Definition

Erythroplakia is the clinical diagnostic term A chronic red mucosal macule which cannot be given another specific diagnostic name and cannot be attributed to traumatic, vascular or inflammatory causes, i.e. it is a diagnosis of exclusion.  Once a biopsy is performed the term may still be used but should be modified to included the presence or absence of atypical or dysplastic epithelial cells.  The lesion is a precancer, i.e. it carries a higher than normal risk of malignant transformation.


 

History & More Definitions.

The twentieth century has seen the emergence and acceptance of the idea that certain lesions which are apparently benign and innocuous in appearance are in reality precancerous lesions and carry a greater than normal risk of transforming into, or in some other fashion "becoming," an invasive malignancy. Several such precancers are associated with the membranes of the head and neck (H&N) region, most notably actinic cheilosis, oral leukoplakia, laryngeal keratosis and erythroplakia (Table 1). Of these, erythroplakia is the least known to health professionals, even though it carries one of the highest cancer risks and has been discussed in print for more than eighty years. Much has been learned about erythroplakia and its typical microscopic counterpart, carcinoma in situ, during the past several decades, enough to now be able to present a rather complete picture of the clinical, pathologic and epidemiologic characteristics. Before the century is over, then, it seems appropriate to review our knowledge and understanding of this dangerous and intriguing premalignancy.

A review of premalignant lesions should begin with a number of definitions because considerable confusion has arisen as our understanding of precancers has evolved. 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, from the U.S. textbook standard by Neville et al, are recommended for use with oral precancers and will be used throughout this paper:

Precancerous lesion (precancer, premalignancy, potentially malignant lesion) - An apparently benign, 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.

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 transformation rate/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 disappear with removal of potential etiologic factors (excepting tobacco).

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 (CIS, intraepithelial carcinoma) - An histopathologic diagnosis defined as a proliferation of primitive 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 thin 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 cells into but not completely through the upper third of the epithelium, with most cells manifesting cytologic atypia generally accepted as characteristics of malignancy. No invasion into underlying tissues can be seen.

Superficially invasive squamous cell carcinoma - A histopathologic diagnosis of a routine squamous cell carcinoma, almost always well differentiated, which has invaded only slightly (5 mm. or less) into underlying connective tissues.

It is especially important to remember that a premalignancy is not guaranteed to transform into cancer, as was once the common belief. Many, 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. It should be emphasized at the outset that erythroplakia, like leukoplakia, is a diagnosis of exclusion which requires the clinician to rule out all other erythematous oral lesions before the term can be applied to a specific lesion in a particular patient. Such entities as mechanical trauma, chemical or thermal injury, infectious/allergic/autoimmune mucositis (plasma cell gingivitis, erythema multiforme, psoriasis, etc.), submucosal hemorrhage or vascular anomaly, migratory glossitis and migratory stomatitis, median rhomboid glossitis, denture sore mouth, atrophic glossitis (vitamin deficiency, xerostomia, atrophic candidiasis, etc.), Wegener's granulomatosis (gingival location), and macular mucosal Kaposi's sarcoma must all be considered in the differential diagnosis. In the larynx, inflammatory erythema from smoking ("smoker's larynx") and/or vocal cord trauma must also be excluded.

It should additionally 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 and erythroplakia is still erythroplakia with or without dysplastic epithelial cells, so long as it cannot be classified as a different form of red mucosal lesion.


 

Historical Review

The initial description of erythroplakia was a penile lesion reported in 1911 by Queyrat under the term "erythroplasia," although Fournier and Darier may have first described a penile case in 1893 and Gibb may have described a similar lesion of the vocal cords as early as 1865. The first microscopic analysis of carcinoma in situ was reported in 1910 by Rubin as a distinctive "incipient carcinoma" of the uterine cervix. During the next decade Darier et al published the first H&N example of "erythroplasia of Queyrat," a macular lesion of the buccal mucosa.  In 1932 Broders coined the term "carcinoma in situ," using a laryngeal example, and emphasized its preinvasive status just a few years after Schiller had crystallized the theory of preinvasiveness for the uterine cervix. In contrast to today's understanding of the disease, these early authors presumed that CIS would eventually invade and metastasize in every cases, i.e. it was already a malignancy rather than a premalignancy.

