Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Aspects of carcinogenesis and prognostic significance.

Abstract

The bcl-2 oncoprotein confers a survival advantage to cells by inhibiting programmed cell death (PCD) or apoptosis. Overexpression of bcl-2 probably plays a role in colorectal carcinogenesis. The aims of our study were to determine bcl-2 expression and PCD index in colorectal adenomas and carcinomas in correlation with p53 expression, Ki-67 index, and histopathology, and to test their prognostic significance in patients with colorectal carcinomas. Immunohistologic staining for bcl-2 (MoAb clone 124), the proliferation-associated Ki-67 antigen (MoAb MIB1), and p53 (MoAb DO1) was performed on archival material from 44 colorectal adenomas and 95 adenocarcinomas (TNM classifications pT2 and -3, pN0, and M0). The PCD was visualized by enzymatic detection of DNA fragmentation. bcl-2 was expressed in 86% of the adenomas and 67% of the carcinomas. Mean PCD and Ki-67 rates were 1.7 +/- 0.14% and 35 +/- 13% in adenomas and 1.9 +/- 0.15% and 28 +/- 14% in carcinomas, respectively. In carcinomas, bcl-2 expression was correlated with a low PCD index (< 1.5%; P = 0.005). Furthermore, a high Ki-67 index (> or = 25%) was associated with a high PCD index (> or = 1.5%; P < 0.0001). p53 accumulation was seen in 16% of adenomas and in 42% of carcinomas, and did not correlate with bcl-2 expression or PCD index. In the univariate analyses, significantly longer disease free survival intervals were observed in three groups: all patients with bcl-2-positive carcinomas (P < 0.05); the subgroup of carcinomas with bcl-2 expression and low PCD index (P = 0.037); and the subgroup of bcl-2-positive and p53-negative carcinomas (P = 0.021). In the multivariate analysis, however, only tumor stage and p53 expression were independent risk factors for prognosis. Our data indicate that bcl-2 expression is characteristic of the early phase of colorectal carcinogenesis. Its physiologic function as an inhibitor of PCD is preserved in most colorectal carcinomas, whereas p53 is apparently not involved in the regulation of PCD in colorectal neoplasias. bcl-2 expression in colorectal carcinomas is associated with a better clinical course. This correlation became even more evident in the subgroups of patients with carcinomas that also had low PCD index or lacked p53 immunoreactivity.