Basement membrane changes and Langerhans cell alterations during tumour development

This thesis examines tumour development from two separate perspectives. Firstly, with regard to basement membrane changes in tumour development, this study confirms the prior observation that tumour cells, both in the primary focus and in metastatic deposits, are capable of producing an intact and continuous basement membrane. Assessment as to whether or not a given tumour is invasive, then, requires correlation between the integrity of the basement membrane and the tissue architecture. The mere presence of an intact basement membrane does not mean that a tumour is in an "in—situ" phase if the tissue architecture is that of an invasive carcinoma. In metastatic deposits of epithelial tumours the development of a new basement membrane appears to be dependent upon interaction with mesenchymally derived connective tissue suggesting that the normal formation of epithelial basement membrane requires interaction with stromal connective tissue. In metastatic carcinoma, as in primary tumours (Albrechtsen et al., 1986) the redevelopment of extracellular basement membrane is related to the degree of tumour, cell differentiation. The abrupt loss of basement membrane associated with a focus of invasive tumour growth , seen particularly in nodular basal cell carcinoma, supports the concept that the basement membrane, though flexible, is continuous, insoluble and impermeable to cell movement. Expansion of an intact basement membrane may be seen in superficial spreading basal cell carcinoma and early nodular basal cell carcinoma which therefore, by definition, may be regarded as in—situ tumours. The advent of the immunoperoxidase method, which can be used on paraffin—processed tissue, by allowing the detection of subtle histologic changes, has clarified observations previously noted in the literature on early tumour development. The variation in thickness of the basal lamina in epidermal tumours, previously noted by Frappart et al. (1982), we now believe to be an artefact due to tangential sectioning of the basement membrane. Globular fragments staining positively for laminin and type IV collagen noted by Weber et al. (1982) and van Cauwenberge et al. (1983), in basal cell carcinoma prove to be incorporated stroma and accompanying basal lamina and are not due to defective basement membrane formation by the tumour cells. Secondly, with regard to Langerhans cell changes in in—situ and invasive neoplasia, this study has shown that the Langerhans cell density is significantly increased in intraepidermal carcinoma—in—situ (Bowen's disease), cervical intraepithelial neoplasia, and invasive neoplasms, including squamous cell carcinoma, basal cell carcinoma and keratoacanthoma, when compared to normal epidermis. In addition the Langerhans cell density increases in cervical intraepithelial neoplasia correlating with the severity of the intraepithelial lesion. This increase in Langerhans cell density suggests activation of a local immune mechanism and is supportive evidence for the concept that Langerhans cells play a role in tumour surveillance. In addition to being increased within neoplastic lesions, the Langerhans cell density was also found to be increased in epithelium adjacent to the neoplasm in both skin and cervix, suggesting either that the neoplastic lesion is producing a chemotactic factor which diffuses into the adjacent epithelium or that the adjacent morphologically normal epithelium is functionally abnormal. Langerhans cell density is decreased in cervical wart virus infection and in koilocytic dysplasia and this depletion appears to be related to viral expression rather than to the presence of viral DNA. This finding supports the recent suggestion that human papilloma virus (HPV), the causative agent in cervical wart virus infection, is involved in cervical carcinogenesis as a tumour promoter. Tumour promotion by the human papilloma virus may act both through stimulation of epithelial cell proliferation and through a reduction in Langerhans cell immunosurveillance. Two indirect results of the study include:- 1) the development of a double-staining technique to facilitate differentiation between Langerhans cells and melanocytes in fresh human skin; this procedure is based on the ability of anti-S100 antibody to stain both epidermal Langerhans cells and melanocytes, while L-Dopa stains only melanocytes; and 2) the conclusion that under conditions of varying epithelial thickness Langerhans cell density should be estimated per unit length of surface epithelium in order to determine whether or not there has been a change in Langerhans cell density in abnormal epithelium. Although this study has answered some questions, many more have arisen, ttie solution of which should add greatly to our understanding of early tumour development both in its in-situ and invasive phases