The first emphasis on the high cancer risk of mucosal erythema or "inflammation" in vocal cord leukoplakia (laryngeal keratosis) was published in 1942 by Graham and the early literature on head and neck CIS was considerably dominated by laryngeal cases. Gorlin, in his classic 1950 paper reported the first collection of cases of oral CIS in order to counter the prevalent belief that the larynx was essentially the only H&N site of involvement. Shedd et al joined him with an additional series of cases and the flurry of clinical research which followed allowed Shafer and Waldron in the 1970s to provide an extensive clinicopathologic characterization of oral lesions and to recommend the use of the term "erythroplakia" as the most appropriate clinical diagnosis for the red mucosal macules. Miller, Bauer and Kambic provided similar influential reviews for laryngeal CIS.

Recent emphasis has also been placed on the red mucosal changes associated with oral erythroleukoplakia, the leukoplakia type or phase with the highest malignant transformation rate. The epidemiologic characteristics of CIS were delineated in the late 1980s, confirming that it is, indeed, a rare entity. As few as 1,300 H&N cases are diagnosed annually throughout the United States.

Much insightful information relating to premalignancy has been gleaned from the study of H&N erythroplakia and CIS, despite the fact that clinicopathologic investigations have included very few cases. These lesions have frequently been found adjacent to invasive carcinoma of the mouth and other H&N sites, and Mashberg and Samit have provided an invaluable service by stressing the innocuous erythematous nature of early oral cancers and their adjacent tissues. The juxtapositioning of these preinvasive and invasive lesions of the mouth was also an important impetus for the early development of the well-known "field cancerization" theory of Slaughter et al.

Frequent occurrence in close proximity to carcinoma, of course, only suggests a malignant transformation role for erythroplakia. Follow-up studies of a number of these precursor lesions must demonstrate a greater than normal risk of transformation or "degeneration" into an invasive malignancy. No prospective studies of purely red mucosal lesions has been published. A few investigations, however, have followed a total of 272 patients with microscopically proven severe epithelial dysplasia and/or carcinoma in situ of the mouth, beginning with the Tennessee study by Mincer et al. in 1972 (Table 2). These studies have determined a malignant transformation rate of 26%, but the type and extent of treatment is unclear for most reported cases and so there is still some doubt as to the validity of the rates. Follow-up studies of laryngeal CIS have been in the literature since 1952 and have found a similar transformation rate for treated lesions at that site (Table 3).


Etiologic Factors

Oral and vermilion cases. The causes of erythroplakia are assumed to be the same as the causes of invasive squamous cell carcinoma. More than 94% of CIS patients, for example, smoke tobacco and more than 65% abuse alcohol. On the lower lip, ultraviolet irradiation damage, called actinic cheilosis or actinic cheilitis, plays an important etiologic role for CIS. Almost all vermilion cases have microscopic evidence of solar elastosis of the submucosal connective tissues.

Candida albicans has often been demonstrated in erythroleukoplakia and the red component (the white component as well) has been shown to diminish or disappear after antifungal therapy in some cases. The clinical erythema in such cases may be the result of inflammation rather than dysplasia, although Barrett et al have shown a positive correlation between the severity of dysplastic epithelial cells and the presence of the fungus.

Human papillomavirus (HPV) is a second micro-organism implicated in mucosal carcinoma of the H&N region, but the significance of this association remains unclear. The virus is certainly a common feature of CIS of the uterine cervix, and HPV-16 and HPV-18 infection of in vitro cervical epithelium (otherwise sterile) has been shown to produce quite dysplastic cells. The virus has also been demonstrated in as many as 40% of oral leukoplakia lesions. However, HPV is also found in a certain proportion of normal oral mucosa and recent investigations have determined a much smaller proportion of HPV-affected tissue in leukoplakia cases. To date, no positive correlation has been specifically reported between HPV and CIS or severe epithelial dysplasia of the H&N, although a rare and unique papillary form of oral CIS, bowenoid papulosis, seems to be obviously associated.

The Epstein-Barr virus (EBV) has also been reported in 50% of oral erythroplakias and 40% of oral CIS lesions. Again, the significance of this in unclear and it is not known whether the EBV is acting as a carcinogen, simply exists (thrives?) within altered or otherwise damaged lesional cells, or is being shed at higher levels because of tumor-related immunodepression.

Tumor-suppressor genes and other cell maturation factors are involved in the initiation and progression of a wide variety of cancers, including H&N carcinoma. These have not been specifically investigated relative to erythroplakia or CIS, but Table 4 lists those with the strongest reported association with dysplastic H&N epithelium. To date, these factors have contributed little of practical application to precancers of this region but it is expected that future investigations will confirm prognostic correlations of importance.

Laryngeal cases. Virchow was probably the first to suggest that voice and alcohol abuse could produce precancers of the vocal cords, but since his time surprisingly few investigators have addressed etiology in their research. Epidemiologic evidence has, however, strongly implicated tobacco smoking in the etiology of laryngeal carcinoma and autopsy studies have demonstrated a strong correlation between daily tobacco consumption and the presence of laryngeal dysplasia. Almost half of all persons smoking more than 20 cigarettes daily have dysplastic vocal cord mucosa at autopsy, compared to 4% for nonsmokers. Unfortunately, no study has specifically addressed erythroplakia or CIS.

Tobacco chewing also appears to be a significant risk factor for laryngeal carcinoma, but only in persons who chew all day, every day. Alcohol abuse has been shown to have a synergistic association with tobacco abuse in the production of laryngeal carcinoma, but no data is available relative to laryngeal precancers. Available data somewhat implicate HPV in the etiology of some laryngeal carcinomas, but this has not been addressed for CIS.


Epidemiology

CIS of all anatomic sites annually affects 26.1 persons per 100,000 population (4.5 for males and 46.9 for females), excluding skin cases. Ninety percent of these are found at only four body sites: uterine cervix, breast, colon and corpus uteri. H&N lesions account for only 2% of the total, although the H&N is unique in being the only site with a strong male predilection.

Oral cases. There are no annual incidence data (number of new cases diagnosed annually) for oral erythroplakia, but the few epidemiologic investigations which have determined point prevalence rates (number of cases in a population at a given point in time) for nondescript red mucosal patches have found them in 1-17 per 1,000 adults. One of these studies distinguished between inflammatory and precancerous red patches, finding the latter to represent half of focal mucosal erythemas in a cohort of dental school patients (erythroplakia prevalence: 3 per 1,000 males, 1 per 1,000 females, 2 per 1,000 both genders). The erythroplakia prevalence rate of 17 per 1,000 U.S. adult tobacco users established by Prout et al also excludes an additional 43 per 1,000 inflammatory/traumatic red patches.

CIS, including severe epithelial dysplasia for purposes of discussion in this section, represents 80-90% of oral true erythroplakias and several H&N incidence investigations are available for CIS/severe dysplasia. These studies have shown that biopsy-proven oral CIS is a rare disease, diagnosed in only 0.1-0.6 of every 100,000 persons annually in the U.S., 0.2-1.0 if oropharyngeal lesions are included.

CIS usually accounts for only 2% of oral carcinomas but in communities with a strong health consciousness and early detection procedures in place, this proportion could reach as high as 17%. With the contemporary emphasis on early cancer detection and routine oral soft tissue examinations, the relative frequency of oral cancers found in this premalignant/preinvasive stage is greater today than it was half a century ago, and the incidence of CIS has increased accordingly, even as the incidence of invasive oral cancers has slightly decreased.

