MLH1 promoter methylation, mismatch repair and intestinal differentiation markers in papillary thyroid carcinoma: real-world evidence from Galicia (Northwest Spain)

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy and is generally associated with a favorable prognosis. However, a subset of these tumors exhibits more aggressive behavior, underscoring the need for refined molecular and immunohistochemical characterization to improve diagnostic precision and prognostic stratification. Given the shared embryologic origin of the thyroid gland and gastrointestinal tract from the endoderm, intestinal differentiation markers (CDX2 and SATB2) and alterations in DNA mismatch repair (MMR) pathways, including MLH1 promoter methylation, may represent biologically relevant features in thyroid tumors. This study performed MLH1 promoter methylation analysis by pyrosequencing and protein expression of MLH1, PMS2, MSH2, MSH6, SATB2 and CDX2 by immunohistochemistry in 63 PTCs. Clinicopathological and molecular data were also collected for comparative analyses and correlation with progression-free survival (PFS). All PTCs retained expression of MMR proteins (MLH1, PMS2, MSH2, and MSH6), including the three tumors with MLH1 promoter hypermethylation. CDX2 positivity was detected in only two (3.2%) PTCs (classic and follicular subtypes), and SATB2 expression was absent in all cases. No significant association was identified between MLH1 promoter methylation, MMR protein expression, CDX2 or SATB2 expression, and PFS. In contrast, venous invasion was confirmed as a significant predictor of worse PFS (HR = 3.34; 95% CI 1.27–8.76; p = 0.014) in univariate analysis. MLH1 promoter methylation, MMR deficiency, and CDX2 are rare events in PTC and do not appear to influence PFS. Although infrequent, the expression of CDX2 is not exclusive to any PTC subtype.