High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO 3)

Neuroendocrine neoplasms (NEN) are classified according to morphology and their proliferative fraction. The WHO 2010 classification defines NEN as either well-differentiated low-grade (G1-G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinoma (NEC). NEN G3 have a proliferation rate (Ki67) above 20% or >20 mitoses 10 HPF. The 2017 WHO classification of pancreatic neuroendocrine tumors defined a new group of well-differentiated high-grade pancreatic tumors (NET G3) (Kløppel 2017). The NET category should now only be used for well-differentiated tumors regardless of their proliferation index (G1-G3), whereas NEC category is used for poorly differentiated high-grade carcinomas (G3). The terminology of NEN G3 relates to all high-grade (G3, Ki67 > 20%) neuroendocrine malignancies; that is both NET G3 and NEC. NEC can originate anywhere in the gastrointestinal tract but are mainly located in the esophagus, pancreas, and large bowel, whereas NET G3 are mainly located in the pancreas. For patients with localized disease, an aggressive multimodal approach should be scheduled as many of these patients may be cured. Adjuvant therapy with 4–6 cycles of cisplatin/carboplatin and etoposide has been recommended after radical surgery of NEC. Advanced NEC is an aggressive disease where rapid referral to an oncologist is necessary, as performance status often deteriorates rapidly. Median survival in patients not given chemotherapy is only 1 month. Advanced NEC patients are treated with platinum-based chemotherapy combined with etoposide. Recent results show a response rate of 30–40%, progression free-survival of 4–6 months, and median survival of 8–13 months. No differences in response rate and survival are seen comparing cisplatin-based to carboplatin-based chemotherapy. Tumors with a Ki67 < 55% are less responsive to platinum-based chemotherapy but have a significant longer survival. Small retrospective studies have shown benefit of second-line chemotherapy with temozolomide, oxaliplatin-, or irinotecan-based treatments. NET G3 patients do not respond well to platinum-based chemotherapy and other treatment alternatives should be considered.