Clinical Significance of Protein Expression of Cyclooxygenase-2 and Somatostatin Receptors in Gastroenteropancreatic Neuroendocrine Tumors

Abstract

PurposeThis study was undertaken to evaluate the significance of cyclooxygenase-2 (COX2) overexpression and the expression of somatostatin receptor (SSTR) subtypes in gastroenteropancreatic neuroendocrine tumors (GEP-NETs).Materials and MethodsTwo hundred and forty-seven cases of GEP-NET, comprising 86 foregut and 156 hindgut primary NETs, and 5 metastatic NETs in the liver, were studied retrospectively with immunohistochemistry for COX2, chromogranin A, Ki-67, SSTR1, SSTR2, and SSTR5.ResultsCOX2 overexpression was observed in 54%(126 of 234), and SSTR1, SSTR2, and SSTR5 positivity in 84%(196 of 233), 72%(168 of 233), and 55%(128 of 232), respectively. COX2 overexpression was found to be positively correlated with Ki-67 labeling index and inversely correlated with the expression of SSTR subtypes. In addition, the expression of SSTR subtypes was tightly correlated in any comparative pairs. A significant inverse correlation was found between COX2 and SSTR2 expression in the foregut, but not hindgut NETs. Kaplan-Meier analyses showed that COX2 overexpression (p=0.003) and high Ki-67 labeling index (p<0.001) were associated with poor overall survival (OS), whereas expression of SSTR2 (p<0.001) was associated with better OS of GEP-NET patients. Multivariate analysis revealed negative SSTR2 expression as an independent prognostic marker in GEP-NET patients (p<0.001).ConclusionOur results suggest that expression of SSTR subtypes is associated with favorable prognosis, whereas COX2 overexpression is associated with poor prognosis in GEP-NETs. Taken together, COX2 could be a possible therapeutic target in some subsets of GEP-NETs.

Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures

“…functionality. The sst expression patterns in the primary cells of pNETs were similar to those previously found in GEP-NET tumor tissues by our group (O'Toole et al 2006) and by others (Reubi et al 2001, Papotti et al 2002, Ono et al 2007, Srirajaskanthan et al 2009, Kim et al 2011: sst 2 remains the primary sst expressed, sst 1 is the secondary subtype expressed, both in terms of percentage of positive tumors and of quantitative mRNA level.…”

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

“…COX-2 overexpression in gastroenteropancreatic NENs was significantly associated with poor survival. However, only 10/247 NENs in this cohort originated in the pancreas [116]. In a cohort of mid-gut carcinoids comprising NENs of the distal duodenum, jejunum, ileum and proximal part of the colon, a higher COX-2 histoscore was significantly associated with worse survival within the COX-2 positive group [118].…”

“…In a cohort of mid-gut carcinoids comprising NENs of the distal duodenum, jejunum, ileum and proximal part of the colon, a higher COX-2 histoscore was significantly associated with worse survival within the COX-2 positive group [118]. The correlation between COX-2 and proliferation activity by Ki-67 could at least partially explain the negative prognostic meaning of COX-2 [116]. COX-2 expression in gastroenteropancreatic NENs correlated significantly with grade, but not primary location [116].…”

“…The correlation between COX-2 and proliferation activity by Ki-67 could at least partially explain the negative prognostic meaning of COX-2 [116]. COX-2 expression in gastroenteropancreatic NENs correlated significantly with grade, but not primary location [116]. In contrast, Bergmann et al concluded that COX-2 expression was independent of the malignant potential of pancreatic endocrine tumours [3].…”

“…In phaeochromocytoma, COX-2 is associated with malignant behaviour and, along with lack of nm-23 and presence of galectin-3, can be applied to predict malignancy [114]. Immunohistochemical expression of the COX-2 protein has been identified in 54-75% of gastroenteropancreatic [115,116] and 65% of pancreatic NENs [117]. In our study, we showed statistically significant up-regulation of COX-2 expression in PNENs, contrasting with invariably negative islets (p = 0.016) and providing in vivo evidence that COX-2 is involved in the pancreatic neuroendocrine tumorigenesis.…”