Oral Precancer: Dysplasia, Molecular Biology, Microbiology
Dysplastic epithelial cells, as seen here, are the hallmark of the precancer designation. Especially note the large, dark, irregularly shaped (often angular) nuclei.
Before looking further into oral leukoplakia it should be emphasized that the diagnosis of leukoplakia is a diagnosis of exclusion which requires the clinician to be so well acquainted with all other white oral lesions as to be able to rule them out prior to using the term leukoplakia for a particular keratosis in a particular patient. It must also be emphasized that the term leukoplakia is a clinical one. Even though biopsy and microscopic evaluation is frequently required in order to identify dysplastic or malignant cells, the presence of such cells does not alter the clinical diagnosis, and leukoplakia is still leukoplakia with or without dysplastic epithelial cells. In retrospect it seems surprising that histology was once considered essential to the diagnosis of this disease in which only one of every four cases is ever biopsied.
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Experience has taught us that certain cellular and tissue alterations are associated with malignancy and premalignancy. Altered cells appear to be more primitive than normal and so these changes are presumed to be examples of immature or inappropriate differentiation, although pathologists typically refer to them as dysplasia or atypia. Animal models for oral carcinogenesis have reliably demonstrated that normal epithelium passes through stages of more and more severe dysplasia prior to the onset of invasive neoplasia. As a general rule, fewer than 20% of oral leukoplakias will demonstrate dysplasia, 8% will have severe dysplasia. On the other hand, erythroplakias show severe changes more than 90% of the time.
Cellular changes in dysplasia. Specific alterations of individual epithelial cells are important in the determination of epithelial dysplasia. Cells and nuclei take on a more primitive appearance, similar to those of basal cells with enlarged nuclei (nuclear hyperplasia), dark-staining nuclei (hyperchromatism), enlarged, often eosinophilic nucleoli (prominent nucleoli), and with an increased nuclear-to-cytoplasmic ratio. These cells also appear to be crowded more closely together than normal keratinocytes (increased cellular density). Such changes are not exclusive to carcinogenesis, as they may be seen in reactive epithelium or epithelium influenced by a variety of systemic alterations. Flow cytometry and image cytometry add significantly to the pathologist's ability to assess nuclear changes associated with eventual cancer development.
There is often an increase in mitotic activity in dysplastic epithelium, but this also is seen in many reactive lesions. Enlarged, tripolar or star-shaped mitotic figures (abnormal mitoses), however, are much more indicative of precancerous changes. Abnormal mitosis may also be defined as mitotic figures found in unusual locations above the basal cell layer.
A key alteration of dysplastic epithelial cells is variation in the shape of the cells and nuclei. This pleomorphism is unusual outside of cancers and precancers. Premature production of keratin below the surface layer is another important alteration, but it is much more commonly seen in oral carcinomas than in oral premalignancies. This dyskeratosis may be represented by individually keratinized cells or by tight concentric rings of flattened keratinocytes (epithelial pearls). The pathologist must be careful not to misinterpret a keratin-filled surface indentation cut tangentially as true intraepithelial keratosis. Not all dyskeratosis is related to malignancy or premalignancy. Individually keratinized cells, for example, are also characteristic of hereditary benign intraepithelial dyskeratosis (Witkop disease).
Cellular necrosis and loss of cellular cohesiveness (acantholysis) are major signs of poorly differentiated carcinoma but are extremely rare in the epithelial dysplasia of oral precancer. When present, these features must be distinguished from intercellular edema, intraepithelial inflammatory cells and degenerating cells with pyknotic nuclei and vacuolated cytoplasm. Virus-induced koilocytes may be seen but are not necessary to the diagnosis, nor does their appearance appear to be of prognostic significance.
When dysplasia is seen in epithelium which otherwise has the microscopic features of lichen planus (liquefactive degeneration of basal cells, saw-toothed rete processes, hyperkeratosis, subepithelial band of inflammatory/immune cells, etc.), the lichen planus features are essentially ignored and the lesion is graded according to the below-mentioned criteria for epithelial dysplasia, although the term lichenoid dysplasia may be applied to the case.
Many oral precancers show excess surface keratin (hyperkeratosis, hyperparakeratosis, hyperorthokeratosis) and most show hyperplasia of the spindle cell layer (acanthosis), but both changes are common to a number of mucosal lesions without a cancer transformation potential and neither is necessary to the diagnosis of dysplasia.
Smokeless tobacco keratosis is characterized by a somewhat unique intracellular vacuolization or "edema" of superficial layers, perhaps interspersed with streaks of parakeratinized cells. This change most likely results from a low-grade chemical burn from the alkaline tobacco used. It has been referred to as surface etching and has no implications one way or another relative to the risk of malignant transformation.
