Consensus and controversy on subtype classification of gastric neuroendocrine neoplasms

Abstract

Gastric neuroendocrine neoplasms (g-NENs) are a heterogeneous group of tumors. Often silent, g-NENs may however be aggressive and sometimes mimic the course of gastric adenocarcinoma. Well-differentiated gastric neuroendocrine tumors (NET) can be subclassified into 3 distinct groups (type1, type 2 and type 3) according to Neuroendocrine Neoplasm Society (ENETS) guideline version 2006 as well as North America Neuroendocrine Tumor Society (NANETS) and National Comprehensive Cancer Network (NCCN) guidelines. However, since the publication of ENETS guideline version 2012, the subtype classification of g-NENs has been confusing due to the revised definition of type 3 g-NEN in versions 2012 and 2016. ENETS version 2012 indicated that type 3 g-NEN was usually solitary and its pathology was mostly WHO grade 3 (neuroendocrine carcinoma, NEC G3) with higher Ki-67 index, greater tumor diameter and infiltrative growth. While ENETS version 2006 showed that type 3 g-NEN was well-differentiated or moderate-differentiated, neither type 1 nor type 2, and other g-NENs without basic diseases. Besides, in renewal consensus guidance of ENETS version 2016, description about clinical and histological features altered as "well-differentiated g-NEN can be classified as type 3", but its pathology is still NEC G3. According to such classification, those gastric NET patients with well-differentiated, neither type 1 nor type 2 tumors, seem to be unable to classify. In this article, description about the subtype classification of g-NENs in several guidelines, including ENETS versions 2006, 2012 and 2016, NANETS version 2010 and NCCN version 2016, is introduced and the controversy focuses on type 3 g-NEN definition by ENETS versions 2012 and 2016. Hence, the four-type classification of g-NENs is recommended, which has been written in Chinese Consensus for the Diagnosis and Management of GEP-NEN (version 2016). Well-differentiated gastric NET is classified as type 3, and poor-differentiated gastric NEC as type 4. This four-type classification of g-NENs covers all the patients with g-NENs. Advances on clinical research of g-NENs in China are reviewed and the existing problems are analyzed. We also put forward the research direction in the future.