The cell biology of basal cell carcinoma. relationship to histology and clinical outcome.

Basal cell carcinomas presents with extremely diverse clinical and histological appearances and behaviour. Currently there is little understanding of the biological processes that determine these variations. In an attempt to understand these differences, this thesis evaluated some aspects of the cell biology of BCC both a prospective series and in archival specimens. A variety of measurements were assessed in combination with patient factors (age, presentation etc.) and medical factors (type and adequacy of treatment). The cell kinetics of BCC was studied in vivo following administration of bromodeoxyuridine, which was analysed by flow cytometry. The growth fraction (Ki-67 immunohistochemistry) and the contribution of cell loss to the overall tumour kinetics were studied by evaluating apoptosis (morphologically) and the bcl-2, bax and p53 protein expression, using immunohistochemistry, in both the prospective and archival specimens (including non recurrent, recurrent and horrifying BCCs). It was apparent that BCCs are highly proliferative tumours with a median Ts of 7.6 hours (range 5.0-14-6), Tpot 2.8 days (range 4.0-18.3 days), LI 14%, and Gf 32%. Cell production rates were related to the histological growth pattern with infiltrative and morpheic tumours having a higher Gf than the nodular tumours (p<0.01) and a shorter Tc and Tpot. Cell proliferation was not related to differentiation status. The median apoptotic index was 1% (range l%-5%) and in the absence of apoptotic rate measurements, it was difficult to equate the contribution of apoptosis to the paradox of the slow clinical growth of BCCs. However, the concept of a high apoptotic rate was not supported by bcl-2 and bax protein expression. 88% of BCCs expressed bcl-2 and 23% expressed bax. The relationship between p53 expression and apoptosis was unclear since there was no correlation of p53 with bax, bcl-2 or apoptosis. The apoptotic parameters displayed some relationship to the histological growth patterns. The infiltrative and morpheic tumours exhibited the least apoptosis and least bcl-2 expression (p=0.02), but p53 did not correlate with tumour histology. The contribution of biological factors in determining outcome (the development of recurrence or a horrifying tumour) in BCC are limited because patient factors (late presentation) and treatment factors are dominant. Incomplete excision was associated with recurrence and the development of a horrifying tumour when compared to non recurrent tumours (p<0.01). Primary radiotherapy was also associated with the development of a horrifying tumour (p<0.01). A novel treatment modality, the optomechanically flash scanned carbon dioxide laser, was evaluated to assess its ability to completely ablate BCCs. Complete ablation was associated with ablation depth (p