title: The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories.
abstract: OBJECTIVE
  Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS).
  
  
  METHODS
  Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features.
  
  
  RESULTS
  With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C).
  
  
  CONCLUSIONS
  The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.
authors.affiliation: Anatomic Pathology, Department of Pathology and Laboratory Medicine, IRCCS Foundation National Cancer Institute, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Milione
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Francesca
authors.initials: F
authors.lastname: Spada
authors.forename: Alessio
authors.initials: A
authors.lastname: Pellegrinelli
authors.forename: Paola
authors.initials: P
authors.lastname: Spaggiari
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.forename: Eleonora
authors.initials: E
authors.lastname: Pisa
authors.forename: Massimo
authors.initials: M
authors.lastname: Barberis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Buzzoni
authors.forename: Sara
authors.initials: S
authors.lastname: Pusceddu
authors.forename: Laura
authors.initials: L
authors.lastname: Concas
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012044:Regression Analysis; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D007473:Ion Channels; D019394:Ki-67 Antigen; C515204:PIEZO1 protein, human; D019009:Proto-Oncogene Proteins c-kit