine Stomatitis (Pipe Smoker's Palate)

Nicotine stomatitis is a response of oral ectodermal structures to prolonged pipe and cigar smoking. It is usally found in middle-aged and elderly men, posterior to the palatal rugae, on the soft palate, and sometimes extending onto the buccal mucosa. Rarely, the dorsum of the tongue is affected; these tobacco-associated changes of the tongue have been termed glossitis stomatitis nicotina.

Nicotine stomatitisshows progressive changes with time. The irritation initially causes the palate to become diffusely erythematous. The palate eventually becomes grayish-white secondary to hyperkeratosis. Multiple discrete keratotic papules with depressed red centers develop that correspond to dilated and inflamed excretory duct openings of the minor salivary glands. The papules enlarge as the irritation persists but fail to coalesce, producing a characteristic cobblestone (parboiled) appearance of the palate. Isolated but prominent red-centered papules are common. Whether the lesion areises as a consequence of heat or of tobacco is a matter of debate. Pipe smoking and reverse cigarette smoking, a habit of some women, produces similar findings. Smoking cessation usually results in regression. Biopsy is rarely needed to confirm the diagnosis.

Syphilitic Leukoplakia

Oral leukoplakia in tertiary syphilis was at one time important, but has become so rare as to be mainly of historical interest. Clinically, a syphilitic plaque is typically on the dorsum of the tongue, irregular in outline and thickness, and may show nodular thickening or erosions. Either of the latter is likely to be the result of malignant change, the risk of which is traditionally regarded as being exceptionally high.

Erythroplakia

Erythroplakia is defined as a persistent red patch that cannot be characterized clinically as any other condition. This term, like "leukoplakia," has no histologic connotation; however, most erythroplakias are histologically diagnosed as epithelial dysplasia or worse and thus have a much higher propensity for progression to carcinoma than leukoplakia. Erythroplakias appear most prevalent in the mandibular mucobuccal fold, oropharynx, and floor of the mouth. The redness of the lesion is a result of atrphic mucosa overlying a highly vascular submucosa. The border of the lesion is usually well demarcated. There is no sexual prdilection, and patients older than age 60 are most commonly affected.

Three clinical variants of erythroplakia have been recognized: 1) the homogenous form, which is completely red; 2) erythroleukoplakia, which has red patches interspersed with occasional leukoplakic areas; and 3) speckled erythroplakia, which contains white specks or granules scattered throughout the lesion. Biopsy is mandatory for all types of erythroplakia because 91% of erythroplakias represent severe dysplasia, carcinoma in situ, or invasive squamous cell carcinoma. Close inspection of the entire oral cavity is also required because 10-20% of these patients have several erythroplakic areas, a phenomenon known as field cancerization.

Erythroleukoplakia and Speckled Erythroplakia

Erythroleukoplakia and speckled srythroplakia, or "speckled leukoplakia,: as some authers prefer, are precancerous red and white lesions. Erythroleukoplakia is a red patch with isolated leukoplakic areas, whereas speckled erythroplakia is a red patch that contains white speckles or granules throughout the entire lesion. A variant red-white lesion that has a nodular appearance is called proliferative verrucous leukoplakia.

Erythroleukoplakia and speckled erythroplakia have a male predilection, and most lesions are detected in patients older than age 50 years. They may occur at any introoral site but frequently affect the lateral border of the tongue, buccal mucosa, and soft palate. These lesions are often associated with heavy smoking, alcoholism, and poor oral hygiene.

Fungal infections are common in speckled erythroplakias, Candida albicans, the predominant organism, has been isolated in most cases; thus, the management of these lesions should include analysis for candida. The cause-and-effect relationship between candidiasis and speckled leukoplakia is unknown, but erythroplakia with leukoplakic regions confers a greater risk for atypical cytologic changes. Because of the increased risk for carcinoma, biopsy of all red-white lesions is mandatory.

Actinic Cheilosis (Actinic Cheilitis)

Actinic cheilosis is a clinical lesion of the lower lip caused by excessive solar radiation damage. Older, fair-skinned men with outdoor occupations are typically affected. In early stages, the lower lip is mildly keratotic with a subtle blending of the vermilion border with the adjacent skin. With increased exposure to the sun focal white zones that have distinct or diffuse borders become apparent. The lipslowly becomes firm, scaly, slightly swollen, fissured, and everted. Ulceration with encrustation is typical of the chronic condition. The ulcers may be caused by loss of elasticity, or they may be an early sign of carcinomatous transformation. Histologic features include atrophic thinning of the epithelium, subepithelial basophilic degeneration of collagen, and increased elastin fibers. Biopsy is recommended to rule out similar sun-related diseases such as epithelial dysplasia, carcinoma in situ, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, keratoacanthoma, cheilitis glandularis, and herpes labialis.

Actinic cheilosis is considered a precancerous condition. Clinicians should warn the patient of the likelihood of disease progression without the use of sunscreen protective agents. Dysplastic changes should be treated surgically or by topical application of 5-fluorouracil.

© Department of Oral Pathology,
School of Dentistry,
Case Western Reserve University.

Posted by: nxd21 (Nickoli Dubyk) January 14, 2005 07:32 PM | Category: Oral Cancer

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