Oral Erythroplakia, 1995 paper

Jerry E. Bouquot, D.D.S., M.S.D. , Director of Research, The Maxillofacial Center for Diagnostics and Research, Morgantown, West Virginia; Dental Director, West Virginia Department of Health & Human Resources, Charleston, West Virginia; and Hillel Ephros, D.M.D., M.D., Associate Professor, Department of Oral & Maxillofacial Surgery, Seton Hall University School of Graduate Medical Education, South Orange, New Jersey; Chairman, Department of Dentistry, St. Joseph's Hospital and Medical Center, Paterson, New Jersey

Abstract

Much has been written about the malignant potential of oral leukoplakia, but too often the dental profession has ignored the more dangerous discoloration, erythroplakia, which carries a much greater cancer risk than the white lesions. Erythroplakia is an uncommon and subtly innocuous change of the oral mucosa, but it has very specific and identifiable clinical characteristics, specific therapies, and specific prognostic features. As the most dangerous of all the oral cancer precursor lesions, a search for erythroplakia should be a part of every oral soft tissue examination in persons older than 35 years of age. Unlike leukoplakia, no erythroplakia should ever be left untreated. A clear understanding of this lesion may help to save lives by identifying oral cancers prior to invasion or at such an early stage that affected patients need not anticipate mutilating therapy or the spread of disease to other parts of the body.

Introduction

For most of this century a body of knowledge has been slowly evolving relative to a type of oral mucosal macule which is red yet does not seem to be produced by trauma, infection, hemorrhage or vascular tumors. Some of the greatest names in oral pathology have contributed significantly to our understanding of this lesion which is now universally accepted as a premalignancy of major importance. Known today as erythroplakia (or erythroplasia), this lesion seems to carry the highest risk of being or becoming cancer. However, due in part to its innocuous clinical appearance, it is rarely identified. So much has been written about leukoplakia, the most common of the so-called oral premalignancies,1-6 that some authorities have bemoaned the fact that erythroplakia has not received the same emphasis.7 We agree that erythroplakia must become much better known to the dental profession because of the very great danger it poses to those patients afflicted with it. For this reason the present paper reviews the historical and contemporary features of this lesion.

Erythroplakia - Terminology & Diagnosis

As with other precancers, considerable misunderstanding has arisen because concepts and lesions have been poorly defined in the past. In order to avoid such misunderstandings relative to the present topic, the following definitions, largely from a recent textbook of oral and maxillofacial pathology,8 are recommended for use and will be used throughout this paper:

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

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

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

Carcinoma in situ (intraepithelial carcinoma) - A histopathologic diagnosis defined as a proliferation of basal epithelial cells from the basement membrane to the surface, with almost all cells manifesting cytologic atypia generally accepted as characteristics of malignancy. Immediate maturation into a superficial keratin layer is possible, but no invasion into underlying connective tissues can be seen.

Severe epithelial dysplasia - A histopathologic diagnosis defined as a proliferation of basal epithelial cells into the level of the upper third of the epithelium, with most cells manifesting cytologic atypia generally accepted as characteristics of malignancy.

Superficially invasive (microinvasive) squamous cell carcinoma - A histopathologic diagnosis of a routine squamous cell carcinoma, usually well differentiated, which has invaded only slightly into underlying connective tissues.

It is especially important to remember that a premalignancy is not guaranteed to eventually transform into cancer, as is often but erroneously believed. Many precancers, in fact, do so only in a small proportion of cases, forcing the clinician to make some very real choices relative to the management of such lesions.

A diagnosis of exclusion. One of the most confusing aspects of erythroplakia is that it is, like leukoplakia, a diagnosis of exclusion. This means that the clinician must rule out all other erythematous oral lesions (Figures 1-4) before the term can be applied to a specific lesion in a particular patient. At the very least, the following entities must be excluded prior to the use of this diagnostic term:

It should also be emphasized that the term erythroplakia is a clinical one, even though biopsy evaluation almost always is able to identify dysplastic or malignant cells at the microscopic level. The presence of such cells does not alter the clinical diagnosis. Erythroplakia is still erythroplakia with or without dysplastic epithelial cells, so long as it cannot be classified as one of the other forms of red mucosal lesions.

Is it Cancer or Is it Precancer?

