A. State of the Science

The development of oral cancer seems to begin in
many cases with exposure of the mucosal surfaces(1-4)of the upper
aerodigestive tract to topical carcinogens, predominantly alcohol
and tobacco. In some persons exposed to these carcinogens or co-carcinogens,
premalignant and malignant lesions

(5,6) develop in a multi-step process within the mucosa. However, oral cancers occur in some patients with no history of tobacco or alcohol usage and no other apparent risk factors. Additionally, it is not clear that all of the tumors have an apparent “precancerous” state.

There is an emerging body of evidence that persons who develop head or neck cancer may have undergone alterations in or other tumor suppressor genes; however, this has not been proven. 7-13 In addition, there is evidence that altered genes may cooperate with other oncogenes, such as ras, to generate cells with a growth advantage for tumor progression, a multifunctional process associated(14)with cutaneous carcinogenesis as well. Increasing immunosuppression from HIV infection also appears to be a factor in predisposing oral mucosa to malignant changes (see Chapter III).

Neoplasms of diverse cellular origin arise in the oral regions, including nasopharyngeal carcinoma, lymphoma, mucosal melanoma, sarcomas, and salivary gland tumors. This chapter will focus on squamous cell carcinomas and their variants, as these cancers constitute over 90% of oral malignancies.

The earliest detectable morphologic changes are the appearance of the “premalignant” lesions of leukoplakia and erythroplakia. Genetic alterations in these premalignant lesions have also been(17-19)demonstrated
(see Chapter IV). Leukoplakia is a white plaque that cannot be removed by gentle scraping and for which no other etiology can be identified. Microscopically, leukoplakias exhibit hyperplasia of keratinocytes, as represented by hyperorthokeratosis, hyperparakeratosis, and/or acanthosis.

The term dysplasia is reserved for lesions showing combinations and degrees of cytologic atypia (e.g., hyperchromatism, increased nuclear size, pleomorphism, dyskeratosis, and increased or (1,18) abnormal mitotic figures). Atypia confined to basilar and parabasilar keratinocytes constitutes mild dysplasia , whereas atypia extending into the midspinous layer is termed moderate dysplasia. When cellular atypia extends to the surface layer, the terms severe dysplasia and carcinoma in situ (complete top-to-bottom cytologic atypia) are applied. Architectural changes are also a feature of dysplasia, the most significant being a bulbous or teardrop shape of rete ridges. For oral mucosa in general, up to 20% of clinically defined leukoplakias that are biopsied may exhibit dysplasia; lesions (19) located in the floor of the mouth approach a 40% prevalence of dysplastic change. Dysplastic leukoplakias have a high propensity to progress to invasive squamous cell carcinoma. However, leukoplakias without present evidence of dysplastic changes may progress to dysplasia and subsequently to carcinoma; still, many leukoplakias fail to undergo malignant transformation. (20,21)

Erythroplakia is a velvety red patch of oral mucosa that does not conform to other defined oral disease processes that appear red clinically. There is a high prevalence of dysplastic change among(1,2,22) these lesions, approaching 80-90%, and progression to invasive carcinoma is high. Although dysplastic, the epithelium is usually atrophic, and submucosal vasodilation with inflammatory cell infiltration is a consistent finding. When erythroplakias coexist with white foci, they are termed speckled leukoplakias or erythroleukoplakias; such lesions will exhibit hyperkeratosis in the white areas.

Malignancies arising from the mucosa of the oral cavity are epithelial in origin and are, therefore,(23,24)classified as squamous cell carcinomas more than 90% of the time. According to the degree of differentiation, three subtypes are defined: (1) well-differentiated squamous cell carcinoma showing more than 75% keratinization; (2) moderately differentiated squamous cell carcinoma with 25-75% keratinization; and (3) poorly differentiated squamous cell carcinoma with less than 25%(1,2)keratinization. The majority of cases are of moderate differentiation. A clear relationship between histologic differentiation and clinical prognosis has not been established, although a lack of differentiation has been associated with more rapid growth and spread. The morphologic classification of squamous cell carcinoma by degree of differentiation is used in the description of the histopathologic specimen.

There are histopathologic variants of squamous cell carcinoma, all of which are rare, that affect prognosis and the selection of therapeutic mo dal ities. Spindle cell or sarcomatoid squamous cancers, occasionally found in the oral cavity, are most frequently encountered on the lip and in the larynx. Radiation therapy to a pre-existing conventional squamous cell carcinoma is a common antecedent (25) event; however, spindle cell carcinomas may arise de novo. Other rare variants of oral, head, and neck carcinoma include pseudoglandular, basaloid, and small cell neuroendocrine carcinomas, the latter two being radiosensitive. Because these tumors share histopathologic features with other neoplasms (i.e., melanomas, neuroblastomas, lymphomas), the use of specific immunohisto-chemical markers is warranted.

Verrucous histopathologic patterns characterize a subset of oral epithelial tumors. Because there is evidence that these carcinomas evolve from leukoplakias that also exhibit a verrucoid architecture,(17) they are termed proliferative verrucous leukoplakia (PVL). Two specific forms of squamous cancers may arise from PVL lesions. The first, verrucous carcinoma, is characterized by marked hyperparakeratosis, acanthosis, parakeratin crypts, and large “pushing” bulbous rete ridges, said to(26) resemble “elephant’s feet.” It should be noted that verrucous carcinomas do not have dysplastic cytologic features; they also do not metastasize.

The second variant, also often preceded by PVL, is the papillary form of squamous cell carcinoma. Histologically, these lesions exhibit either an exophytic papillary pattern of growth or a verrucous (27,28) inverting architecture. Both patterns harbor dysplastic cytologic changes; a small number (less than 10%) have been shown to metastasize to regional nodes.

Oncogenes and proto-oncogenes are DNA sequences that encode factors that drive the cell cycle and include growth factors, their ligands, internal signaling pathway protein kinases, cyclins, cyclin­associated kinases, and DNA transcription factors, many of which can be demonstrated in tumor tissues. Conversely, anti-oncogene or tumor suppressor gene protein products retard or inhibit the cell cycle or activate pathways that lead to programmed cell death (apoptosis). Loss of suppressor gene product or inactivation by mutation of both alleles will favor cell proliferation and malignancy. These proteins can also be detected in tissues by immunohistochemical and molecular analytic methods.

Oncogenes and tumor suppressor genes are currently being studied in both defining the multistep(1,6) carcinogenetic process and as prognostic factors for disease-free and overall survival. For example, amplification of the epidermal growth factor receptor (EGFR) gene has been demonstrated in human(29,30)specimens. In one study, EGFR levels were shown to be higher in poorly differentiated tumors(31)than in well-differentiated or moderately differentiated tumors. In addition, increased EGFR levels (32) have been shown to correlate with larger primary tumor lesions. On the other hand, studies of the erb-B-2 oncoprotein have indicated that t