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

Igarashi, Toru; Jiang, Shi Xu; Kameya, Toru; Asamura, Hisao; Sato, Yuichi; Nagai, Kanji; Okayasu, Isao

doi:10.1038/modpathol.3800176

Cited by 58 publications

(49 citation statements)

References 28 publications

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“…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.…”

Section: Discussionsupporting

confidence: 79%

“…[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.…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Faggiano

Sabourin

Ducreux

et al. 2007

Cancer

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BACKGROUND.Poorly differentiated large cell neuroendocrine carcinomas (LCNEC) comprise a rare and still scarcely known subgroup of neuroendocrine tumors. The objective of this study was to investigate the epidemiology, clinical presentation, prognostic factors, and molecular pathways of patients with poorly differentiated LCNEC.METHODS.Forty‐one patients who had a confirmed diagnosis of poorly differentiated LCNEC according to the criteria of the most recent World Health Organization classification of neuroendocrine tumors of the lung entered the study. The clinicopathologic features of patients with poorly differentiated LCNEC were reviewed, prognostic parameters for their survival were studied, and the prognostic roles of the proteins involved in cell cycle regulation were investigated with tissue array analysis in a subset of patients with LCNEC.RESULTS.Twenty‐four men and 17 women with a median age of 63 years (age range, 26–81 years) who had LCNEC were studied. LCNEC developed after therapy for a first cancer in 14% of patients. Neither a personal or familial history of endocrine tumors nor a primary association that was compatible with an inherited syndrome was observed. The increase of at least 1 serum biologic marker was observed in 93% of patients. A primary tumor was identified in only 63% patients. Thirty‐one patients had distant metastases, and 10 patients had only lymph node metastases at the time of the diagnosis. The 5‐year survival rate was 24%. High mitotic count, low expression of neuroendocrine markers, and a Bcl‐2/Bax ratio > 1 were unfavorable prognostic factors for survival (P < .01). All patients who had isolated peripheral lymph node LCNEC achieved a cure.CONCLUSIONS.The results from this study highlighted distinctive clinical features and prognostic indicators of poorly differentiated LCNEC. Peripheral isolated lymph node clinical presentation is proposed as a new clinical entity. Cancer 2007. © 2007 American Cancer Society.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Faggiano

Sabourin

Ducreux

et al. 2007

Cancer

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“…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.…”

Section: Ink4mentioning

confidence: 99%

“…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.…”

Section: Ink4mentioning

confidence: 99%

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

2012

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Small cell lung cancer (SCLC) comprises 14% of all lung cancers, and 430 000 new cases are diagnosed per year in the United States. SCLC is one of the most distinctive malignancies in the entire field of oncology with characteristic clinical properties, responsiveness to specific chemotherapy, genetic features and a highly reliable pathological diagnosis. SCLC is defined by light microscopy, and the most important stain is a goodquality hematoxylin and eosin (H&E)-stained section. The vast majority of cases can be diagnosed on H&E alone; however, in problem cases, immunohistochemistry can be very helpful in making the distinction from other tumors. Cytology is also a powerful tool, often being more definitive than small biopsies with scant tumor cells, crush artifact and/or necrosis. As virtually all SCLCs present in advanced stages, most patients are diagnosed based on small biopsy and cytology specimens. Historically, there has been significant evolution in the histological subclassification of SCLC dating from 1962 when Kreyberg proposed the oat cell and polygonal cell types. The current subclassification recognizes only two subtypes: pure SCLC and combined SCLC. Pathologists need to do their best to make a diagnosis of SCLC or other histological types of lung cancer and this can be achieved in most cases. This review will address some of the diagnostic problems that occur in the minority of cases and outline practical ways to address them. Brief reference will be made to other neuroendocrine lung tumors with an overview of the molecular pathogenesis of this spectrum of tumors.

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“…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.…”

mentioning

confidence: 99%

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

et al. 2007

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Solid pseudopapillary neoplasms of the pancreas almost consistently show a b-catenin mutation activating the Wnt-signaling pathway, resulting in overexpression of cyclin D1, but not in overt malignancy of this tumor. Besides cyclin D1, a set of markers (ie FLI-1, CD56 and progesterone receptor), whose genes map to chromosome 11q, are frequently expressed in solid pseudopapillary neoplasms. Chromosome 11q is a region that is also often affected in pancreatic neuroendocrine tumors. This immunohistochemical study was undertaken to gain insights into the downstream regulation of the Wnt-signaling pathway and the significance of overexpressed gene products belonging to chromosome 11q for the tumorigenesis in solid pseudopapillary neoplasms. Fourteen solid pseudopapillary neoplasms were analyzed for the expression of cyclin-dependent kinase inhibitors p21, p27, p16 and hyperphosphorylated retinoblastoma (pRb) proteins. In an extended series of 93 solid pseudopapillary neoplasms, b-catenin, cyclin D1, FLI-1 and CD56 expression was examined and compared with that in 22 pancreatic neuroendocrine tumors. Solid pseudopapillary neoplasms (98%) showed aberrant expression of b-catenin with a concomitant cyclin D1 expression in 69% of the cases, but no expression of pRb (0%) was found. p27 and p21 were expressed in 100% (14/14) and 86% (12/14) of the cases, but only 2/14 (14%) were positive for p16. FLI-1 was expressed in 63% of solid pseudopapillary neoplasms, but only in 1/22 pancreatic neuroendocrine tumors (5%), cyclin D1 expression was present in 14% of the latter. We conclude that in solid pseudopapillary neoplasms the activated Wnt-signaling pathway is disrupted, and that p21 and p27 are contributing to this fact by blocking of the hyperphosphorylation of the Rb protein, thus causing the very low proliferation rate characterizing the solid pseudopapillary neoplasms. The accumulation of high expression of proteins whose genes are located on chromosome 11q is characteristic of solid pseudopapillary neoplasms, but not of pancreatic neuroendocrine tumors. Modern Pathology (2007) 20, 955-960;

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

Cited by 58 publications

References 28 publications

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

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

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

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