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% large-cell 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 high-grade 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 (P < 0.0001, r = 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.