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

Mod Pathol. 2004 Oct;17(10):1259-67. doi: 10.1038/modpathol.3800176.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / biosynthesis*
  • Carcinoid Tumor / metabolism
  • Carcinoid Tumor / pathology
  • Carcinoma, Large Cell / metabolism
  • Carcinoma, Large Cell / pathology
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology
  • Cyclin B / biosynthesis
  • Cyclin B1
  • Cyclin D1 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / biosynthesis
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology*
  • Retinoblastoma Protein / biosynthesis
  • Signal Transduction
  • Survival Analysis


  • Biomarkers, Tumor
  • CCNB1 protein, human
  • Cyclin B
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen
  • Retinoblastoma Protein
  • Cyclin D1