Basal cell hyperplasia, as discussed above, is of major importance to the diagnosis as well as to the grading of dysplasia. Other tissue changes, however, are important features of oral epithelial dysplasia, especially certain alterations of the rete processes.
Extremely elongated rete processes with minimal cellular atypia are of little concern, as they are characteristic of a variety of hyperplastic conditions, including papillomavirus infections, frictional keratosis, psoriasis and pseudoepitheliomatous hyperplasia. Rete processes with a bulbous enlargement of the lowermost region (drop-shaped rete processes), however, are worrisome regardless of their size, especially if secondary projections or nodules are seen to arise from the basal layer and branch at indifferent angles into the lamina propria and connective tissue papillae. There is no physiological explanation for secondary nodules extending laterally from a rete peg of the oral mucosa. To many, these alterations are ominous enough to alter the histopathologic grading of a lesion to a higher level.
Dysplastic epithelium may be atrophic as well as acanthotic and some experts believe that atrophic forms have a higher risk of malignant transformation. Atrophic epithelium often lacks rete processes and may be ulcerated, thereby mimicking a traumatic or inflammatory lesion with thin, regenerating epithelium creeping in from the margins. Regenerating epithelium, fortunately, often has granulation tissue beneath it to distinguish it from precancerous dysplasia in atrophic epithelium. The very nature of thin, atrophic epithelium presents a diagnostic grading dilemma because basilar hyperplasia very quickly extends to the surface. There are no standards for this situation but Speight et al (1997) have recommended that these be regarded as severe dysplasias. Leukoplakias of the vermilion border of the lower lip in actinic cheilitis (actinic cheilosis, farmer's lip, sailor's lip) are especially prone to these difficulties.
An alarming morphological alteration of dysplastic epithelium is loss of stratification (loss of polarization) due to an apparent inability to properly differentiate and mature from basal cells to prickle cells to flattened keratinocytes. Cells high in the epithelium have the same immature appearance as those in the basal layers. This feature is especially pronounced in severe epithelial dysplasia and carcinoma in situ.
The pathologist must pay particular attention to the appearance of the epithelial cells at the lateral surgical margins, and the presence or absence of dysplasia should be mentioned in the histopathologic description of the lesion. The presence of squamous metaplasia of the excretory ducts of the minor salivary glands should also be mentioned, especially when cellular atypia is evident. Many treatments for oral precancers remove or destroy only the most superficial portions of the submucosal tissues, thus leaving behind the salivary glands and their ducts.
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Most pathologists grade oral epithelial dysplasia according to a combination of cellular and tissue changes. Low-grade lesions are considered to be less "severe" than high-grade lesions but this assessment is a subjective one and it is not unusual for different pathologists to place emphasis on different aspects of dysplastic alteration, thereby arriving at somewhat different diagnostic conclusions. Regardless of individual emphasis, however, certain oral precancer grading criteria are in general use:
Oral epithelial dysplasia is subdivided into three prognostically significant categories, mild, moderate and severe. Mild (grade I) dysplasia demonstrates proliferation of atypical or immature basal cells above the parabasal region but not extending beyond the lower third of the epithelium. Moderate (grade II) dysplasia demonstrates a similar proliferation into the middle one-third of the epithelial cross-section. The term severe (grade III) dysplasia is reserved for abnormal proliferation from the basal layer into the upper third of the epithelium. Carcinoma in situ, thought by some to be a premalignancy and by others to be an actual preinvasive malignancy, requires top-to-bottom change with undifferentiated, primitive cells from the basal layer to the topmost layer, although most authorities accept a thin layer of surface keratin with abrupt transition into the underlying atypical cells. The grading of dysplastic oral epithelium must also take into consideration the degree of cellular atypia, as described above, and those lesions with marked alteration are elevated into a higher grade level.
It is difficult to determine the amount of basal cell hyperplasia in oral precancers because of transverse sectioning of tissue samples and because of the natural undulation of the inferior margin of squamous epithelium. It may be helpful to make this determination from the top of the connective tissue papillae because of the great variability of rete process length in acanthomatous epithelium, but there is no established standard and in many cases the basal hyperplasia is confined to the rete processes themselves.
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While the microscopic features of dysplasia are now relatively well established, few investigations have actually followed lesions with specific dysplastic grades or changes in order to determine their natural history. This is, of course, made quite difficult by the following facts:
Keeping the above caveats in mind, as a general rule it seems to be accepted that the biological behavior of severe epithelial dysplasia and carcinoma in situ are identical, or so similar as to make the distinction mote. Investigations have found that 20-35% of severely dysplastic lesions develop carcinoma, which is similar to the figures for carcinoma in situ, as was previously mention (see follow-up web page). At the opposite end of the spectrum, mild epithelial dysplasias so seldom eventuate in carcinoma, and are so similar to reactive epithelial changes, that few pathologists consider them a serious threat or recommend complete removal of the associated white lesion.
