Tumor grade and molecular characteristics associated with survival in sporadic medullary thyroid carcinoma

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid cancers (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of the present study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan–Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (IQR: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) high grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (P=0.001), and were more frequently classified high-grade than low-grade MTC (P