Men are affected with intraoral CIS four times more frequently than women (annual incidence rates: 0.4-1.0 vs 0.1-0.2 per 100,000 males and females, respectively).30-32 This is drastically different from the gender predilection of lesions of the urogenital tract where females are much more frequently affected, largely because the uterine cervix is such a common site for this disease.30 Persons 55-75 years of age are most often affected by oral CIS and this disease is almost unheard of before the fourth decade of life (Figure 1A). In contrast, CIS of the uterine cervix typically affects women in the 25-44 year age bracket and more than 10% of cases occur in 15-24 year olds.31

There seem to be only minor differences between racial and ethnic groups relative to oral CIS, with Hispanics, American Indians and Japanese Americans showing the lowest incidence among U.S. population subgroups.31 There also seems to be a slight urban/rural variation in frequency, with rural populations demonstrating somewhat lower incidence rates than urban populations.

Vermilion cases. Most cases of CIS of the vermilion borders of the lips are not included in federal epidemiology studies, but where effort has been made to identify such cases it has been shown to be the most common site of H&N involvement, accounting for 42% of all cases.32 Vermilion lesions are diagnosed in 1.0 of every 100,000 persons annually in the U.S. Approximately 88% of vermilion CIS occurs in males and the average age at diagnosis is 70 years, almost a decade older than the average age of persons with oral lesions (Table 5). Incidence at this site continues to increase throughout life (Figure 1B).

Laryngeal cases. There are no statistics relative to the frequency of laryngeal erythroplakia in any population. Annual incidence rates, however, have been published for CIS of this site, showing a rate that is less than the rate for oral CIS: 0.2-0.4 cases per 100,000 persons each year. The laryngeal lesions are much more common in males (88%) than in females and are usually diagnosed in persons 60-80 years of age (Figure 1C), somewhat older than the age at diagnosis for the oral counterpart.


Clinical Features

Erythroplakia, as the name implies, is an asymptomatic red macule or patch on a mucosal surface. The reason for the red color is unclear, but seems to be related to a combination of dilation and engorgement of the subepithelial microvascular system and a thinning of the keratin layer or of the entire epithelium. The vascular change is presumably part of an immunologic or inflammatory response to the dysplastic epithelial cells, and the lack of keratin seems to be a simple case of inadequate cellular maturity to produce this end product.

All mucosal surfaces of the upper aerodigestive tract are susceptible to erythroplakia and CIS development. Almost half of all CIS cases, however, occur on vermilion or intraoral surfaces, with the rest being evenly divided between the larynx and the pharynx. The most frequent oral sites of involvement, in decreasing order of frequency, are the lips (vermilion), lateral and ventral tongue, oral floor and soft palate. In the larynx, almost all cases occur on the vocal cords. The least likely site of H&N involvement is the nasopharynx and, in fact, not a single case of erythroplakia or CIS has thus far been reported from that location.

Oral cases. The typical oral lesion is less than 1.5 cm. in greatest diameter, but examples larger than 4 cm. have been seen. It may be quite sharply demarcated from the surrounding pink mucosa or it may gradually blend into normal tissues (Figure Figures 2A, 2B). Its surface is typically smooth and regular in coloration, but occasional lesions demonstrate a pebbled or granular surface change similar to that seen in granular or phase III leukoplakia. Rarely, a true papilloma-like appearance is seen (papillary CIS, bowenoid papulosis) with multiple, clustered erythematous patches, although the papillary nature may be clinically indistinct (Figure 2C).

Smooth erythroplakia is soft to palpation, often described as having a velvety feel to the examiner with hands unencumbered by latex gloves. The pebbled lesions tend to be somewhat firm, but erythroplakia never actually becomes hard or truly indurated until a deeply invasive carcinoma develops within it.38 Superficially invasive squamous cell carcinoma is likewise seldom palpable.

