Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology

Abstract

Objectives Emerging data suggests that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Methods Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival (OS) were determined. Results Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median OS in G3 WD-panNET patients was 52.2 months (95% confidence interval (CI) 19.3 to 86.9 months) compared to 10.1 months (95% CI 6.9 to 12.4 months) in PDNEC patients (p-value = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Conclusions Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. OS was significantly greater in G3 WD-panNETs compared to PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Peptide Receptor Radionuclide Therapy with Radiolabelled Somatostatin Analogues

“…The concept of spatial concordance between lesions identified on SSTR imaging and those expressing the glycolytic phenotype in selecting patients for PRRT [66] is a fundamental principle underpinning the theranostic paradigm [67]. There is increasing recognition that the degree of differentiation on histopathological examination varies within the group of tumours with a Ki-67 >20%, i.e., grade 3 NEN, and that this impacts prognosis [68,69]. A new classification of well-differentiated grade 3 NET is likely to be included in the revised World Health Organization grading system of NEN.…”

Assessment of cytologic differentiation in high‐grade pancreatic neuroendocrine neoplasms: A multi‐institutional study

“…Pancreatic neuroendocrine neoplasms with Ki‐67 proliferation rates exceeding 20% (WHO G3) are rare. It has recently been recognized that these high‐grade neoplasms include both WD neuroendocrine tumors and PD neuroendocrine carcinomas, which have distinct biologies, therapeutic management, and outcomes . These findings are reflected in the new 2017 WHO classification of pancreatic neuroendocrine neoplasms, which includes both WD PanNETs and PD PanNECs within the G3 category.…”

“…The 2017 World Health Organization (WHO) classification of tumors of the digestive system defines well‐differentiated (WD) pancreatic neuroendocrine tumors (PanNETs) as morphologically resembling nonneoplastic islet cells, whereas poorly differentiated (PD) pancreatic neuroendocrine carcinomas (PanNECs) are uniformly high‐grade and exhibit a large cell or small cell morphology (large cell neuroendocrine carcinoma or small cell carcinoma) . The distinction between WD and PD tumors is supported by different underlying genetic alterations, treatment responses, and outcomes . Emerging genotypes for WD PanNETs include mutations in death domain–associated protein ( DAXX ), α thalassemia/mental retardation syndrome X‐linked ( ATRX ), and menin 1 ( MEN1 ), whereas PD PanNECs show more similarity to conventional ductal adenocarcinomas and may exhibit mutations of TP53 , retinoblastoma 1 ( RB1 ), and KRAS , among others .…”

“…Thus, PD PanNECs are uniformly high‐grade, whereas WD PanNETs can exhibit a spectrum ranging from low‐grade to high‐grade. Prognoses and therapeutic responses are markedly different between G3 WD PanNETs and PanNECs, with better median overall survival for G3 WD PanNETs (52 vs 10 months, respectively) but worse response rates to platinum‐based therapy (10% and 37%, respectively) …”

Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors

“…High-grade (G3) poorly differentiated neuroendocrine carcinomas (NECs) are typically much more aggressive and nearly always metastatic at diagnosis. Tumors in the recently identified category of well-differentiated G3 NETs are thought to harbor an intermediate prognosis (closer to traditional well-differentiated NETs) (22).…”