Assessment of mismatch repair deficiency, CDX2, beta-catenin and E-cadherin expression in colon cancer: molecular characteristics and impact on prognosis and survival - an immunohistochemical study

Abstract

Microsatellite instability (MSI) or the deficiency of mismatch repair (MMR) proteins is one of the molecular pathways of colorectal tumorigenesis and may have important clinical implications in predicting the treatment response. We evaluated the relationship between clinicopathological features and MMR proteins [mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), postmeiotic segregation increased 2 (PMS2)], adhesion molecules (E-cadherin, beta-catenin) and caudal-type homeobox 2 (CDX2) in 31 patients with colon adenocarcinoma, using immunohistochemistry. We also aimed to assess the prognostic value of the studied proteins. MLH1 loss was correlated to PMS2 loss (p=0.006) and MSH2 loss (p=0.023); MSH2 loss was significantly associated to MSH6 loss (p=0.011). Tumors with MSH6 loss, together with tumors with PMS2 loss, covered all the patients with MSI status. We found a significant correlation between MSI tumors and mucinous histological type (p=0.03), but no significant associations with other clinicopathological features or with survival rate. There was a significant correlation between E-cadherin expression and differentiation degree (p=0.018) and between beta-catenin expression and lymph node invasion (p=0.046). No significant association between CDX2 loss and any clinical or pathological features was found (p>0.05). No significant differences were identified in overall survival according to E-cadherin, beta-catenin or CDX2 expression (p>0.05). In our study, PMS2 loss was significantly correlated with CDX2 loss (p=0.03). In conclusion, the molecular analysis of biological markers for colon cancer may be important for patient stratification, in order to select the optimal treatment algorithm. Our results suggest that probably the double panel (MSH6 and PMS2) is enough to detect the MSI status, instead of using the quadruple panel.

Figure 1

Immunohistochemical staining for MLH1 in colon cancer: (A) Positive nuclear immunostaining for MLH1 in tumor cells and normal intestinal mucosa (upper right corner) (×100); (B) Strong nuclear immunoreactivity for MLH1 in tumor cells (×200); (C) MLH1 loss in tumor cells, with positive internal control of stromal lymphocytes (×200). MLH1: mutL homologue 1

Figure 2

Immunohistochemical staining for MSH2 in colon cancer: (A) Positive nuclear immunostaining for MSH2 in normal intestinal mucosa and in tumor cells (upper right corner) (×100); (B) Strong nuclear immunoreactivity for MSH2 in tumor cells (×200); (C) Low intensity of nuclear immunostaining for MSH2 in tumor cells (×200); (D) MSH2 loss in tumor cells (×200). MSH2: mutS homologue 2

Figure 3

Immunohistochemical staining for MSH6 in colon cancer: (A) Positive nuclear immunostaining for MSH2 in normal intestinal mucosa (left upper corner) and in tumor cells (×100); (B) Strong positive nuclear immunoreactivity for MSH6 in tumor cells (×200); (C) Absence of nuclear immunostaining for MSH6 in tumor cells in a mucinous colon cancer (×200). MSH6: mutS homologue 6

Figure 4

Immunohistochemical staining for PMS2 in colon cancer: (A) Positive nuclear immunostaining for PMS2 in tumor cells (×100); (B) Strong positive nuclear immunostaining for PMS2 in tumor cells (×200); (C) PMS2 loss in tumor cells (×200). PMS2: Postmeiotic segregation increased 2

Figure 5

Immunohistochemical staining for E-cadherin in colon cancer: (A) Normal membranous immunoexpression of E-cadherin in normal colon mucosa (×200); (B) Strong cytoplasmatic and membranous immunoexpression of E-cadherin in tumor cells (×200)

Figure 6

Immunohistochemical staining for beta-catenin in colon cancer: (A) Diffuse beta-catenin immunopositivity in a mucinous colon adenocarcinoma (×100); (B) Strong nuclear immunostaining for beta-catenin in tumor cells (×200).

Figure 7

Immunohistochemical staining for CDX2 in colon cancer: (A) Positive nuclear immunostaining for CDX2 in normal intestinal mucosa (×100); (B) Strong positive nuclear immunoreactivity for CDX2 in tumor cells (×200); (C) Absence of nuclear immunostaining for CDX2 in tumor cells (×200). CDX2: Caudal-type homeobox 2