Somatic genetics

In studies addressing the genetic changes underlying pre-malignant lesions of the head and neck, the larynx and hypopharynx are often dealt with in a broader anatomic context including the oral cavity. True to current models of carcinogenesis, malignant transformation of the mucosa lining the larynx and other

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Fig. 3.42 Severe dysplasia (SIN 3, atypical hyperplasia). A The atypical epithelial cells occupy two thirds of the epithelial thickness. Note partially preserved epithelial stratification, expressed cytologic atypia and increased mitotic activity. Keratin layer is present on the surface. B Carcinoma in-situ (SIN 3). Prominent architectural disarray, marked cytologic atypia and increased mitotic figures with pathologic forms.

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Fig. 3.42 Severe dysplasia (SIN 3, atypical hyperplasia). A The atypical epithelial cells occupy two thirds of the epithelial thickness. Note partially preserved epithelial stratification, expressed cytologic atypia and increased mitotic activity. Keratin layer is present on the surface. B Carcinoma in-situ (SIN 3). Prominent architectural disarray, marked cytologic atypia and increased mitotic figures with pathologic forms.

regions of the head and neck is fundamentally a genetic process that involves activation of key oncogenes and inacti-vation of critical tumour suppressor genes. These genetic alterations generally occur in order of progression, however, it is fundamentally the net accumulation of multiple genetic alterations that dictates the frequency and pace of progression to invasive carcinoma {318, 319}. Genetic progression does not imply a uniform orderly progression through various stages of histologic progression. By some estimates, progression from normal mucosa to invasive squamous cell carcinoma requires as many as ten independent genetic events {2156}. Loss of heterozygosity studies indicate that the earliest alterations appear to target specific genes located on chromosomes 3p, 9p21, and 17p13 {318}. These alterations, particularly LOH at 9p21, may precede histopathologic evidence of dysplasia {317,2667}. Hyperplasia without any histologic evidence of dys-plasia has been found to represent clon-al populations of cells sharing the same genetic alterations found in SCC. Alterations that tend to occur in association with higher grades of dysplasia and SCC can include cyclin D1 amplification, pTEN inactivation, and LOH at 13q21, 14q32, 6p, 8, 4q27 and 10q23 {318,787}. Advanced precursor lesions of the head and neck demonstrate a spectrum of genetic alterations that is qualitatively and quantitatively similar to SCC {230, 294,2436}.

For some of the chromosomal regions commonly lost or amplified in precursor lesions of the head and neck, the targeted genes have been identified. Two tumour suppressor genes residing at 9p21 : p16 (CDKN2/MTS1) inhibit cell cycling via the Rb pathway, and p14(ARF) inhibits cell cycling via the p53 pathway {1022}. The p53 tumour suppressor gene resides at chromosome 17p13. p53 is involved in several cellular regulatory pathways including DNA repair, cell cycle control, and apoptosis {1115}. The cyclin D1 oncogene resides on chromosome 11q13 and is amplified in about a third of SCC {321,811}. However, for most regions of common chromosomal loss such as loss at chromosome 3p, the targeted gene(s) have not yet been well characterized. Retrospective studies examining the prognostic value of molecular markers, including LOH of chromosomes 3p, 9p21, and 17q13 as well as general ane-uploidy, have demonstrated that genetic alterations confer significant risk of malignant progression of precursor lesions. These precursor lesions included clinically defined leukoplakia, with corresponding histologic diagnoses varying along the spectrum of benign to precursor lesions mentioned above. In some cases, retrospective genetic analysis was able to define risk of malignant progression in hyperplastic lesions {1627,2201,2492}.

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