One of the great ironies of the world of oral precancers is the apparent fact that the correlation between the clinical appearance of leukoplakia and cancer transformation is relatively good while any microscopic changes less than severe are not particularly helpful in determining prognosis. Recent investigators have even concluded that they were better able to correlate the presence of papillomavirus with the clinical appearance of oral precancers than with the microscopic grade of dysplasia. Much is yet to be learned. Perhaps the addition of molecular biologic parameters to the mix will shortly provide better prognostic indicators.
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Several microorganisms are associated with proliferative epithelial lesions. The 70+ types of human papillomaviruses (HPVs) are often suspected of playing an important role in the development or malignant transformation of oral precancers, in particular the high-risk subtypes HPV-16 and HPV-18, which are associated with cervical and upper aerodigestive tract carcinoma (up to 90% and 54% of cases, respectively). The case for an etiologic role for this virus is strengthened by the fact that HPV E6 protein is known to bind to and inactivate the p53 tumor suppressor gene, possibly allowing chromosomal instability and subsequent neoplastic growth. HPV-16 has also been shown by McCance and colleagues (1988) to produce obviously dysplastic epithelial cells in differentiating tissue cultures which are otherwise sterile. HPV-31, HPV-33 and HPV-35 have also been associated with oral precancers and cancers, although the association is not as strong as that for HPV-16/18.
High-risk HPVs are found in 15-42% of leukoplakias, in 50% of erythroplakias, in 50-100% of oral squamous cell carcinomas, and in up to 10% of normal oral mucosa. Verruciform leukoplakias are especially prone to contain viruses, with 89% of PVL specimens having recently demonstrated positively for HPV 16 or HPV-18. There seems to be a distinct predilection for HPV-associated leukoplakias to occur on the buccal mucosa, while lesions of the ventral tongue and oral floor are much less likely to contain the virus. There also seems to be a confusing lack of a positive correlation between HPV presence and the severity of the histopathologic grade of epithelial dysplasia, a feature also of some studies of HPV in oral carcinoma. The male gender predilection seen in oral carcinomas with HPV has not yet been demonstrated in oral precancers, nor has HPV been associated with younger oral precancer patients, as it is with oral carcinoma patients.
The prognostic significance of HPV presence in oral precancers is yet to be determined by large follow-up investigations, but the 1996 study of 49 lesions (10 erythroplakias, 39 leukoplakias) followed by Nielsen et al for an average of 6.3 years found HPV in all three cases which eventuated in malignant transformation. Two of the transformed cases were initially erythroplakias and one was a verrucous leukoplakia. It may be significant that this Danish study, using four different sophisticated laboratory techniques, were unable to demonstrate HPV in any of its 20 control subjects. Survival from oral carcinoma does not appear to be associated with the presence or lack of HPV.
Herpes simplex virus (HSV), especially type 2 HSV, was once considered to be the cause of a large proportion of cancers of the uterine cervix, and it has been suggested that it plays a role in oral carcinoma. Epidemiologic evidence now suggests that it may be no more than a common companion infection in persons with HPV infections and that the latter virus plays a much more important carcinogenic role. Currently, the evidence to prove a causal relationship between HSV and oral precancers or cancers is insufficient, but continued research may eventually show a relationship.
Candida albicans is the other microorganism with a major association with oral precancers. It has been found in up to half of biopsies from verruciform/nodular leukoplakias and erythroleukoplakias. Investigations using fungal cultures instead of biopsy samples have found the microorganism in essentially all examined cases of verruciform or nodular leukoplakia. Some authors prefer to include this group in a separate leukoplakia subtype called candida leukoplakia, chronic hyperplastic candidiasis, or candida hyperplasia. There were early indications that three times as many candida leukoplakia cases developed carcinoma than leukoplakias without candida (30% and 10%, respectively), and case reports certainly associate chronic hyperplastic candidiasis with dysplastic cells and carcinoma development. More recent investigations, however, have found that the same proportion of cases go on to malignancy whether or not candida is present in the epithelium.
It may be that the fungus is merely growing in an altered epithelium, epithelium with a strong susceptibility to transform into carcinoma. It might also be that the fungus is producing the keratosis and dysplasia, perhaps in concert with tobacco smoke or another carcinogen. Laboratory experiments have shown that the yeast is capable of actually producing keratotic plaques on the tongues of rats, and certain strains of candida have been shown to produce carcinogenic nitrosamines. It has also been shown that at least some candida leukoplakias diminish in size or become less irregular in appearance when treated with antifungal therapy. Some oral pathologists are now recommending a course of medication prior to biopsy of a suspected candida leukoplakia in order to reduce the abnormal histopathologic appearances of epithelial cells in the biopsied tissue.
