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RHAMM, p21 Combined Phenotype Identifies Microsatellite Instability-High Colorectal Cancers with a Highly Adverse Prognosis

Authors' Affiliations: ¹ Institute of Pathology, University Hospital of Basel, Basel, Switzerland; and ² Department of Pathology, McGill University, Montreal, Quebec, Canada

Requests for reprints: Inti Zlobec, Institute of Pathology, University Hospital of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland. Phone: 41-61-26-52895; Fax: 41-61-26-52966; E-mail: izlobec{at}uhbs.ch.

Purpose: The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features.

Experimental Design: Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid–mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses.

Results: RHAMM overexpression [P < 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P < 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P < 0.001). Both node-negative and node-positive patients with RHAMM– tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21– patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21– node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021).

Conclusion: These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM– tumors.