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Management of advanced high grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): comprehensive review of the current literature

A Mohamed

A Mohamed Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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M Trybula

M Trybula Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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S L Asa

S L Asa Department of Medicine, UH Seidman Cancer Center Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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T R Halfdanarson

T R Halfdanarson Division of Medical Oncology, Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota, USA

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M B Sonbol

M B Sonbol Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Phoenix, Arizona, USA

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The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.