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Investigations at the level of cellular biology continue to provide exciting and much needed insight into oral premalignancy. Tumor suppressor genes which function as negative regulators of cellular proliferation have received the most recent attention. When inactivated by deletion or mutation, unrestrained cellular growth ensues. The suppressor gene most frequently altered in carcinomas of the upper aerodigestive tract is the p53 gene, located on chromosome 17p, but doc-1 (deleted in oral cancer-1) and BRCA1 gene mutations have also been seen. Tissue samples are necessary for proper study of these genes, although serum levels for some of their associated proteins are now being evaluated.
Results from several studies suggest that the p53 gene in its normal state is capable or arresting the cell cycle after DNA damage to that cell. Mutated p53 genes not only loose this ability but tend to accumulate within the nucleus because they have a longer half-life than the normal or wild-type genes. The resulting p53 over-expression or mutation has been demonstrated more frequently (43%-93% of cases) in oral mucosal carcinoma cells than in any other human cancer, and its occurrence in oral dysplasias and microscopically normal mucosa adjacent to head and neck carcinomas suggest that its alteration is an event which occurs early in carcinogenesis. Some investigators have evaluated the next step in the process, i.e. the interaction of p53 proteins with various other cellular proteins and viral oncoproteins, for example, finding that 36% of oral carcinomas and 19%of oral dysplasias demonstrate complexes formed by the binding of p53 with heat shock proteins.
Alterations of the p53 state are thought to be prognostically significance in a number of human malignancies. Only a few precancer studies, however, have used cases from patients who eventually developed head and neck malignancy. These showed a correlation of p53-positive immunostaining with increasing severity of dysplasia (10% of control cases were positive, as were 50% of hyperkeratoses without dysplasia, 67% of low-grade dysplasias, 85% of high-grade lesions, and 89% of invasive carcinomas). It also appears that as the severity of epithelial dysplasia increases in precancers the proportion of immunoreactive cells increases. Interestingly, there seems to be no strong correlation between p53 positivity and markers for cell proliferation rates, such as Ki-67, at least for carcinoma in situ lesions. Less surprising is the fact that routine markers for normally differentiating oral epithelium, such as cytokeratin-4, are lacking in carcinoma in situ.
Proto-oncogenes are genes that normally promote cell growth. Alteration of the structure or function of a proto-oncogene converts it to an oncogene, which in turn produces an abnormal protein or oncoprotein. In cancers of the head and neck region, over-expression of the p21 ras oncoprotein has been observed more frequently than any other, but this has not been evaluated in precancers of that region, nor is there any apparent prognostic significance to its presence.
Growth factors necessary for normal growth and development may also play a role in oral cancer and precancer. Fibroblast grown factors (FGF) are widely distributed in normal and neoplastic tissues. They are involved in angiogenesis and wound healing, and have also been shown to be mitogenic for keratinocytes. Almost all oral carcinomas are immunoreactive to FGF and oral carcinoma cells in culture are capable of expressing FGF. Biopsy samples of oral dysplastic lesions have also demonstrated positive focal staining which becomes stronger with increasing immaturity or severity of the dysplastic cells. The significance these findings is yet to be determined but they suggest that over-expression in mucosal lesions might reflect malignant change.
Epidermal growth factor receptor (EGFR) is the protein of the proto-oncogene c-erb. Its expression has been correlated somewhat with an increased rate of recurrence in some cancers of the head and neck region, but study results vary and the final significance of EGFR has yet to be determined. Thus far, investigators have not evaluated this aspect of oral precancers.
The proliferative activity of a tumor may reflect its biological potential and can be measured in various ways, including the immunohistochemical demonstration of proliferation markers such as proliferating cell nuclear antigen (PCNA) or the nonhistone nuclear protein, Ki67 (MIB 1). Local recurrence has been associated with a decreased PCNA expression or increased Ki67 expression in head and neck cancers, but evaluation of these events in oral precancers has not yet been reported.
Flow cytometry is a readily available means by which to assess proliferative and tumor activity, especially aberrations such as DNA aneuploidy and nondiploidy. In laryngeal precancers, aneuploidy and nondiploidy is significantly more frequent in lesions which precede to laryngeal carcinoma. As with p53 mutation, DNA alterations are considered to be early changes of carcinogenesis, although one does not necessarily precede the other. Also, p53 immunoreactivity and DNA aberration show a high degree of complementarity, with almost all precancers proven to eventuate in invasive carcinoma displaying one or the other alteration. These two alterations appear to hold the greatest hope of becoming important and practical tests for the evaluation of highest-risk oral precancer, but at the present time neither is quite a feasible for routine practice.
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