title: Colorectal neuroendocrine carcinomas and adenocarcinomas share oncogenic pathways. A clinico-pathologic study of 12 cases.
abstract: OBJECTIVE
  Neuroendocrine carcinomas (NECs) are rare neoplasms with an increasing incidence. Oncogenetic pathways of colorectal NEC are still poorly understood, and no treatment standards are available for these rare tumors.
  
  
  METHODS
  We analyzed retrospectively the clinical records and histology of 12 patients with colorectal NEC. KRAS and BRAF mutations were investigated after the dissection of exoendocrine and neuroendocrine components. ALK alterations and EML4-ALK transcripts were detected by in-situ hybridization and determination of fusion transcripts, respectively.
  
  
  RESULTS
  At the time of diagnosis, the mean age of the patients was 60 years (40-79) and 10 patients had synchronous metastases. A transient response occurred in two patients and one patient treated with cisplatin-etoposide or fluoropyrimidine-oxaliplatin, respectively. Tumor progression-related death occurred in 11 of 12 patients. Ten tumors contained an exocrine component, accounting for 5-70% of the tumor, and the other two contained an amphicrine component. BRAF/KRAS mutations were found in six of 10 tumors, corresponding to BRAF(V600E) (n=2) or KRAS(G12D) (n=2), KRAS(G12V) or KRAS(G13D). DNA was obtained from both exocrine and endocrine components in seven cases, and the BRAF/KRAS status was identical in all cases. Split of the ALK locus was detected in a minority of tumor cells in two of eight cases, but EML4-ALK transcripts were absent.
  
  
  CONCLUSIONS
  The association of an exocrine component in all cases and the similar profile of BRAF/KRAS mutations indicate that colorectal NEC may correspond to a high-grade transformation of colorectal carcinoma. New chemotherapy regimens using targeted therapies should be assessed in these tumors.
authors.affiliation: EA4340, Versailles University, APHP, Boulogne, France.
authors.forename: Raymond
authors.initials: R
authors.lastname: Karkouche
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sandrini
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mitry
authors.forename: Christophe
authors.initials: C
authors.lastname: Penna
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Saint André
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000236:Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins