Diagnostic relevance of p53 and Rb status in neuroendocrine tumors G3 from different organs: an immunohistochemical study of 465 high-grade neuroendocrine neoplasms

The double inactivation of TP53 and RB1 is considered typical of neuroendocrine carcinomas (NECs) but is assumed to be rare in high-grade neuroendocrine tumors (NETs). The immunohistochemical determination of the p53 and Rb status has therefore been proposed as a diagnostic tool. We studied this status in a large series of high-grade neuroendocrine neoplasms, from multiple origins, in order to (a) assess the patterns observed in the different histopathological categories, (b) compare them between the various anatomic sites, and (c) evaluate their possible diagnostic relevance. Four hundred sixty-five cases from 9 organ systems (142 high-grade NETs -NET-G3-, 162 large-cell NECs -LCNEC-, 144 small-cell NECs -SCNEC-) and 60 cases of NET G1/G2 were included. The expression of both proteins was normal in 96.7% of NET G1/G2, 76.7% of NET-G3, and 5.8% of all NECs. p53 expression was abnormal in 12.7% of NET-G3 and 91.5% of NECs. Rb expression was lost in 10.6% of NET-G3 and 68.3% of NECs. Rb loss was significantly less frequent in LCNEC than in SCNEC (57.3% versus 80.6%); abnormal p53 expression was comparable in the two categories. Patterns were comparable between primary sites, except for head and neck NECs. For diagnostic purposes, taking into account, Rb status improved, but only marginally, the performances of p53 status. In conclusion, our study underlines the molecular heterogeneity of NET-G3 and LCNEC, irrespectively of the primary, and provides further insight on the diagnostic relevance of p53/Rb immunodetection in high-grade neuroendocrine neoplasms.