title: Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications.
abstract: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer. However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21-55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21-55% Ki-67.
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. Electronic address: nicola.fazio@ieo.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.affiliation: 1(st) Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS Foundation National Cancer Institute, Milan, Italy. Electronic address: massimo.milione@istitutotumori.mi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Milione
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D007414:Intestinal Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D060787:Neoplasm Grading; D010190:Pancreatic Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017671:Platinum Compounds / Q000008:administration & dosage; D011379:Prognosis; D013274:Stomach Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D019394:Ki-67 Antigen; D017671:Platinum Compounds; D005047:Etoposide
keywords: Classification; GEP; Morphology; Neuroendocrine carcinoma; Prognosis; Proliferation; Therapy