Erythroplakia may be admixed with or adjacent to leukoplakia in the mouth, in which case it is usually designated as erythroleukoplakia and considered to be part of the spectrum of leukoplakic lesions or phases (Figure 2D). The red areas of erythroleukoplakic lesions 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 clinical localization of dysplastic epithelial cells with enlarged, hyperchromatic nuclei is aided by coating suspicious mucosa with toluidine blue. After rinsing with acetic acid, residual stain indicates areas with immature cells (Figure 3). The clinician must be cautious, however, because many false positive toluidine tests are produced by inflammatory erythema.

The clinician must also be thorough in his or her clinical examination of adjoining mucosa because erythroplakia and erythroleukoplakia are seen adjacent to or part of 33% and 60%, respectively, of all early squamous cell carcinomas of the mouth. While it has been shown that oral carcinomas with associated or adjacent leukoplakia behave in a less aggressive fashion than carcinomas without such lesions, no similar data are available relative to carcinomas associated with erythroplakia.

Vermilion cases. Almost all examples of vermilion CIS are associated with actinic cheilosis.  Actinic irradiation damage frequently produces a vermilion border with a generalized but blotchy intermixing of pale and erythematous areas. The erythema, however, typically has a bluish hue and there is usually a surface keratin layer which prevents the appearance of the bright red change so characteristic of internal mucosal erythroplakia. More than half of all CIS lesions of the vermilion border, moreover, are ulcerated at the time of biopsy, probably secondary to the minor but chronic trauma of holding a cigarette in the area. Ulceration is a decidedly uncommon occurrence with the internal mucosal erythroplakic or CIS lesion unless it is associated with an obvious oral carcinoma (Table 5).

Laryngeal cases. Erythroplakia and erythroleukoplakia have been largely ignored in the laryngeal literature. This has occurred in part because red mucosa has long been considered to be simple inflammatory hyperemia, which is an almost constant feature of "smoker's" larynx. Ironically, a few authors have actually included mucosal erythema as a routine and required part of their definition of a white lesion, laryngeal keratosis or leukoplakia. Beginning at the century's midpoint, however, at least a few authors warned that the more heavily "inflamed" keratoses were at greatest risk of dysplastic or malignant change. Now, of course, the redness associated with laryngeal keratosis is well accepted as a dysplastic rather than purely inflammatory feature and is seen in 16% of keratoses, according to population studies. It seems to be unusual for a purely red vocal cord lesion to be biopsied prior to invasion, those with this appearance account for less than 15% of the CIS lesions of the larynx.


Microscopic Features

Almost all erythroplakic lesions contain dysplastic cells. The histopathology may be only mild or moderate epithelial dysplasia but more typically it is CIS or severe epithelial dysplasia. A certain proportion also demonstrate microinvasive squamous cell carcinoma. This is usually seen in only 5-10% of cases, but in one clinicopathologic review of 58 cases more than half were invasive.

Microscopic features of CIS are the same for oral, pharyngeal and laryngeal lesions. The two essential criteria for a diagnosis of this disease are (Figure 4):

  • a complete disorganization of cells throughout all layers of the epithelium, i.e. "top-to-bottom" dysplasia

  • an intact and well-defined basement membrane

Nuclei are typically hyperchromatic and enlarged, with the amount of cytoplasm diminished. Lesional cells are usually quite similar one to another (Figures 4A, 4B), but extreme variation in cellular size and shape may be present in some areas (Figure 4C). Mitotic activity is sometimes pronounced and abnormal mitotic figures may be noted. Keratin pearls are almost never seen.

The purists among us do not accept even the smallest hint of surface keratinization in their diagnosis of CIS, but most pathologists appear to accept the presence of flattened keratinocytes on the surface, with abrupt transition from the underlying dysplastic cells, as part of the disease (Figure 5). Vermilion CIS almost always demonstrates a thin layer of surface keratin, and in this regard is quite similar to Bowen's disease or CIS of sun-damaged skin.

The lateral transition from normal epithelium to CIS is often abrupt, but the altered epithelium may gradually "shade off" into the adjacent normal epithelium without a clear zone of demarcation (Figure 6). Additional areas of dysplasia may be seen at remote sites within the epithelium. The pathologist should carefully evaluate all such areas for signs of invasion because multifocal carcinoma is not a rare event in the H&N region.

