Long-term outcomes of World Health Organization G 3 pancreatic neuroendocrine neoplasms : a retrospective study in combination of morphological and proliferative analysis

Background: The prognostic assessment of pancreatic neuroendocrine neoplasms (p-NENs) has been significantly improved since systematical classification of this disease into three grades were recommended by the 2010 World Health Organization (WHO) guidelines in which G3 p-NEN is equal to pancreatic neuroendocrine carcinoma (p-NEC) with a poor prognosis. Limited investigations recently uncovered a subgroup of G3 p-NENs morphologically well-differentiated with better survival outcomes compared with the traditional poorly-differentiated pNENs, prompting us to assess the clinical and pathologic characteristics and prognosis of patients with G3 p-NENs. Methods: The databases for patients pathologically diagnosed as G3 p-NENs of the author’s institution from January 2003 to December 2015 were identified and analyzed retrospectively, as well as morphological differentiation according to the WHO 2000 classification. Results: Overall, 76 patients with pathologically confirmed G3 p-NENs were incorporated in our study, in which 21 (27.6%) and 55 (72.4%) cases showed well differentiated or poorly differentiated morphological features, defined as G3 p-NETs and G3 p-NECs respectively. Patients with G3 p-NETs were significantly more likely to have a less-progressive (P=0.0038) and lymph-negative (P=0.004) tumor against G3 p-NECs. Median Ki-67 positive index in G3 p-NECs (42%, range: 22-75) was significantly higher than in G3 pNETs (12%, range: 4-26; P<0.001). Those with G3 p-NETs had significantly longer overall survival (OS) than ones with G3 p-NECs (P<0.001). Morphological differentiation (HR, 0.311; P<0.001), tumor stage (HR, 0.362; P=0.009) and surgical margin status (HR, 0.534; P=0.013) were all independent predictors for OS of this disease. Conclusion: Our studies provide credible evidences on heterogeneity of G3 p-NENs including poorly-differentiated ones with aggressive nature and well-differentiated with better survival outcomes. The current WHO classification of G3 p-NENs seems controversial and further modification is warranted, thus further prospective clinical trials are necessary to provide more convincing grading classifications for clinicians.