Immunohistochemical expression of Ki-67, INSM1, and SSTR2A in medullary thyroid carcinoma: correlation with tumour size, vascular invasion, and biochemical outcome

In the management of medullary thyroid carcinoma (MTC), current prognostic tools have limited discriminatory power, and no widely accepted tissue markers are available aside from proliferative activity and tumour necrosis, recently validated in a grading system. Herein, we assess the prognostic value of selected immunohistochemical biomarkers in MTC: proliferation index Ki-67, insulinoma-associated protein 1 (INSM1), and somatostatin receptor subtype 2A (SSTR2A). We retrospectively analysed 43 patients diagnosed at our centre between October 2003 and July 2024 with histologically confirmed MTC (mean follow-up, 52.5 months). Expression of Ki-67 (> 3%), INSM1, and SSTR2A was evaluated on formalin-fixed, paraffin-embedded tissue sections. Associations between these biomarkers and clinicopathological variables, as well as biochemical cure, were analyzed. Additionally, we compared 13 patients with double tumours (DT)—with medullary and papillary/follicular components—to the remaining 30 patients to identify significant differences. A Ki-67 index > 3% significantly correlated with larger tumour size (26.0 mm vs 9.6 mm; p < 0.001) and vascular invasion (80% vs 31.6%; p = 0.035). INSM1 expression was associated with larger tumour size (12.9 mm vs 3.2 mm; p = 0.021), vascular invasion (43.2% vs 0%; p = 0.042), and lower biochemical cure rate (54.1% vs 100%; p = 0.033). SSTR2A expression correlated with biochemical cure (100% vs 54.1%; p = 0.033) and was more frequent in DT patients (66.7% vs 24.3%; p = 0.036). Among all comparisons, only SSTR2A expression significantly differed between DTs and other tumours. In conclusion, Ki-67 and INSM1 identify patients with more aggressive MTC, while SSTR2A defines a favourable subgroup with complete remission.