Careful observation by dentists will reveal erythroplakia in association with a majority of early invasive oral carcinomas,7,9 although this feature is reported by only 4% of oral cancers diagnosed by physicians.10 Erythroplakia may also be associated with precancerous lesion leukoplakia. While leukoplakic lesions are diagnosed much more often than erythroplakias, the latter lesions appear to be of far more serious consequence, and in mixed red and white lesions, it is the red portion that is more worrisome than the white.

Under the microscope, erythroplakia typically presents as carcinoma in situ (Figure 5), but severe epithelial dysplasia and superficially invasive carcinoma may also be found.8-13 In very high risk settings, such as oral floor lesions in heavy smokers and drinkers, 80% of these red patches already may contain focal areas of invasive cancer at the time of initial biopsy.7

Severe epithelial dysplasia is a well-established precancer and has been shown to proceed to malignant transformation in at least one-third of all oral cases and carcinoma in situ is considered by many to already be a cancer, one which has been fortuitously diagnosed during its preinvasive stage.9-13 Relative to the latter concept, there is a long-standing, unresolved controversy, and carcinoma in situ is also frequently thought of as a premalignancy rather than a true malignancy, probably because not all lesions will become invasive if left alone. In the mouth, the transformation rates for treated cases, including those with invasive carcinoma already at biopsy, vary from 14-50% (Table 1). There is no information relative to the length of time an untreated oral carcinoma in situ typically exists before it begins to invade into underlying connective tissues, or the proportion which will actually invade if left untreated. Three laryngeal carcinoma in situ studies, however, have followed untreated lesions for long periods of time and have determined malignant transformation rates ranging from as low as 33% to as high as 90%.15,16

Depending on which study one prefers, then, invasive malignancy may be a minority event or almost guaranteed to occur in carcinoma in situ, a precancer or a preinvasive carcinoma. Ironically, severe dysplasia, which has seldom been discussed as anything but a precancer, has demonstrated a higher malignant transformation rate than carcinoma in situ in some studies.16 In acknowledgement of the fact that this discussion may never end, several authorities have suggested combining these two entities into a single diagnostic term, such as 'Grade III oral intraepithelial neoplasia (OIN III),' and presume that all epithelial dysplasias are neoplastic to one degree or another, albeit less aggressive in their early stages.16,17 There is much merit to this idea, but it thus far has gained little acceptance.

Evolution of the Disease

The first mention of a nonhemorrhagic red patch of an upper aerodigenstive tract site may have been a vocal cord lesion reported in 1852.18 The first truly descriptive paper of erythroplakia, however, was a 1911 report by Queyrat19 of a red macule on the glans penis of a syphilitic patient. It was Queyrat who coined the term "erythroplasia." About the same time Rubin20 used the term "incipient carcinoma" to describe the microscopic features of erythroplakia's most common histopathologic diagnosis, carcinoma in situ, based on his experience with lesions of the uterine cervix.

In 1924 the French dermatologist, Darier,21 published the first oral case of "erythroplasia of Queyrat," but very little new information was added relative to oral lesions until the Minnesota oral pathologist Robert Gorlin22 published his now classic analysis of collected cases of carcinoma in situ in 1950. A flurry of clinical and basic research investigations during the 1960s and early 1970s allowed Shafer and Waldron12,13,23,24 to provide the profession with a very complete characterization of both the clinical and histopathologic features of this disease and to recommend the use of the term "erythroplakia" as the most appropriate clinical diagnosis for idiopathic red mucosal macules.

Follow-up studies during the 1970s and 1980s clearly established the malignant transformation potential of severe dysplasia and carcinoma in situ (Table 1), and the final disease parameters, that is, those pertaining to its population characteristics, were reported by Bouquot and his associates17,30,32 in the late 1980s. At the present time, research is concentrating on the determination of nuclear and viral alterations in affected tissue.

The Cause

Many theories have been proposed as to the cause of erythroplakia and carcinoma in situ of various mucosal surfaces. In the uterine cervix, human papillomavirus (HPV), especially the cancer-associated types HPV-16 and HPV-18, are so strongly linked to precancerous mucosal lesions, including erythroplakic plaques, that such lesions are now often referred to simply as "HPV lesions" rather than by the older clinical diagnostic terms. Unfortunately, it is not yet known whether HPV is associated with oral erythroplakia. The virus has been demonstrated in as many as 40% of oral leukoplakias,33,34 but not necessarily with the lesions containing dysplastic cells. It is also found in a certain proportion of normal mucosa and recent investigations have found such a small proportion of HPV-positive cases in their leukoplakia cohorts that the frequency approaches that of normal.35,36

It is certainly true that HPV can cause dysplastic-looking cells to occur in epithelium in the absence of any other environmental change,37 but a definitive correlation between HPV and the malignant potential of altered oral epithelium is premature. Likewise, other oncogenic viruses, oncogenes and tumor-suppressor genes are involved in the initiation and progression of a wide variety of neoplasms, including invasive oral cancers, but these have not been well studied relative to erythroplakia.

