Vaginal carcinoma : studies on etiology and prognostic factors

Sammanfattning: Primary carcinoma of the vagina (PCV) is a rare disease, with poor survival, mostly affecting elderly women. Due to its rarity the established knowledge originates from studies based on small materials, therefore little is known regarding the genesis, natural history and factors predicting the prognosis. PCV is supposed to have similar aetiology and natural history as cervical carcinoma, which however mostly occurs at younger ages. Clinical stage is described as the most important prognostic factor. Against this background the objectives of this thesis were focused on the understanding of the genesis of PCV and its prognostic factors. The material in the retrospective studies (paper 1 and 11) is the largest so far published on PCV. A hypothesis was that factors influencing the age at onset of PCV should be connected directly or indirectly with the genesis of the disease. Epidemiological, clinical and histopathological variables were evaluated in relation to age at diagnosis in a retrospective study or 341 cases of PCV, diagnosed 1956 - 1996. According to the statistical analysis the independent predictor for young age at diagnosis was a history of cervical dysplasia and for old age at diagnosis late menarche. Parity >4 as well as nulliparity, smoking and unstable marital status were background factors more common than in the general Swedish female population, but not correlated with age at diagnosis. Clinical and histopathological prognostic factors were evaluated retrospectively in 314 patients with squamous cell carcinoma of the vagina. The 5year discase-specific survival rate was 45 % and in stage 175%. In the multivariate analysis there were only three factors that independently could predict poor survival: high age at diagnosis, large tumors (>4cm) and advanced stage. Common background factors with no prognostic significance were prior hysterectomy, other gynecological malignancies and pelvic irradiation. The immunohistochemical expression of laminin-5gamma2 chain, an epithelial basement membrane protein, implicated in tumour cell invasion, was investigated in 59 cases of primary vaginal malignancies. All epithelial tumours showed gamma2 chain immunoreactivity. High expression of the 72 chain was a good predictor of poor survival in the univariate analysis, but not in the multivariate analysis. A positive correlation between tumour size and gamma2 chain expression could also be observed. Comparative genomic hybridization (CGH) of 16 primary vaginal carcinomas revealed that 70% carry relative copy number increases that map to chromosome arm 3q. The pattern of genomic imbalances was strikingly similar to the one observed in advanced cervical tumours. Most PCV were aneuploid, showed high proliferative activity, low p53 and increased p21 expression. Human papilloma virus was detected in 2/8 cases. In the univariate analysis age at diagnosis, tumour size, and laminin-5 expression were identified as predictors or prognosis. Protein expression patterns in six samples from primary vaginal cancers, in five from normal vaginal tissue and in five primary cervical cancers, were analyzed using twodimensional polyacrylamide gel electrophoresis (2-DE). A total of 23 protein spots were significantly differentially expressed among cervical and vaginal carcinoma. By using these 23 proteins in cluster analysis all samples could be classified into three distinct groups (normal vaginal tissue, vaginal- and cervical carcinoma). There might be a possibility to identify tumour-specific markers among the differentially expressed proteins. In conclusion this thesis supports the theory of related aetiology and tumorigenesis for vaginal and cervical carcinoma. Crude clinical variables (stage, tumour size and age at diagnosis) turned out to be independent predictors of prognosis. PCV appears to be an aggressive tumour characterized by high genomic instability, aneuploidy and high proliferative activity.