The significance of frequent and independent p53 and bcl-2 expression in large-cell neuroendocrine carcinomas of the lung.

Abstract

Both p53 and bcl-2 genes are involved in regulating cell death. Reports, however, concerning the relationship between p53 and bcl-2 expression are contradictory. Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a newly recognized clinicopathologic entity. p53 mutation and bcl-2 overexpression are frequent in small-cell lung carcinoma (SCLC), and we observed a close correlation between bcl-2 expression and cellular neuroendocrine (NE) differentiation in non-SCLC, so we speculated that LCNEC, an NE tumor closely related to SCLC, would exhibit high incidence of both p53 alteration and bcl-2 expression. Immunohistochemical expression of p53 and bcl-2 was evaluated on consecutive sections of 26 LCNECs, including 4 combined LCNECs. p53 accumulation and diffuse bcl-2 staining were observed in 18 (69.2%) of 26 and 24 (92.3%) of 26 LCNECs, respectively, but their immunoreactivities showed no fixed distribution relevance on consecutive sections in individual tumors. Statistical analyses yielded no relationship between p53 and bcl-2 expression (P = .47). In all of the four combined LCNECs, p53 was identically either positive or negative in both tumor cell populations with and without NE differentiation. bcl-2 immunoreactivity was observed only for the tumor cells with NE phenotype in three of the four combined LCNECs and was diffuse among the NE tumor cells but geographic in distribution among the non-NE tumor cells of the remaining one combined LCNEC. Thus, our present findings suggest that p53 and bcl-2 are expressed independently and might have distinct expression significance in LCNECs. A high incidence of p53 expression in LCNECs and equal p53 expression profiles in NE and non-NE tumor cell populations of combined LCNECs suggest that p53 alteration is primarily involved in the tumorigenesis of LCNEC. On the other hand, frequent bcl-2 expression in pure LCNECs and selective bcl-2 expression in tumor cells with NE phenotype in combined LCNECs are suggestive of a role for bcl-2 in regulating cellular NE differentiation.