A secondary infection or superinfection, candidiasis, may be associated with dysplastic oral mucosal cells. Candida albicans has often been demonstrated in erythroleukoplakia lesions and the red component of these lesions (often the white component as well) diminishes or disappears after antifungal therapy in at least some cases.38 Unfortunately, it is not yet known whether the red surface change in such lesions is the result of inflammation, dysplasia or both, and no study has yet shown a positive correlation between the presence of dysplastic epithelial cells and candidal hyphae in pure erythroplakia or carcinoma in situ lacking a white surface appearance.

In addition to the above proposed etiologic factors, it is presumed by most investigators that the primary risk factors for oral squamous cell carcinoma in the U.S. are applicable to oral erythroplakia. Almost all patients with intraoral carcinoma in situ, for example, are chronic cigarette smokers and the overwhelming majority are heavy drinkers.30 Erythroplakia in a patient with these risk factors should be viewed as containing carcinoma until proven otherwise by biopsy.

On the lower lip vermilion ultraviolet radiation plays an important etiologic role for carcinoma in situ, just as it does for other types of precursors to invasive vermilion cancer. Carcinoma in situ, in fact, has been found adjacent to 11% of invasive vermilion carcinomas at the time of diagnosis and two-thirds of patients with such lesions have outdoor occupations.30 By comparison, only 20% for patients with intraoral carcinoma in situ work or have worked outdoors.

The Patient

No prevalence rates (number of active cases in a population at a given point in time) or incidence rates (number of new cases diagnosed each year in a population) are available for erythroplakia. However, epidemiologic investigations of carcinoma in situ, which represents the vast majority of erythroplakias, have found only 6 newly diagnosed oral cases per 1,000,000 persons each year.17,30,32 In other words, only 1,500 cases are diagnosed annually throughout the entire United States. This makes erythroplakia one of the least commonly diagnosed among the group of oral lesions which may be or may become malignant. The failure of clinicians to identify erythroplakia more frequently may be attributed to a variety of factors. These include the generally innocuous appearance of the lesion as well as inadequate training, experience or interest on the part of health professionals. Additionally, the at-risk population consists of older men who are likely to abuse alcohol and who are therefore unlikely to be aware of subtle oral changes and may not be particularly conscientious about routine visits to the dentist or physician. However, with the emphasis on early detection of oral cancer, championed by Mashberg, Samit and their associates,7,9 the proportion of lesions diagnosed early or at the carcinoma in situ stage is increasing over time, even as the incidence of invasive oral cancer is decreasing. In one health-conscious population, in fact, that proportion has increased from 8% in 1935 to more than 17% today.30,32

Over 80% of patients with intraoral carcinoma in situ are men, most of whom are over 50 years of age.32 Patients in the 55-74 year age range are most likely to be affected; for those under 35, erythroplakia is an extremely unlikely finding (Figure 6). Vermilion lesions occur, on the average, a decade later than intraoral lesions (70 and 60 years of age, respectively). In contrast to this late onset, carcinoma in situ of the uterine cervix, the most common location for this lesion in humans, typically affects women in the 25-44 year age bracket and 10% of cervical cases occur in 15-24 year old females.30,32 While the usual patient age at diagnosis for intraoral carcinoma in situ and intraoral invasive carcinoma is essentially the same, carcinoma in situ of the cervix occurs one to two decades earlier than the invasive lesions at that site.

There are no strong racial or ethnic predilections for the oral lesions of carcinoma in situ, although these rather rare entities are found so seldom in U.S. Hispanics, American Indians and Japanese Americans that they are almost nonexistent in those subpopulations.17

The Lesion

Erythroplakia occurs on all mucosal surfaces of the head and neck area. Half of all cases, however, are found on vermilion or intraoral surfaces, with the rest being evenly divided between the larynx and the pharynx.16,17,30 Vermilion lesions are relatively common and are most often seen on the lower lip. Intraorally, the lateral and ventral tongue, oral floor and soft palate are most frequently involved.