As with much dysplastic epithelium, rete pegs frequently are bulbous or tear-drop shaped, often with secondary proliferations or projections of abnormal cells (Figures 4B, 6A, 7). These abnormal shapes are considered to be signs of dysplasia whether or not atypia is found in the individual cells of the rete ridges. The basement membrane must, moreover, be carefully examined for areas of micro invasion. This evaluation can be quite problematic in lesions associated with strong inflammatory (immunologic?) responses, which may result in a degenerated basement membrane. This especially a problem in the rare entity called "lichenoid dysplasia." All the usual features of epithelial dysplasia are present in this disease but the lowest layers of the epithelium demonstrate liquefactive or ballooning degeneration and saw-toothed or completely missing rete ridges. There is a characteristic subepithelial band of chronic inflammatory cells, predominantly T-cells. It is not yet known whether this variant represents premalignant change in a true lichen planus or is simply an unusual immune response to the dysplastic cells.

An occasional interpretive difficulty in the lower regions of CIS-involved epithelium is extension or "creep" of dysplastic epithelium down the ducts of underlying minor mucous glands (Figure 8). While relatively easy to identify, the significance of this feature is not yet clear. Some authorities consider it to be a sign of early invasion while others see it as simple in situ extension of lesion cells in a fashion not unlike the lateral extension at the margins of the lesion.3

Severe epithelial dysplasia may blend subtly into CIS, and some lesions are extremely difficult to differentiate (Figure 7). This difficulty has prompted some authors to suggest combining both microscopic diagnoses into a single entity, usually referred to as grade III dysplasia or grade III oral intraepithelial neoplasia (OIN III). Such a grading system maintains the two less severe types of epithelial dysplasia but renames them as grade I (mild dysplasia) and grade II (moderate dysplasia) intraepithelial neoplasia. Although a classification system with some merit, this grading of a continuum of neoplastic development appears not to be popularly accepted.

In routine epithelial dysplasia, i.e. those cases not thought to be CIS, there is a gradual transition from abnormal cells of the lower epithelium into normal or more mature superficial epithelial cells. When the atypical cells remain within the lowest third of the epithelium, a diagnosis of mild dysplasia is used. When such cells extend from the basement membrane to the middle third of the epithelium, a diagnosis of moderate dysplasia is used.

Only when primitive or atypical cells extend above the middle third of the epithelium is the diagnostic term severe (premalignant) epithelial dysplasia used. This implies that dysplastic change does not extend completely to the surface of the epithelium but, in truth, many lesions show atypical cells so close to the surface that it is impossible to accurately distinguish between severe dysplasia and CIS. The distinction, fortunately, appears to be moot, as both lesions have a similar biological behavior.


Treatment and Prognosis

Oral and vermilion cases. Erythroplakia should always be removed or destroyed, either as an excisional biopsy or after an incisional biopsy has demonstrated dysplastic cells. A conservative surgical procedure such as mucosal stripping is usually performed, with minimal damage to deeper connective tissues. This has the distinct advantage of preserving tissue for microscopic evaluation of potential regions of invasion, but destructive techniques such as laser ablation, electrocoagulation and cryotherapy have proven to be effective. Some surgeons advocate a more aggressive approach on the assumption that there may already be an invasive carcinoma present.

The key to therapy in this disease is extended clinical follow-up and patients should be examined every 3 months for the first year and semi-annually for an additional 4 years. Follow-up investigations of hundreds of lesions have demonstrated a malignant transformation rate of 14-50% (Table 2). This rather broad range may be due to the use of different histopathologic criteria, different biases in case selection, or real differences in various patient groups. Results must also be strongly influenced by the fact that most lesions are completely removed once a microscopic diagnosis is made. Recently, Lumerman et al47 compiled a table of 91 patients with oral epithelial dysplasia (all types) who received no further surgical treatment after the initial biopsy. Their results indicated that 58% remain the same, 9% increase in size and 15% develop invasive carcinoma.

