title: Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype.
abstract: OBJECTIVE
  Host immune response to tumor may be an important prognostic factor for colon cancer patients. However, little is known on prognostic significance of histopathologic lymphoid reaction to tumor, independent of the number of lymph nodes examined and tumoral molecular alterations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), both of which are associated with lymphocytic reaction and clinical outcome.
  
  
  METHODS
  Using 843 colorectal cancer patients in two independent prospective cohorts, we examined patient prognosis in relation to four components of lymphocytic reaction (i.e., Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes) and overall lymphocytic score (0-12). CIMP was determined using eight markers including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1. Cox proportional hazard models computed hazard ratio for mortality, adjusted for covariates including tumor stage, body mass index, lymph node count, KRAS, BRAF, p53, cyclooxygenase-2 (PTGS2), MSI, CIMP, and LINE-1 methylation.
  
  
  RESULTS
  Increasing overall lymphocytic reaction score including tumor-infiltrating lymphocytes was associated with a significant improvement in colorectal cancer-specific and overall survival (log-rank P < 0.003). These findings remained significant (adjusted hazard ratio estimates, 0.49-0.71; P(trend) < 0.009) in multivariate models that adjusted for covariates, including body mass index, MSI, CIMP, LINE-1 hypomethylation, and cyclooxygenase-2. The beneficial effect of tumoral lymphocytic reaction was consistent across strata of clinical, pathologic, and molecular characteristics.
  
  
  CONCLUSIONS
  Lymphocytic reactions to tumor were associated with improved prognosis among colorectal cancer patients, independent of lymph node count and other clinical, pathologic, and molecular characteristics.
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Natsumi
authors.initials: N
authors.lastname: Irahara
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008198:Lymph Nodes / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D053842:Microsatellite Instability; D011379:Prognosis