Erythroplakia, as the name obviously implies, is an asymptomatic, nonelevated, red macule or patch on an epithelial surface. The exact cause of the red appearance is unknown, but may be related to an increase in the number of underlying blood vessels through which the blood flows, which in turn may be secondary to localized inflammatory or immunological responses occasioned by the dysplastic, i.e. 'foreign,' epithelial cells. In some cases the color may result from a lack of surface keratin or extreme thinness of the epithelium.

Regardless of the cause of the color change, the typical lesion is less than 1.5 cm. in greatest diameter and half are less than 1.0 cm, but examples larger than 4 cm. have been seen. It usually is quite sharply demarcated from the surrounding pink mucosa and its surface is typically smooth and regular in coloration (Figure 7). Occasional lesions demonstrate a pebbled or granular surface change similar to that seen in granular or Phase III leukoplakia (Figure 8), although this may not be readily apparent unless the mucosal surface is thoroughly dried. Rarely, a true papilloma-like appearance is seen, often with multiple, clustered lesions, and these have been referred to as papillary carcinoma in situ (Figure 9). Some lesions appear to change slightly on a day to day basis, possibly because of varied traumatic events, salivary covering or immune responses.

Smooth erythroplakia is soft to palpation and has often been described as having a velvety feel (prior to the days of latex gloves). The pebbled lesions tend to be somewhat firm, but erythroplakia never actually becomes hard or indurated until an invasive carcinoma develops within it. However, even early invasive squamous carcinoma is generally nonpalpable, and induration is a feature of more advanced, more deeply invasive lesions.7

It is quite common to see erythroplakia admixed with or adjacent to leukoplakia in the mouth (Figure 10). In such lesions, the red areas are the sites most likely to contain or to develop dysplastic cells and should, therefore, be the sites most readily biopsied and most carefully examined clinically. The danger of such red mucosa is considered by some to be so great that they recommend excluding all mixed lesions from the leukoplakia category and considering them instead to be a subcategory of erythroplakia (leukoerythroplakia?).7

It should be mentioned that carcinoma in situ of the vermilion border is seldom a purely red lesion and is typically leukoplakic or erythroleukoplakic in its clinical appearance. Almost half of the vermilion lesions, moreover, are ulcerated at the time of diagnosis, a decidedly uncommon event with intraoral lesions. Hemorrhage, either spontaneous or on slight provocation, is also a decidedly uncommon occurrence with this lesion, red though it may be.

We have mentioned that erythroplakia is commonly seen adjacent to invasive oral cancers (Figure 11). In fact, almost a third of early intraoral carcinomas have this association, and almost all early oral cancers have at least some associated red areas if we include lesions with a mixture of red and white patches.7,9,10 While it has been shown that oral carcinomas with associated or adjacent leukoplakia behave in a less aggressive fashion than carcinomas without such lesions,10 no similar data is available relative to carcinomas associated with erythroplakia.

Unlike leukoplakia, erythroplakia is seldom multiple and seldom covers extensive areas of the mouth. Also unlike leukoplakia, erythroplakia seems seldom to expand laterally after initial diagnosis, although this may be an artifactual feature because most lesions are completely removed or destroyed immediately after formal diagnosis.

The typical patient with carcinoma in situ has been aware of an alteration in the involved site for at least 2.7 years prior to biopsy.10,30 Ironically, persons with the more readily visualized lesions of the lip vermilion wait much longer, 3.4 years, before seeking professional help. Nor is it uncommon for a physician or dentist to miss completely or delay the diagnosis because of the innocuous clinical appearance of the lesion. In screening programs aimed at high risk patients, asymptomatic erythroplakias are readily identified and biopsied. Most of these presumably existed for some time prior to diagnosis without any awareness on the part of the patient.

Mashberg and Samit7 have given strong reasons for the use of toluidine blue to aid in the diagnosis of erythroplakic lesions and early, asymptomatic oral carcinomas. This metachromatic dye selectively stains areas of dysplastic epithelium (presumably their enlarged nuclei) and its topical application to suspicious but subtle lesions can often provide a clearly defined lesional outline which was not readily apparent without the use of the dye (Figure 12). Since inflammatory lesions may give false positive results, any potential irritants must be addressed two weeks prior to staining. With close adherence to the protocol for its application (Table 2), toluidine blue maintains a sensitivity and specificity of approximately 90%. It should be clear that clinical suspicion mandates biopsy regardless of the outcome of staining.

