title: 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% 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.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Igarashi
authors.forename: Shi-Xu
authors.initials: SX
authors.lastname: Jiang
authors.forename: Toru
authors.initials: T
authors.lastname: Kameya
authors.forename: Hisao
authors.initials: H
authors.lastname: Asamura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sato
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagai
authors.forename: Isao
authors.initials: I
authors.lastname: Okayasu
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002276:Carcinoid Tumor / Q000378:metabolism / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000378:metabolism / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D019938:Cyclin D1 / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; D019938:Cyclin D1