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Several previous studies have demonstrated that the CDX2-negative (CDX2−) and/or CK20-negative (CK20−) phenotypes of colorectal cancers (CRCs) might be associated with high levels of microsatellite instability (MSI-H). The aim of this study was to investigate the clinicopathologic and molecular features of MSI-H CRCs with different CDX2/CK20 expression statuses. The CDX2 and CK20 expression statuses were immunohistochemically evaluated in 109 MSI-H CRC tissue samples, and the correlations of these statuses with clinicopathologic, molecular, and survival data were statistically analyzed. Of the 109 MSI-H CRCs, 15 were CDX2− (13.8%), and 19 were CK20− (17.4%). The simultaneous loss of CDX2 and CK20 expression (CDX2−/CK20−) was observed in 9 cases (8.3%). CDX2 loss was correlated with lymph node metastasis, poor differentiation, MLH1 loss, the mutation of BRAF, and CpG island methylator phenotype-high (CIMP-H) status. Right-sided tumor location, nodal metastasis, poor differentiation, and CIMP-H status were significant characteristics of CK20− tumors. The CDX2−/CK20− phenotype was associated with older age (above 56 y), higher stage (stage III or IV), deep invasion (pT3 or pT4), lymph node metastasis (pN1 or pN2), poor differentiation (nonmedullary/non–signet ring cell type), the mutation of BRAF, and CIMP-H status among MSI-H CRCs. Patients with CDX2−/CK20− tumors exhibited worse overall and disease-free survival compared with the patients with CDX2+ and/or CK20+ tumors (P<0.001). In the multivariate analysis for disease-free survival, the CDX2−/CK20− phenotype was an independent prognostic factor for MSI-H CRC (P=0.030, hazard ratio=3.288). The CDX2−/CK20− phenotype defines a distinct subgroup of MSI-H CRCs with poor differentiation, CIMP-H status, and unfavorable prognosis.