The colorectal
adenoma-
carcinoma sequence was examined in relation to the ectopic expression of the oncofoetal
Small Intestinal Mucin Antigen (SIMA), to the development of morphologic changes in the
adenoma and perineoplastic mucosa and to indices of malignant potential. Four anti-SIMA MAbs, which define a novel hierarchy of SIMA
epitopes in the normal small intestine and adjacent to
colorectal cancers, were used in a retrospective immunohistochemical study of
Familial Adenomatous Polyposis (FAP, n = 183) and non-familial (n = 44)
adenomas. Inappropriate expression of SIMA
epitopes was first detected in mucosa adjacent to minute microadenomas larger than three glands, and with increase in size, in increasing amounts within
adenomas themselves, but not with microadenomas smaller than three glands or regions of flat mucosa free of
adenomas. SIMA
epitope expressed in mucosa adjacent to
adenomas preceded changes in perineoplastic morphology, which progressed with
adenoma growth to resemble transitional mucosa (TM) adjacent to
cancers. Thus, the onset of both SIMA expression and morphological changes in TM were consistent with reactive rather than pre-existing field change phenomena. The previously reported hierarchy of four SIMA
epitopes (5C5, 3D4, 4D3, 6C5) was also consistently observed in the
adenoma-
carcinoma sequence, and applied to (i) the order of
epitope detection, (ii) the number of positive
adenomas and (iii) extent of staining; (iv) the height in the crypt and (v) distance from the
adenoma to which
epitopes were expressed in perineoplastic mucosa. These observations are consistent with a progression of changes in
mucin composition with
adenoma development. The percentage of positive
adenomas and reactivity scores for each anti-SIMA MAb correlated with increasing
adenoma size, degree of dysplasia and growth pattern. SIMA expression appears to
predate the earliest reported oncogene and tumour suppressor gene changes, was persistent and increased throughout
adenoma development. SIMA
epitopes are thus markers of very early neoplastic change, whose expression correlates with malignant potential and may contribute to the accumulation of changes necessary for tumourigenesis.