title: Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas?
abstract: BACKGROUND
  The WHO classified pancreatic neuroendocrine neoplasms in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to the Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs.
  
  
  METHODS
  We retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated NEC (WDNEC) and poorly differentiated NEC (PDNEC). The latter was further subdivided into large-cell and small-cell subtypes.
  
  
  RESULTS
  The median Ki67 LI was 69.1% (range 40-95%). Eleven WHO-NECs were subclassified into 4 WDNECs and 7 PDNECs. The latter was further separated into 3 large-cell and 4 small-cell subtypes. Comparisons of WDNEC vs. PDNEC revealed the following traits: hypervascularity on CT, 50% (2/4) vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40-53%) vs. 85% (54-95%) (P = 0.001); Rb immunopositivity, 100% (4/4) vs. 14% (1/7) (P = 0.015); KRAS mutations, 0% (0/4) vs. 86% (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0% (0/2) vs. 100% (4/4) (P = 0.067), and median survival, 227 vs. 186 days (P = 0.227).
  
  
  CONCLUSIONS
  The WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing profiles of Ki67 LI, Rb immunopositivity and KRAS mutation, and distinct response to chemotherapy. Further studies for the reevaluation of the current WHO 2010 classification are warranted.
authors.affiliation: Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan, rizasusu@aichi-cc.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Hijioka
authors.forename: Waki
authors.initials: W
authors.lastname: Hosoda
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Mizuno
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imaoka
authors.forename: Vikram
authors.initials: V
authors.lastname: Bhatia
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Mekky
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tajika
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishihara
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Yogi
authors.forename: Hideharu
authors.initials: H
authors.lastname: Tsutumi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Fujiyoshi
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sato
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hieda
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Yoshida
authors.forename: Nozomi
authors.initials: N
authors.lastname: Okuno
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Niwa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine / Q000145:classification* / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000145:classification* / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015203:Reproducibility of Results; D012189:Retrospective Studies; D014944:World Health Organization
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D016283:Proto-Oncogene Proteins p21(ras)