The Treatment & the Prognosis

Incisional biopsy is always the preferred method for establishing a microscopic diagnosis of suspicious intraoral lesions. Since erythroplakia is so closely correlated with severe dysplasia, carcinoma in situ and invasive carcinoma, incisional biopsy is especially indicated. Excisional biopsy of a potential malignancy may result in undertreatment and violation of surgical oncologic principles.

The definitive treatment of erythroplastic lesions remains controversial. A conservative surgical procedure such as mucosal stripping is often performed, with minimal damage to deeper connective tissues. While this has the distinct advantage of preserving tissue for microscopic evaluation of potential regions of invasion, destructive techniques such as laser ablation, electrocoagulation and cryotherapy have also proven to be effective.13,15,16,26 A recent investigation has found that even lesions with superficially invasive or microinvasive carcinomas (less than 3 mm of extension into submucosal fibrous tissues) can be safely and successfully treated by a mucosal stripping procedure, at least on the lip vermilion.40

While conservative treatment of erythroplakia now seems to be accepted by some, there are still those who advocate a more aggressive approach on the assumption that there may be an invasive carcinoma already present. Since intraoral red areas may have zones of dysplasia or carcinoma in situ bordering zones of microinvasive carcinoma, one must consider a biopsy to be merely a sampling of the visually altered mucosa. Based on this, many clinicians would at least rebiopsy an area of severe dysplasia or carcinoma in situ prior to selecting any procedure other than a definitive excision with appropriate oncologic margins. Close observation or conservative measures as described above are, of course, logical choices for lesions of less intense (mild or moderate) dysplasia.

The key to therapy in this disease is extended clinical follow-up. Patients should be examined every 3 months for the first postoperative year and every 6 months for an additional 4 years. After that, annual reevaluation with a thorough head and neck examination is advisable. Follow-up investigations of treated cases of severe epithelial dysplasia and/or carcinoma in situ have demonstrated a malignant transformation rate of 14-50% (Table 1). This rather wide range of transformation rates may be profoundly affected by the biopsy procedure, with complete or even incomplete excision leading to moderation of a lesion's clinical course. Also, anatomic location is important: the rate for vermilion lesions is considerably less than for intraoral lesions.

It is clear that surgical management is only the beginning of therapy for this entity; clinical follow-up is an essential component of the treatment, and should include the periodic use of topical toluidine blue. With close follow-up, however, erythroplakia patients can enjoy an excellent prognosis. This follow-up should extend to the entire upper aerodigestive tract, as persons with a history of oral carcinoma in situ are also at increased risk of developing invasive carcinomas of mucosal sites other than the site of the precancer or preinvasive lesion. Two of the patients in the recent study by Lumerman and associates25 who were followed after identification of oral epithelial dysplasia developed invasive carcinoma at oral sites remote from the original dysplastic lesions. Also, in the follow-up study by Bouquot and his associates,30 invasive cancers developed at additional upper aerodigestive tract sites more often than at the original site of the carcinoma in situ. This is consistent with other studies indicating that patients with early asymptomatic intraoral squamous cell carcinomas are at risk for the synchronous (at the same time) or metachronous (at different times) development of other upper aerodigestive tract primaries,6 and serves to emphasize the 'field cancerization' concept described by Slaughter et al40 and by Berg et al.41 This concept is an important one, and one that should guide the management of at-risk patients with suspicious mucosal alterations.

Conclusions

Leukoplakia figures prominently in the curricula of dental and medical schools and in the current scientific literature. Its potential for harboring malignancy has been reported by numerous authors. Many of these studies, however, have included a high proportion of mixed red and white (Phase IV, as per Bouquot and Whitaker5,6) lesions, and it is the red component of these mixed lesions that is generally the site for detection of severe dysplasia, carcinoma in situ and invasive carcinoma. While purely white mucosal alterations (Phase I-II leukoplakias) should not be ignored, it should be recognized that they have a relatively low potential for malignant transformation. The disproportionate interest in leukoplakia prevalent in the literature and in academic settings must not distract the clinician from the critically important task of identifying erythroplakias, particularly in patients at risk for oral cancer. Every dentist should, therefore, be familiar with the appearance of erythroplakia, its risk factors and the oral sites with which it is most often associated.

