Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors

Abstract

A total of 111 pulmonary neuroendocrine tumors comprising 13 typical carcinoids, five atypical carcinoids, 44 large-cell neuroendocrine carcinomas and 49 small-cell carcinomas were immunohistochemically studied for dysregulated cyclin B1 expression and disruption of the Rb/p16/cyclin D1 pathway (Rb pathway), and the results were correlated with tumor proliferation activity and clinical outcome. Overexpression of cyclins B1 and D1, respectively, was detected in no and 15% typical carcinoids, 20 and 20% atypical carcinoids, 84 and 32% large-cell neuroendocrine carcinomas, 84 and 10% small-cell carcinomas. Loss of Rb and p16 expression, respectively, was observed in no and 14% typical carcinoids, no and 40% atypical carcinoids, 49 and 18% largecell neuroendocrine carcinomas, 84 and 8% small-cell carcinomas. In summary, 29% typical carcinoids, 20% atypical carcinoids, 78% large-cell neuroendocrine carcinomas and 93% small-cell carcinomas had Rb pathway aberrations. Rb pathway aberration was mostly attributed to Rb loss in small-cell carcinomas, while p16 loss and/or cyclin D1 overexpression besides Rb loss also played an important role in large-cell neuroendocrine carcinomas, while cyclin D1 overexpression was the only cause of Rb pathway aberration in carcinoid tumors. Thus, both cyclin B1-associated G2/M arrest and Rb-mediated G1 arrest are consistently compromised in highgrade large-cell neuroendocrine carcinoma and small-cell carcinoma, but are generally intact or occasionally altered in carcinoid tumor; the mechanisms involved in Rb pathway aberration among the tumor categories are different, reflecting a genetic divergence among the individual tumor categories. Cyclin B1 expression closely correlated with the Ki-67 labeling index either in the individual tumor categories or overall tumors (Po0.0001, r ¼ 0.742), suggesting that cyclin B1 is one of the key factors regulating cell proliferation in pulmonary neuroendocrine tumors. Neither cyclins B1 and D1, Rb, p16, nor Ki-67 correlated with patient survival in individual tumor categories, suggesting that the prognostic significance of these factors is tumor-type specific.

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

“…The loss of its function has been observed at an early stage in LCNEC, 43 and others demonstrated that p16 loss affected LCNEC preferentially compared with SCC and was associated with a significantly worse survival. 31,39,41 We observed a positive correlation between p16 loss and extensivestage disease, suggesting a more aggressive phenotype in keeping with previous observations. 31 Finally, none of the molecular markers that we studied differed between pulmonary, extrapulmonary and unknown primary tumor sites.…”

“…[30][31][32] Biologic studies have highlighted markers to distinguish poorly differentiated from well-differentiated tumors and even from subgroups of tumors within these 2 categories. 16,18,21,[33][34][35][36][37][38][39][40][41][42][43] The Loss of retinoblastoma (Rb), p16, and p53 function and increased expression of cyclin D1 and Bcl-2 have been described in LCNEC.…”

Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas

“…55,63 In SCLC, Rb loss is frequent in SCLC and LCNEC but not in TC and it can be found in 60% of AC. In high-grade tumors, there is an inverse relationship between Rb and P16, and in all neuroendocrine tumors, there is a direct relationship between cyclin D1 and Rb, indicating that p16 and cyclin D1 act exclusively on the Rb pathway for cell-cycle regulation.…”

“…These data demonstrate that the RB pathway of G1 arrest is consistently compromised in SCLC and LCNEC, but is intact in TC with intermediate aberrations in AC. 55,63 The C-kit protein expression has been found in high-grade pulmonary neuroendocrine tumors. Frequent positive membranous/cytoplasmic expression in high-grade tumors with 77/44% of LCNEC, 70/ 67% of SCLC was found by Pelosi et al 64 but it was found in only 7% of carcinoid tumors.…”

Solid pseudopapillary neoplasms of the pancreas show an interruption of the Wnt-signaling pathway and express gene products of 11q

“…This expression is accompanied by cyclin D1 overexpression, a cell cycle associated protein and primary target of Wnt signaling, that has also been reported in neuroendocrine tumors. 3,4 Cyclin D1 expression is often associated with tumor progression in various cancers and a marker of mantle cell lymphoma. 5,6 Phenotypically, most or a considerable number of solid pseudopapillary neoplasms express markers that are related to neuroendocrine features.…”