Laryngeal cases. CIS of the larynx has been more extensively followed than CIS of the mouth or pharynx. Overall, 29% of treated laryngeal lesions eventuate in invasive disease, while untreated cases transform at a much higher rate (Table 3). Laryngeal lesions should all be treated and subjected to the same follow-up schedule as oral lesions.


Is It Cancer or Is It Not?

We believe that it is best to consider CIS as a premalignancy rather than true carcinoma, as not all lesions will become invasive malignancy if left alone (Table 3). Its biological behavior, moreover, seems to be strongly influenced by its location. Santa Cruz has emphasized, for example, that Bowen's disease of the skin has the exact histopathology as a CIS of the mucous membranes but it seldom becomes invasive. This observation dramatically highlights another of his conclusions that "few topics in pathology are as controversial as carcinoma-in-situ." The situation is greatly compounded for H&N cases by the fact that there is poor intraexaminer and interexaminer reliability or consistency in the diagnosis of epithelial dysplasia.

There is no information relative to the length of time an oral CIS typically exists before it begins to invade into underlying connective tissues, or the proportion which will actually invade if left untreated. Three laryngeal CIS studies, however, have followed untreated lesions and have determined a malignant transformation rate ranging from as low as 33% to as high as 90% (Table 3). In other words, no investigation has yet proven that CIS of any H&N site is guaranteed to invade underlying tissues or metastasize to distant anatomic regions. Even in the uterine cervix, where the vast majority of CIS cases occur, various follow-up studies have shown a wide range of malignant (invasive) transformation rates, from 21% to 90%.

Under the microscope, erythroplakia typically presents as CIS, severe epithelial dysplasia, or occasionally as superficially invasive carcinoma. The relative frequency of each of these diagnoses is variable, depending on whether one looks at an entire population, a dental school's patient pool, or a high risk group such as patients in a Veterans Administration hospital. In high risk groups, 90% of erythroplakias are CIS, 7% are severe epithelial dysplasia and 3% are superficially invasive squamous cell carcinomas.


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Table 1: Estimated relative malignant transformation potential of precancerous lesions (clinical terms only) of the oral, pharyngeal and laryngeal mucosa. Modified from Speight et al, Curr Diag Pathol 1997; 3:165-167.3

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Disease Name

Malignant Transformation Potential

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

  # reverse smoking: smoking with the lit end of the cigarette in one's mouth
## leukoplakia phases are explained in Bouquot1 and Bouquot and Whitaker2

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Table 2: 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.

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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

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Table 3: Malignant transformation rates (%) for laryngeal CIS and/or severe dysplasia, as determined by all English language follow-up studies published to date, listed by year of publication.

Author(s) Year Country # Pts

% Malignant

Transformation

Altman et al48 *

1952

U.S.A. 29 3.5
McGavran et al49 ** 1960 U.S.A. 18 11.1
Kleinsasser50 @ 1963 Germany 20 90.0
Norris & Peal51 ** @ 1963 U.S.A. 16 33.3
Miller & Fisher52 1971 U.S.A. 203 15.8
Gabriel & Jones53 ** 1973 U.S.A.   7.3
Pene & Fletcher54 1976 U.S.A. 26 4.0
Doyle et al55 1977 U.S.A. 28 7.1
Elman et al56 1979 U.S.A. 81 17.0
Hintz et al57 ** @ 1981 Germany 27 63.0
Hellquist et al58 ** 1982 Norway 20 25.0
Hojslet et al59 ** 1989 Germany   40.0
Bouquot et al60 * 1991 U.S.A. 15 6.7
Total, Treated Cases: 501 26.4% @@
Total, Untreated Cases: 53 60.0% @@

  * includes only cancers developing in the anatomic area of the previously recorded dysplastic lesions
** includes all epithelial dysplasias: mild, moderate and severe dysplasia, and CIS
  @ includes only untreated cases
@@ weighed for different sample sizes, excludes untreated cases

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Table 4: Molecular and other markers of potential significance to oral epithelial dysplasia & CIS.