Erythroplakia is a lesion which should be consciously sought for in every oral soft tissue examination of patients older than 35 years of age. It is most often encountered in middle-aged and older men, primarily in those who are chronic cigarette smokers and/or are heavy drinkers. This lesion is found most frequently on the vermilion border of the lip, the ventral tongue, the oral floor and the soft palate. It is usually small at diagnosis and may show surface changes as well as its characteristic red color. Most lesions have been present for two or more years before a diagnostic biopsy is finally performed, but in fact, no idiopathic red mucosal macule should be left more than a few weeks without a definitive diagnosis.

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3. Bouquot JE, Gorlin RJ. Leukoplakia, lichen planus and other oral keratoses in 23,616 white Americans over the age of 35 years. Oral Surg Oral Med Oral Pathol 1986; 61:373-381.

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8. Neville B, Damm D, Allen C, et al. Oral and maxillofacial pathology. Philadelphia: W. B. Saunders, 1995; pp. 284-288.

9. Mashberg A, Morrissey JB, Garfinkel L. A study of the appearance of early asymptomatic oral squamous cell carcinoma. Cancer 1973; 32:1436-1445.

10. Bouquot JE, Weiland LH, Kurland LT. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/pharyngeal carcinoma in Rochester, Minnesota, 1935-1984. Oral Surg Oral Med Oral Pathol 1988; 65:199-207.

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17. Bouquot JE, Gnepp DR. Epidemiology of carcinoma in situ of the upper aerodigestive tract. Cancer 1988; 61:1685-1690.

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20. Rubin IC. The pathologic diagnosis of incipient carcinoma of the uterus. Am J Obstet 1910; 62:668-676.

21. Darier J, Lemaitre F, Monier L. Les modes de debut des cancers de la bouche et des machiores. Bull Cancer (Paris) 1924; 13:256-272.

22. Gorlin RJ. Bowen's disease of mucous membrane of the mouth; review of literature and presentation of cases. Oral Surg Oral Med Oral Pathol 1950; 50; 3:35-51.

23. Shafer W, Hine L , Levy B . A textbook of oral pathology, 3rd edition. Philadelphia: W. B. Saunders, 1972.

24. Waldron CA. Oral epithelial tumors. In: Gorlin RJ, Goldman HM (editors). Thoma's oral pathology, 6th ed. St. Louis: C. V. Mosby; 1970, pp. 824-826.

25. Lumerman H, Freedman P, Kerpel S. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol 1995; 79:321-329.

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33. Gassenmaier A, Hornstein OP. Presence of papillomavirus DNA in benign and precancerous oral leukoplakias and squamous cell carcinomas. Dermatologica 1988; 176:224-233.

34. Kashima HK, et al. Human papillomavirus in squamous cell carcinoma, leukoplakia, lichen planus, and clinically normal epithelium of the oral cavity. Ann Otol Rhinol Laryngol 1990; 99:55-61.

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Tables

Table 1: Malignant transformation rates (%) for oral CIS and/or severe epithelial dysplasia, listed by year of publication. Lesions appeared clinically as red, white or combined red and white macules, i.e. not all were pure erythroplakias. Cancers not arising from the site of the precancer are excluded.

Author(s)	Year	Country	# Pts	Person-Years of Follow *	Average Follow-Up ( Years)	% Malignant Transformation
Mincer, et al⁴⁰ ^**	1972	U.S.A.	16	48	3.0	18.1
Pindborg, et al⁴¹	1977	India	21			14.3
Banoczy, Csiba⁴²	1976	Hungary	68	428	6.3	13.2
Gupta, et al⁴³	1980	India	90	945	10.5	7.0
Silverman, et al⁴⁴	1984	U.S.A.	22	162	7.4	36.4
Amagasa, et al⁴⁵ ^{*** @}	1985	Japan	12	120	10.0	50.0
Vedtofte, et al⁴⁶	1987	Denmark	14	55	3.9	35.7
Bouquot, et al³² ^{** @ @@}	1988	U.S.A.	32	346	10.8	15.6
Lumerman, et al⁴⁷ #	1995	U.S.A.	7	11	1.5	14.3
TOTAL:			272	887	7.1	26.3 ##

* sum total of time which lesions were collectively followed (mean follow-up times are in parentheses)
^** includes only CIS cases
^*** assumes an average follow-up time of 3 years (range=1-8 years); data not available from the report
^@ average follow-up time was 10 years or more
^@@the only population-based study; represents middle-class whites
# average follow-up time was less than 2 years
## statistically weighed for different follow-up time periods and sample sizes

Table 2: Technique for the topical application of toluidine blue in order to enhance the appearance of dysplastic mucosal tissues, according to Mashberg.7

* toluidine blue is a metachromatic dye used as a tissue stain in pathology labs. It has been shown to
be innocuous when used topically within the mouth.

