Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma

Abstract

<b><i>Background:</i></b> The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. <b><i>Methods:</i></b> 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 <i>RET</i> and <i>RAS</i> 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 <i>RET</i> mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. <b><i>Results:</i></b> We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 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%) as high-grade. Patients carrying a <i>RET</i> mutation had more aggressive features and shorter disease-specific survival (DSS) (<i>p</i> = 0.001) and were more frequently classified high-grade than low-grade MTC (<i>p</i> < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], <i>p</i> = 0.005). <i>RET</i> mutations, in particular <i>RET</i>-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in <i>RET</i>, 46.9% vs. 12.7% mutated in <i>RET</i>-M918T; <i>p</i> < 0.001). None of the high-grade tumors was mutated in the <i>RAS</i> gene, but the mutation was present in 11.8% of low-grade tumors. <b><i>Conclusions:</i></b> IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with <i>RET</i> and <i>RAS</i> patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.