SIX1 Expression and its Clinicopathological Significance: Difference between Classic and Follicular Variant Papillary Thyroid Carcinoma

Abstract

<title>Abstract</title> Background Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, representing the majority of thyroid cancer cases. Most patients with PTC have an excellent prognosis following treatment, yet approximately 10% face mortality within ten years, primarily due to lymph node metastasis (LNM) or local recurrence. The SIX1 gene, a member of the SIX gene superfamily, encodes a transcription factor integral to the development of certain tissues during embryogenesis. The impact of SIX1 in different subtypes of PTC ha<italic>s</italic> not been studied previously. Objective The purpose of this study was to investigate the expression of SIX1 protein in PTC and to explore its relationship with clinical behavior in two subtypes of PTC: classic PTC (C-PTC) and follicular variant PTC (FV-PTC). Material and Methods Using immunohistochemistry, the study analyzed 125 primary PTC cases, including 85 cases of C-PTC and 40 cases of FV-PTC. Results The study found significant positive associations between high SIX1 expression and several adverse clinical features across the PTC samples. High SIX1 expression was linked with increased tumor size, multifocal tumors, LNM, high-grade tumor features, advanced tumor stage, lymphovascular invasion, perineural invasion, and extrathyroidal extension (ETE). Within the classic PTC subgroup, high SIX1 expression showed significant positive correlations with Tumor size (P = 0.04), Multifocality (P = 0.02) and High-grade features (P = 0.03). In the follicular variant subgroup, high SIX1 expression was significantly associated with Lymph node metastasis (LNM) (P = 0.001), Lymphovascular invasion (P = 0.03), ETE (P = 0.003) and Tumor stage (P = 0.007). Conclusions The findings of this study indicate that SIX1 expression is a marker of poor prognosis in PTC, suggesting that its high expression is linked with more aggressive tumor characteristics and advanced disease stages. Importantly, the impact of SIX1 expression varies between C-PTC and FV-PTC, predicting distinct prognostic factors in each subtype. This suggests that SIX1 could be utilized not only as a prognostic biomarker but also in developing subtype-specific therapeutic strategies for PTC patients.