Legends for Figures

Figure 1: Most red mucosal lesions are of vascular origin, as is this lower lip hematoma, produced when the patient bit his lip while anesthetized for a routine dental procedure. This particular lesion is somewhat elevated, unlike the ecchymotic forms of submucosal hemorrhage.

Figure 2: Burning tongue syndrome, in this case secondary to candidiasis (note the angular cheilosis and fungal colonies at the arrows), usually presents as a generalized smooth redness of the entire dorsum of the tongue, as seen here, but less involved cases may show only focal involvement.

Figure 3: Many contact allergies present as nonelevated, nonblistering red macules, as seen here under a partial denture (arrows)

Figure 4: Plasma cell gingivitis presents as a bright red mucosal discoloration of the attached gingiva and may be generalized or localized, as seen here, and can mimic the red color of erythroplakia. It may persist after removal of the allergin (usually mint candy or gum).

Figure 5: Carcinoma in situ demonstrates dysplastic cells from the top to the bottom of the epithelium, with little or not maturation ('polarization' or layering). It is often more thin than normal and has inflamed submucosal tissues. Part A above is a low-powered photomicrograph of the erythroplakia pictured in Figure 7, with the in situ lesion on the right and mildly dysplastic epithelium on the left. Part B is a high-power view showing the disorganized immature cells.

Figure 6: The annual incidence rates for carcinoma in situ (the majority of erythroplakias) of the mouth increase with age and are greater for men than for women at all ages after 35 years of age. The lesion is extremely rare before 35 years of age.

Figure 7: This small, well-demarcated, smooth erythroplakia of the buccal mucosa proved to be carcinoma in situ at biopsy (Figure 5). The patient was unaware of it at the time of examination.

Figure 8: Some erythroplakias have a pebbled or granular surface change, as seen here on the lateral border of the tongue. This was an unusually large lesion which proved on biopsy to be all carcinoma in situ.

Figure 9: Rare cases of papillomatosis with carcinoma in situ of the lesional mucosal have been reported, as seen here on the maxillary alveolar ridge of a 72 year old woman.

Figure 10: Erythroeukoplakia may present as multiple red or pink patches on a white background, as seen here, as seen here on the ventral tongue and oral floor, or as multiple white patches on a red background. Erythroplakia is seldom seen as multiple macules unless there is a leukoplakic component.

Figure 11: Erythroplakia is often seen in association with invasive oral carcinoma, as seen along the posterior aspect of this oral floor cancer. The carcinoma itself was ulcerated and indurated.

Figure 12: Erythroplakia may be very subtle and innocuous in its clinical appearance, as demonstrated by the left soft palate lesion in Part A above. After topical use of toluidine blue the dysplastic epithelium is clearly represented by a blue discoloration (Part B).

Questions (Answers are at End of Questions)

2. Which of the following statements is TRUE relative to the clinical appearance of erythroplakia?

3. Which of the following oral mucosal sites is LEAST LIKELY to present with erythroplakia?\

4. Which of the following statements is TRUE relative to patients with erythroplakia?

5. How many cases of oral carcinoma in situ are diagnosed each year in the United States?

6. Oral carcinoma in situ is being diagnosed with less frequency today than it was half a century ago.

8. As with mild (Phase I or II) leukoplakia, some erythroplakias need not be biopsied once they are clinically identified.

9. Which of the following mucosal lesions can look very much like erythroplakia during a clinical oral examination?

10. Which of the following statements is TRUE relative to the treatment/management of erythroplakia?

d. other mucosal surfaces of the upper aerodigestive tract should be periodically examined in addition to the mouth

e. topical use of toluidine blue is an effective therapy when used for extended periods of time

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Erythroplakia Review	Erythroplakia Bibliography		Epithelial Dysplasis & CIS

The Maxillofacial Center for Diagnostics & Research

ERYTHROPLAKIA -- THE DANGEROUS RED MUCOSA