Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin
- 318 Downloads
Neuroendocrine neoplasms (NENs) are derived from endocrine cells in various organs and share common morphological features. This study aimed to clarify whether NENs of different organs are comparable at the molecular pathologic level. We retrospectively collected 99 cases of NENs from gastro-entero-pancreatic, lung, and other organs and reclassified these according to identical criteria. Grade, site, and molecular expression profile including NE markers, Ki-67, p53, somatostatin receptor type 2A (SSTR2A), and phosphatase and tensin homolog (PTEN) were compared. PTEN immunoreactivity was also compared with genomic copy number by fluorescence in situ hybridization (FISH) and droplet digital polymerase chain reaction (ddPCR). No significant differences were observed in the immunoreactivities of NE markers, p53, SSTR2A, or PTEN expression in NENs between the different organ sites. PTEN and p53 functional inactivation along with the loss of membranous SSTR2A expression appeared to be commonly involved in high-grade NEN. FISH results were significantly correlated with the level of PTEN immunoreactivity and with the findings of ddPCR analyses. The demonstration that these tumors are comparable at the molecular level will likely contribute to the broadening of therapeutic options such as the use of somatostatin analogues and mTOR inhibitors against NENs regardless of the affected organ, whereas molecular characterization of tumor grade will be useful for determining treatment strategy.
KeywordsNeuroendocrine neoplasm PTEN SSTR2A p53 FISH ddPCR
This work was supported in part by a collaborative research grant from the Atomic Bomb Disease Institute, Nagasaki University. We would like to thank Editage (www.editage.jp) for English language editing.
Compliance with Ethical Standards
The present study was an unlinkable anonymized study strictly following the principles established in the Declaration of Helsinki and was approved by the Committee for Ethical Issues of Nagasaki University Graduate School of Biomedical Sciences (Date of approval; Aug. 20, 2015, Protocol No. 15682035). As this was a retrospective research study involving minimal risk to the participants, detailed information of the research was released to the public on the institution’s homepage (http://www-sdc.med.nagasaki-u.ac.jp/pathology/index.html) following the guidelines of the Ethical Committee’s official disclosure system.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 2.Travis WD, Gazdar A, Brambilla E et al. (2004) Carcinoid tumour. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (eds) Pathology and genetics of tumours of the lung, pleura, thymus and heart (World Health Organization Classification of Tumours). IARC Press, Lyon, pp 59–62.Google Scholar
- 3.Klimstra DS, Arnold R, Capella C et al. Neuroendocrine neoplasms of the pancreas. (2010) In: Bosman FT, Carneiro F, Hruban RH Theise ND (ed) WHO classification of tumours of the digestive system (World Health Organization Classification of Tumours). IARC Press, Lyon, pp 322–326.Google Scholar
- 6.Mussazhanova Z, Miura S, Stanojevic B et al. (2014) Radiation-associated small cell neuroendocrine carcinoma of the thyroid: a case report with molecular analyses. Thyroid 24:593–598.Google Scholar
- 9.Pavel ME, Hainsworth JD, Baudin E et al. (2011) Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carinoid syndrome (RADIANT-2): a randomised, placebo- controlled, phase 3 study. Lancet 10:2005–2012.Google Scholar
- 14.Rinke A, Müller HH, Schade-Brittinger C et al. (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report From the PROMID Study Group. J Clin Oncol 27:4656–4663.CrossRefPubMedGoogle Scholar
- 15.Travis WD. The concept of pulmonary neuroendocrine tumours. (2004) In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (eds) Pathology and genetics of tumours of the lung, pleura, thymus and heart (World Health Organization Classification of Tumours). IARC Press, Lyon, 19–20.Google Scholar
- 20.Estrozi B, Bacchi CE. (2011) Neuroendocrine tumors involving the gastroenteropancreatic tract: a clinicopathological evaluation of 773 cases. Clinics (Sao Paulo) 66:1671–1675.Google Scholar
- 24.Przygodzky RM, Finkelstein SD, Langer JC et al. (1996) Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. Am J Pathol 148:1531–1541.Google Scholar
- 26.Grabowski P, Schrader J, Wanger J et al. (2008) Loss of nuclear p27 expression and Its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. Clin Cancer Res 14:7378–7384.Google Scholar
- 29.Tan HL, Sood A, Rahimi HA et al. (2014) Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 20:890–903.Google Scholar