Section 4 -

Molecular Biology of Squamous Cell Carcinoma Adel K. El-Naggar

Background: Head and neck squamous carcinoma (HNSC) is the 6th most frequent cancer in the US with an approximately 50% mortality rate. While death due to disease is comparatively less than other major cancer types, the disease inflicts considerable psychological, functional, and physical morbidity on its subjects. Despite advances in diagnosis, clinical assessment, and therapeutic modalities in the last decades, the outcome of patients with HNSC remains unchanged. Therefore, efforts have recently been devoted to identifying molecular markers that may lead to better stratification and management of these tumors. These efforts have centered on the analysis of vital cellular pathways including cell proliferation, death, and differentiation. Risk Factors, Field Cancerization and Squamous Tumorigenesis: The etiologic factors associated with the development of HNSC are varied and include tobacco and alcohol abuse and viral infection. Exposure of the entire mucosal surfaces to these risk factors renders them susceptible to cancer development and form the basis for the field cancerization hypothesis. Although the exact mechanism of how these risk factors induce tumorigenesis remains unknown, it's generally accepted that they initially induce non-clonal genomic instability that may be reversible but if persist, subsequent critical alterations lead to clonal development and tumorigenesis. These events precede and/or coincide with the gross and phenotypic changes in the squamous mucosa. Progenitor and Basal Cell Origin: The cell of origin for HNSC is unknown. The evolution of squamous carcinoma of the head and neck is the result of the progressive accumulation of molecular alterations of vital cellular pathways' normal squamous mucosa. It is, therefore, conceivable that the primary cell of origin in mucosal squamous carcinoma can be either differentiated or dormant totipotent basal cells capable of proliferation. In either case, multiple genomic hits are required for the neoplastic transformation in which the subsequent phenotypic outcome depends on the state of differentiation and host cell interaction. Phenotypic and Molecular Progression Model: The pathologic stages of squamous mucosal pre-malignancy are well characterized and form an ideal model to study the molecular alterations associated with the initiation and progression of squamous carcinoma. Clinical lesions considered to carry a risk for the development of squamous carcinoma are leukoplakia, verrucous hyperplasia, and proliferative verrucous hyperplasia. The incidence of carcinoma from leukoplakia (hyperplasia and hyperkeratosis) is wide and ranges from 3 to 25%. These lesions, in contrast to other sites, can be easily visualized and are accessible to observation and repeated histological evaluation. The alterations associated with early development, invasion, and metastasis consist of genetic and/or epigenetic events that disrupt cell differention, adhesion, proliferation, and survival. The genetic changes occur at the DNA level and are comprised of chromosomal deletions and/or amplifications and gene mutations. The epigenetic alterations include histone acetylation, DNA methylation, and/or chromatin modeling. It is believed that these cellular alterations precede and persist during the phenotypic alterations of squamous mucosa and the progression of pre-malignant lesions to invasion and metastasis. Although these modifications are primarily of epithelial cellular origin, the influence of submucosal stroma and host non-neoplastic elements in the induction of invasion and subsequent progression has recently been recognized. In that context, of changes in the underlying epithelial stroma takes place at undefined points of the pre-malignant progression and leads to the acquisition of mesenchymal phenotype by squamous cells prior to invasion. Identifying these events is critical to developing screening and diagnostic markers, biological predictors of response and behavior, pathomolecular stratification, and biological targets for therapy. The presentation will highlight the current status of molecular pathways associated with head and neck squamous carcinogenesis. Bibliography Batsakis JG, Cleary KR, Cho KJ. Lichen planus and lichenoid lesions of the oral cavity, Ann Otol Rhinol Laryngol 1994;103:495-7. Beckhardt RN, Kiyokawa N, Xi L, et al. HER-2/neu oncogene characterization in head and neck squamous cell carcinoma, Arch Otolaryngol Head Neck Surg 1995;121:1265-70. Choi HR, Sturgis EM, Rosenthal DI, et al. 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