Apoptosis-related factors p53, Bc12, and Bax in neuroendocrine lung tumors (original) (raw)

American Journal Of Pathology

Neuroendocrine (NE) lung tumors comprisefour classes ofprogressive aggressiveness for which proliferation and apoptosis rates could both contribute to their distinctive behavior. As p53 mutations may favor escape from apoptosis through changes in Bcl2-Bax expression balance, which are survival and apoptotic genes, respectively, we studied 121 NE lung tumors (16 typical carcinoids (TC), 5 atypical carcinoids (AC), 29 large-ceU NE carcinomas (LCNECs), and 71 small-cell lung carcinomas (SCLCs) using immunohistochemistry. We quantified apoptosis by terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) in 31 ofthese cases. There was a significant increase ofp53 mutant immunophenotype (defined as immunoreactivity with at least two antibodies for at least 20% of tumor cells) between atypical/typical carcinoids group and the LCNEC/SCLC group (P = 0.0003). There was an inverse correlation (P < 0.0001) between the scores of Bax and Bcl2 expression in individual tumors and a significant inversion of the Bcld Bax ratio between low-grade (typical and atypical carcinoids) and high-grade (LCNECs and SCLCs) tumors with a predominant Bax expression in thefirst group and predominant Bcl2 expression in the second. Whereas carcinoids had variable apoptotic indexes, LCNECs had high indexes (1.3 to 6.8%), and SCLCs had almost no apoptosis (<0.1%). Bc12 overexpression, Bax down-regulation, and BclfBax ratio >1 correlated with lower apoptotic index in both LCNEC and the pool ofLCNECs and SCLCs (P < 0.05) and a lower survival rate in the group ofatypical and typical carcinoids and LCNECs (P < 0.002). The highest levels of Bcl2 expression and Bcl2Bax ratios were associated with p53 mutant immunophenotype (P = 0.02). Our results suggest that aggressiveness in NE lung tumors could be linked, in addition to prolferation, to apoptosis-relatedfactors. (AmJ Pathol l996, 149:1941-1952 Lung neuroendocrine (NE) tumors include a spectrum of four clinicopathological entities with varying degrees of aggressiveness. Typical carcinoids (TCs) are lower-grade, well differentiated NE tumors with excellent prognosis (nearly 100% 10-year survival). Atypical carcinoids (ACs) keep morphological NE characteristics but show some cellular atypia, loci of necrosis, and mitotic activity (3 to 10 mitoses per 10 high-power fields).1 High-grade NE lung tumors comprise large-cell NE carcinoma (LCNEC)2 with neuroendocrine morphology but marked cellular pleiomorphism, prominent necrosis, and high mitotic activity (-20 mitoses per 10 high-power fields). Small-cell lung carcinoma (SCLC) and LCNEC differ essentially by cell size and chromatin morphology. The two intermediate categories (AC and LCNEC) have a more unpredictable prognosis than TC and SCLC, and alternative markers are needed to assist classification and prognosis. A few studies have focused on the genetic alterations on the spectrum of NE lung tumors.