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Mucosal Marker/Alteration Ref. Comment
AE1/AE2 (antikeratin antibodies) 72 AE1 reactivity pattern is highly disturbed in dysplasias; AE2 reactivity is quite variable
c-myc 75 Expression of this oncoprotein parallels the severity of dysplasia, although a few nondysplastic epithelia are also positive
Cytokeratin 19 (CK19) 74 This epithelial cytoskeletal protein shows reactivity of the suprabasal layer in 66% of dysplasias but is not specific enough to be a good diagnostic marker
GST-pi (placental glutathione
S-transferase)
79 Cytoplasmic and nuclear reactivity are considerably increased in severe dysplasias
Laser-induced fluorescence (LIF) 84 A characteristic fluorescence peak in the red region of the visible spectrum (630-640 nm) is seen in 92% of dyplasias; color intensity correlates somewhat with dyplasia severity. This is a clinical test.
Mib-1, cyclin D1, centromere-associated protein (CENP-F) 85 These proliferation markers show a 7-9-fold increase in cells above the basal layer in dysplasias
Mitotic index (MI); apoptotic/mitotic ratio (AI/MI) 82 MI is significantly increased in dysplasias; AI/MI ratio is significantly decreased in dysplasias
Monoclonal antibodies (Mab) 17.13 & 63.12 83 Reactivity pattern in 100% of dysplasias resembles that of carcinoma; stain is affected by inflammation
Nuclear DNA content/nuclear area 73 Mean nuclear DNA content and nuclear area is significantly increased in dysplasias
p53 mutation 74,

76

Mutated tumor suppressor gene is detected in at least 1/3 of severe dysplasias; correlated with severity of dysplasia
Proliferating cell nuclear antigen (PCNA) 74,

77

Suprabasal layer reactivity is found in 100% of dysplasias; normal and hyperplastic epithelia show only basal layer staining
Proteolytic activity 80 3-fold increase in dysplasias, but not specific and is also increased in trauma, smoking, pregnancy and diabetes
Tenascin 78 This extracellular matrix protein reactivity extends well below the basement membrane in dysplasia, especially in CIS; presumably represents inductive stromal change by atypical epithelial cells
Toluidine blue vital staining 4,

38,

86

This clinical test usually shows dark blue mucosal staining when epithelial cell nuclei are enlarged or hyperchromatic; also stains inflamed tissues; many false positives
Tumor-suppressor gene deletions, loss of heterozygosity (LOH), allelic imbalance (AI) 81,

87

Gene deletions or allele imbalances at TP53, DCC, 3p21.3-22.1, 3p12.1-13, 17p13.1 (p53) are detected in 50-77% of dysplasias; not detected in normal epithelia



Table 5: Clinical characteristics of CIS of the vermilion border and H&N mucosa. Modified from Bouquot et al, Cancer 1988; 61:1691-1698.32

Characteristic Vermilion H&N Mucosa
% males 88.2% 79.2%
Average age at diagnosis 69.8 yrs. 60.1 yrs.
% tobacco smokers 80.0% 93.3%
% alcohol abuse * 6.7% 68.4%
% with outdoor occupation 64.7% 20.0%
Average lesion size 1.3 cm. 1.4 cm.
Average lesion duration 3.4 yrs. 2.1 yrs.
% with erythroplakia only 0.0% 38.9%
% with leukoplakia 100.0% 66.7%
% with ulceration ** 56.3% 16.7%
% with invasive carcinoma at diagnosis @ 11.8% 16.7%
% with invasive carcinoma after diagnosis @ 0.0% 8.3%
% recurred after treatment (no cancer) 0.0% 12.5%

  * identified as "alcoholic," "heavy drinker," or with a "drinking problem" in medical records
** mucosa ulcers are virtually all invasive carcinomas, while most vermilion ulcers are inflammatory or traumatic in nature
  @ invasive squamous cell carcinoma (excluding CIS)

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