APO-1 is a 48-kDa cell-membrane protein identical to the Fas antigen now designated CD95. It is a member of the NGF/TNF receptor superfamily. Anti-APO-1 monoclonal antibody induces apoptosis in a variety of cell types expressing this antigen. We immunohistochemically investigated APO-1 expression in normal colon mucosa, 20 adenomas, 258 colon carcinomas and 10 liver metastases and carried out in vitro studies using a panel of colon-carcinoma cell lines. Immunohistochemically, APO-1 was regularly expressed at the basolateral membrane of normal colon epithelia. In a minor fraction of colon adenomas and in 39.1% of colon carcinomas APO-1 expression was diminished and in 48.1% of carcinomas, predominantly of the non-mucinous type, APO-1 expression was completely abrogated. The normal level of APO-1 in carcinomas was correlated with the mucinous type. Reduced/lost APO-1 expression was more frequent in rectal carcinomas. Complete loss of APO-1 was more frequent in tumors that had already metastasized. APO-1 expression in liver metastases essentially corresponded to that of the primary tumors. Comparative analysis with data from previous studies revealed that the mode of APO-1 expression is correlated with that of HLA-A,B,C./beta 2m, HLA-DR, HLA-D-associated invariant chain and of the secretory component. Surface expression of APO-1 was heterogeneous in colon-carcinoma cell lines; SW480 expressed considerable amounts of APO-1 on all cells, while HT-29 constitutively did less so and only in a minority of cells. Surface density of APO-1 and the fraction of positive cells in HT-29 was enhanced by interferon-gamma (IFN-gamma) and, additively, by tumor necrosis factor-alpha (TNF-alpha), whereas in SW480 APO-1 expression was not modulated by these cytokines. We conclude that neoplastic transformation of colon epithelium often leads to a loss of the physiologic, high level of surface APO-1 by giving rise either to a stable lack of APO-1 or to an IFN-gamma/TNF-alpha-sensitive phenotype of inducible APO-1 expression.

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The present study compared the diagnostic accuracy of fluorine-18 2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) with conventional staging techniques. The differentiation between malignant and benign lesions and the detection of multifocal disease, axillary and internal lymph node involvement, and distant metastases were evaluated. One hundred and seventeen female patients were prospectively examined using FDG-PET and conventional staging methods such as chest X-ray, ultrasonography of the breast and liver, mammography and bone scintigraphy. All patients were examined on a modern full-ring PET scanner. Histopathological analysis of resected specimens was employed as the reference method. The readers of FDG-PET were blinded to the results of the other imaging methods and to the site of the breast tumour. The sensitivity and specificity of FDG-PET in detecting malignant breast lesions were 93% and 75% respectively. FDG-PET was twofold more sensitive (sensitivity 63%, specificity 95%) in detecting multifocal lesions than the combination of mammography and ultrasonography (sensitivity 32%, specificity 93%). Sensitivity and specificity of FDG-PET in detecting axillary lymph node metastases were 79% and 92% (41% and 96% for clinical evaluation). FDG-PET correctly indicated distant metastases in seven patients. False-positive or false-negative findings were not encountered with FDG-PET. Chest X-ray was false-negative in three of five patients with lung metastases. Bone scintigraphy was false-positive in four patients. Three patients were upstaged since FDG-PET detected distant metastases missed with the standard staging procedure. It is concluded that, compared with the imaging methods currently employed for initial staging, FDG-PET is as accurate in interpreting the primary tumour and more accurate in screening for lymph node metastases and distant metastases. Due to a false-negative rate of 20% in detecting axillary lymph node metastases, FDG-PET cannot replace histological evaluation of axillary status.

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Physiological regeneration of colonic epithelium entails proliferation at the crypt base and cell loss by shedding or cell death. The aim of this study was to localise and assess the rate of apoptosis in normal and neoplastic colonic epithelium with respect to zones of proliferation. Familial adenomatous polyposis (FAP) was chosen as a model to study neoplastic transformation of colonic mucosa at an early stage. Apoptotic cells were detected in situ by TdT-mediated biotin-dUTP nick end labelling (TUNEL) in parallel to cells in cycle determined by immunohistochemistry using the monoclonal antibody MiB-1. By detection of genomic fragmentation, two different patterns of enterocytic apoptosis emerged: (a) apoptotic bodies being engulfed by adjacent epithelial cells, and (b) apoptotic cells with only subtle morphological changes being extruded into the gut lumen. The engulfment pattern was seen predominantly in the crypts of the normal colonic mucosa and, although very rare, was clearly confined to the basal proliferation compartment. The extrusion pattern was restricted to the luminal mucosal surface. Adenomas of FAP showed highly increased numbers of apoptotic bodies, which were scattered throughout the transformed mucosa. Both patterns of apoptosis were topographically intermingled although the extrusion pattern prevailed at the luminal adenoma surfaces. Whereas cells in cycle were somewhat more numerous in the upper parts of the crypts, apoptosis occurred with increased frequency at sites beneath the proliferation maximum suggesting an inverted direction of epithelial cell migration in adenomas. These results suggest two distinct routes towards enterocytic apoptosis in the colonic mucosa leading to engulfment or extrusion of dying cells. Adenomatous transformation ofcolon epithelium is associated with a considerable increase of the cellular turnover rate and with a severe disturbance of the microtopographical localisation of birth and death of enterocytes.