Mixed neuroendocrine non-neuroendocrine tumors: The quest for evidence

Table 1 Proposed grading and systemic management of mixed neuroendocrine non-neuroendocrine neoplasms

Grades	Neuroendocrine component	Non-neuroendocrine component	Systemic management
Low	Well-differentiated NET, Grade 1 Ki-67 < 3%, MI < 2/10 HPF, Grade 2 Ki-67 3-20, MI 2-20/10 HPF	Adenoma	Somatostatin analogs; Radiolabeled somatostatin analogs (when SSTR+); Everolimus; Sunitinib (pancreatic primaries); Temozolomide-based chemotherapy
Intermediate	Well-differentiated NET, Grade 1 Ki-67 < 3%, MI < 2/10 HPF, Grade 2 Ki-67 3-20, MI 2-20/10 HPF	Adenocarcinoma, signet ring cell carcinoma, mucinous neoplasm	5-FU-based regimens (i.e. FOLFIRINOX, FOLFIRI, FOLFOX, etc), Targeted therapies according to molecular profiling
High	NEC (small/large cell)	Adenocarcinoma, squamous cell carcinoma, acinar cell carcinoma, adenosquamous carcinoma, mucinous carcinoma, signet ring cell carcinoma	Etoposide/Platinum 5-FU-based regimens (i.e. FOLFIRINOX, FOLFIRI, FOLFOX, etc), Targeted therapies according to molecular profiling

HPF: High power field; MI: Mitotic index; NEC: Neuroendocrine carcinoma; NET: Neuroendocrine tumor.