Gland Attenuation, a Novel Morphological Feature of Colorectal Cancer: Evidence for an Epithelial-Mesenchymal Transition

PURPOSE: Along the invasive margin, colorectal cancer may show distinctive morphologic changes characterized by an asymmetrically attenuating tumor gland with loss of polarity. The author coined the term ‘gland attenuation (GA)’ for these peculiar changes. The aims of this study were to compare the immunoreactivity of the epithelial-mesenchymal transition (EMT) markers E-cadherin and β-catenin and thus determine whether EMTs occurs at tumor budding (TB) or GA sites and to assess the association of TB and/or GA levels with clinicopathological parameters and prognosis. METHODS: Expression patterns of E-cadherin and β-catenin in the tumor centers at GA and TB sites were examined in 101 patients with well or moderately differentiated CRCs, and the prognostic significance of TB and/or GA was statistically evaluated. RESULTS: GA foci, as well as TB foci, revealed loss of membranous and cytoplasmic E-cadherin expressions and aberrant β-catenin expression with reduced membranous expression and increased localization to the nucleus, suggesting that EMTs occur in GA as well as in TB. The high-TB and the TB-dominant groups were significantly correlated with advanced invasion depth, presence of lymph node metastasis, advanced pathologic staging and presence of lymphovascular invasion. The high-TB and the TB-dominant groups showed poor overall survival (OS) and recurrence-free survival (RFS), and high TB was an independent prognostic factor in the multivariate analyses for OS and RFS. CONCLUSION: This study showed evidence that EMTs occurs at GA sites as well as TB foci. TB is a strong and independent prognostic factor, and TB-dominance may be an indicator of adverse clinical outcome.