title: Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer.
abstract: OBJECTIVE
  To compare the independent prognostic effect of a panel of immunohistochemical protein markers in colorectal cancer (CRC) and determine their ranking among the established prognostic factors T stage, N stage, vascular invasion, tumour budding and tumour grade.
  
  
  METHODS
  A tissue microarray of 1420 CRCs was immunostained for 23 markers and mismatch repair (MMR) proteins. Immunoreactivity was assessed semi-quantitatively. Receiver operating characteristic (ROC) curves were used to determine cut-off scores for tumour marker positivity. Survival time was investigated for each marker in multivariable analysis with T stage, N stage, vascular invasion, tumour budding and tumour grade. The hazard ratio (HR) was used to compare the prognostic effect of each marker on 5 year survival.
  
  
  RESULTS
  To the standard prognostic features, only six markers added independent prognostic information including receptor for hyaluronic acid mediated motility (RHAMM) (HR = 2.39 (1.88 to 3.05)), epidermal growth factor receptor (HR = 1.65 (1.31 to 2.09)), tumour infiltrating lymphocytes (HR = 0.7 (0.54 to 0.92)), urokinase plasminogen activator (HR = 1.38 (1.09 to 1.75)), Raf-1 kinase inhibitor protein (HR = 0.75 (0.58 to 0.96)) and mammalian sterile 20-like kinase 1 (MST1) (HR = 0.75 (0.58 to 0.95). Diffuse (>90% staining) expression of RHAMM ranked above T stage, vascular invasion, tumour budding and tumour grade in terms of adverse prognostic significance and was associated with distant metastasis (p = 0.012) and with worse outcome in patients with metastatic disease (p = 0.031).
  
  
  CONCLUSIONS
  The strong adverse effect of RHAMM on outcome in addition to its position within the hierarchy of well-established prognostic factors suggest that RHAMM should be considered a more important prognosticator than tumour grade, tumour budding and vascular invasion in patients with CRC.
authors.affiliation: Institute of Pathology, University Hospital of Basel, Schönbeinstrasse 40, Basel, CH-4031, Switzerland. izlobec@uhbs.ch
authors.forename: I
authors.initials: I
authors.lastname: Zlobec
authors.forename: L
authors.initials: L
authors.lastname: Terracciano
authors.forename: L
authors.initials: L
authors.lastname: Tornillo
authors.forename: U
authors.initials: U
authors.lastname: Günthert
authors.forename: T
authors.initials: T
authors.lastname: Vuong
authors.forename: J R
authors.initials: JR
authors.lastname: Jass
authors.forename: A
authors.initials: A
authors.lastname: Lugli
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002908:Chronic Disease; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000032:analysis*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis*; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012372:ROC Curve; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor