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, tumor budding and tumor grade.
Design 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 tumor marker positivity. Survival time was investigated for each marker in multivariable analysis with T stage, N stage, vascular invasion, tumor budding and tumor 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 6 markers added independent prognostic information including RHAMM (HR = 2.39 (1.88-3.05)), EGFR (HR = 1.65 (1.31-2.09)), tumor infiltrating lymphocytes (HR = 0.7 (0.54-0.92)), uPAR (HR = 1.38 (1.09-1.75)), RKIP (HR = 0.75 (0.58-0.96)) and MST1 (HR = 0.75 (0.58-0.95). Diffuse (>90% staining) expression of RHAMM ranked above T stage, vascular invasion, tumor budding and tumor 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 tumor grade, tumor budding and vascular invasion in patients with CRC.