Mismatch Repair Proteins Immunostaining in Lip Squamous Cell Carcinoma: A Role in Lip Carcinogenesis?

Lip squamous cell carcinoma (LSCC) is associated with malignant transformation of actinic cheilitis (AC). Since solar radiation alters the functions of mismatch repair (MMR) complex, we evaluated for their possible role in lip carcinogenesis.

Samples of normal lip epithelia (NLE) (n=15), AC (n=30), and LSCC (n=45) were subjected to immunohistochemistry for MutSα (MSH2/MSH6) and MutLα (MLH1/PMS2) to assess the percentage (brown nuclei over all the keratinocytes in NLE and AC or all tumoral cells in LSCC) of nuclear positive cells and MSH2/MSH6 (MutSα-imbalance) and MLH1/PMS2 (MutLα-imbalance) ratios. Clinical-prognostic variables of the primary tumor and histopathological gradation (LSCC and AC) were evaluated. Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests were used (p<0.05, SPSS 20.0).

LSCC and AC showed significant increases in MSH2 (p<0.001), MSH6 (p<0.001), MLH1 (p=0.040) percentage of immunostained cells, and MutSα-imbalance (p<0.001). MutSα-imbalance in AC was higher than MutLα-imbalance (p=0.028). In LSCC, T3/T4 tumors showed higher MutSα-imbalance (p=0.028) and MutLα-imbalance (p=0.014). In LSCC with nodal metastasis, the MutLα-imbalance was significantly higher than the MutSα-imbalance (p=0.046). AC with high-risk dysplasia (p=0.024) and LSCC with vascular invasion (p=0.035) showed lower immunostaining for MSH6. Direct correlations between MMR-proteins increased in LSCC.

Increased MMR expression in lip cancer and the imbalance between MutSa and MutLα is associated with the progression and prognosis of LSCC.