Outcomes Of Neuroendocrine Tumors Research Articles

Tumor Staging But Not Grading Is Associated With Adverse Clinical Outcome in Neuroendocrine Tumors of the Appendix

Appendiceal neuroendocrine neoplasms (NENs) are rare and usually incidentally discovered. Most cases are clinically indolent, although the rare aggressive ones are poorly predictable. The aim of this study was to test the applicability and prognostic significance of the new World Health Organization (WHO) classification and to test the several pathologic features and TNM staging systems (American Joint Committee on Cancer and European Neuroendocrine Tumor Society) in these tumors. A multi-institutional retrospective series of 138 appendiceal NENs was selected on the basis of the availability of both pathologic material and clinical information, including follow-up data. All cases were reviewed to record pathologic features and to apply year 2000 and 2010 WHO classifications, as well as European Neuroendocrine Tumor Society and American Joint Committee on Cancer TNM stages. Clinical and pathologic characteristics were compared with disease outcome by contingency, univariate, and multivariate survival analyses. Although up to one third of cases presented several malignancy-associated pathologic features, only 4 patients died of the disease. Adverse outcome was significantly associated with extramural extension (including mesoappendix), well-differentiated carcinoma diagnosis (2000 WHO classification), pT3-4 stage, older age, and presence of positive resection margins, but not with tumor size, mitotic or proliferative indexes, and, consequently, 2010 WHO grading. In the appendix, at variance with midgut/hindgut NENs, the 2000 WHO classification performs better than the grading-based 2010 WHO scheme and, together with tumor stage, is the most relevant parameter associated with clinical aggressiveness.

Prediction of prognosis in patients treated with everolimus for extrapancreatic neuroendocrine tumors by a single nucleotide polymorphism in PHLPP2.

163 Background: Rapamycin analogs (rapalogs) have improved outcomes in patients with neuroendocrine tumors (NETs). Few factors affecting response to rapalogs have been characterized. PHLPP2 is a phosphatase that inhibits PI3K-Akt-mTOR signaling. We hypothesized that an inactivating single nucleotide polymorphism (SNP) in PHLPP2 may affect outcomes in NETs treated with the rapalog everolimus. Methods: Blood was collected from 32 patients enrolled in a Phase 2 single arm trial of single agent everolimus in patients with NETs. DNA was extracted and RT-PCR products were sequenced to detect the L1016S SNP in PHLPP2. Outcomes analyses determined the role of the SNP in predicting progression-free survival (PFS), overall survival (OS), and response rates (RR) in patients with NETs treated with everolimus. Response rate (RR) assessed by RECIST criteria was evaluated as a binomial endpoint. A subset analysis was conducted to evaluate the NET site-specific role of the SNP. Results: Overall median PFS was 15.2 months (95% Confidence Interval (CI)=11.5 -18.7). The PHLPP2 SNP did not predict for a significant difference in PFS (Median PFS; wild type vs. SNP 16.8 (95% CI=14-20) vs. 11.3 (95% CI=4-19) mos., respectively, Hazard Ratio (HR)=1.2 (95% CI=0.5-3.1)), p=0.154). In a subset analysis, patients with extra-pancreatic NETs treated with everolimus with wild type PHLPP2 demonstrated increased PFS compared to patients with the SNP (Median PFS = 16.8 (95% CI=7-26) vs. 7.7 (95% CI=6-9) mos., HR=10.8 (95% CI=2-67), p=0.002). OS and RR were unaffected by the presence of the SNP in all analyses. Conclusions: In this preliminary study, the L1016S SNP in PHLPP2 may be prognostic for poorer PFS in patients with extrapancreatic NETs treated with everolimus. This study is hypothesis generating and requires validation in larger retrospective and randomized, placebo controlled studies in patients with NETs treated with everolimus.

Are Neuroendocrine Tumors Going Mainstream?

Are Neuroendocrine Tumors Going Mainstream?

Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors

To better understand the molecular pathogenesis of neuroendocrine tumors (NET), we investigated the molecular and clinical characteristics of malignant poorly differentiated colorectal NET and compared these findings with sporadic CRC and well-differentiated benign and malignant fore-/midgut NET. Tumors were analyzed and correlated for microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). NET were scored for proliferation using Ki-67. A total of 34 malignant poorly differentiated colorectal NET, 38 well-differentiated benign and malignant fore-/midgut-NET and 150 sporadic colorectal cancers (CRC) with known MSI status were investigated. Among the sporadic CRC, CIMP was significantly correlated with MSI-high (MSI-H) (p < 0.001). Of the 34 colorectal NET, 0/1 of the MSI-H, 3/5 (60%) of the MSI-L and 13/19 (68%) of the MSS tumors were CIMP+ (p = 0.17). Of the fore-/midgut-NET, none was MSI-H. 20/34 (59%) colorectal NET vs. 11/38 (29%) fore-/midgut-NET were CIMP+ (p = 0.01). The Ki-67 index was significantly higher in poorly differentiated colorectal NET compared to the less malignant fore-/midgut-NET (p < 0.0001). Besides the location in the colon, Ki-67 predicted poor outcome in NET (p < 0.0001). CIMP status did not affect survival. In NET, p16 methylation predicted a poor outcome (p = 0.0004). We conclude that molecular pathogenesis in sporadic CRC and poorly differentiated colorectal NET is different despite some similarities. Main differences between malignant well-differentiated and poorly differentiated NET are the Ki-67 proliferation rate and differential methylation in tumor-associated genes. Predictors of a poor outcome in patients with NET are poor differentiation, a high Ki-67 index and p16 methylation.

Microvascular density does not correlate with histopathology and outcome in neuroendocrine tumors of the pancreas.

Microvascular density (MVD), a marker for tumor angiogenesis, has been demonstrated to have prognostic significance in various malignancies. Previous studies have demonstrated that MVD is an independent prognostic factor in pancreatic adenocarcinoma and that longer survival is associated with hypovascular tumors. The prognostic importance of MVD in pancreatic neuroendocrine tumor (NET) has not been documented. We evaluated MVD in pancreatic NET and correlated it with clinicopathologic features and patient outcome to determine whether MVD is a useful prognostic indicator for these patients. Twenty-five pancreatic NETs from our archival files resected between 1981 and 2000 were identified. The mean MVD was determined for each tumor from the 3 most vascularized 200 x fields. Clinical follow-up ranged from 1 to 19 years, with a mean of 4.9 years. At last follow-up, 6 patients were dead of disease, 10 patients were alive without disease, 4 patients were alive with disease, and 5 patients were alive with disease status unknown. Mean MVD ranged from 43 to 527 microvessels per 200 x field. MVD did not correlate with tumor size, the examined histologic parameters, or patient outcome. MVD in pancreatic NET does not correlate with the clinicohistologic features evaluated in this study or with the patient outcome and is not a useful prognostic indicator in these patients. These results suggest that factors other than the simple number of microvessels are important in determining pancreatic NET behavior. However, most tumors were highly vascular, and additional studies may be helpful to clarify further the role of vascularity and assess the utility of antiangiogenic agents in the treatment of pancreatic NET.