Markers of Epithelial-Mesenchymal Transition and Mucinous Histology Are Significant Predictors of Disease Severity and Tumor Characteristics in Early-Onset Colorectal Cancer

Abstract

Approximately 20% of patients with colorectal cancer (CRC) are diagnosed with a mucinous subtype of this tumor, have a worse prognosis, and often show resistance to available therapies. Molecules from the mucin family are involved in the regulation of epithelial-mesenchymal transition (EMT), which significantly determines the cancer aggressiveness. This study aimed to examine the diagnostic and prognostic significance of mucinous histology and EMT markers in patients with early-onset CRC and their association with disease severity and tumor characteristics. This study included tumor tissue samples from 106 patients diagnosed with CRC before the age of 45, 53 with mucinous and 53 with non-mucinous tumors. The EMT status was determined by immunohistochemical analysis of E-cadherin and Vimentin in tissue sections. Mucinous tumors had significantly higher Mucin-1 (p < 0.001) and cytoplasmic E-cadherin (p = 0.043) scores; they were significantly less differentiated (p = 0.007), more advanced (p = 0.027), and predominately affected right the colon (p = 0.039) compared to non-mucinous tumors. Epithelial tumors were significantly better differentiated (p = 0.034) and with less prominent tumor budding (p < 0.001) than mesenchymal tumors. Mucin-1 and Vimentin were independent predictors of tumor differentiation (p = 0.006) and budding (p = 0.001), respectively. Mucinous histology and EMT markers are significant predictors of disease severity and tumor characteristics in early-onset colorectal cancer.

Keywords: early-onset colorectal cancer; epithelial–mesenchymal transition; mucinous tumor.

Figure 1

Immunohistochemical staining for epithelial–mesenchymal markers (magnification ×40). Intensity of E-cadherin cytoplasmatic and Vimentin staining (from left to right): colorless scored 0; pallide-flavens scored 1; yellow scored 2; and brown scored 3. Intensity of E-cadherin membrane staining (from left to right): intensive for continuous staining of the membrane with the creation of a honeycomb-shaped pattern; moderate for continuous staining present in 40–90% of membranes; weak for continuous staining present in 10–39% of membranes; negativefor staining in <10% membranes.

Figure 2

Representative mesenchymal tumor within the group of mucinous tumors. (A) The black square highlights the invasive front where EMT was observed (H&E, magnification ×2.5); (B) detailed view of the invasive front (H&E, magnification ×40); (C) very pale and negative immunohistochemical staining for E-Cadherin (magnification ×40); (D) immunopositive staining for Vimentin (magnification ×40).

Figure 3

The Kaplan–Meier analysis of patients’ survival according to (A) the <40 and the >40 age groups in non-mucinous tumors; (B,C) the Dukes’ classification for mucinous and non-mucinous tumors, respectively; (D) the T stage for mucinous tumors, (E) the N stage for non-mucinous tumors, and (F) the Mx and M1a-c stages for all patients; all presented differences in overall survival are statistically significant (p < 0.05).