Medullary Thyroid Carcinomas Classified According to the International Medullary Carcinoma Grading System and a Surveillance, Epidemiology, and End Results-Based Metastatic Risk Score: A Correlation With Genetic Profile and Angioinvasion

Due to the lack of a standardized tool for risk-based stratification, the International Medullary Carcinoma Grading System (IMTCGS) has been proposed for medullary thyroid carcinomas (MTCs) based on necrosis, mitosis, and Ki67. Similarly, a risk stratification study using the Surveillance, Epidemiology, and End Results (SEER) database highlighted significant differences in MTCs in terms of clinical-pathological variables. We aimed to validate both the IMTCGS and SEER-based risk table on 66 MTC cases, with special attention to angioinvasion and the genetic profile. We found a significant association between the IMTCGS and survival because patients classified as high-grade had a lower event-free survival probability. Angioinvasion was also found to be significantly correlated with metastasis and death. Applying the SEER-based risk table, patients classified either as intermediate- or high-risk had a lower survival rate than low-risk patients. In addition, high-grade IMTCGS cases had a higher average SEER-based risk score than low-grade cases. Moreover, when we explored angioinvasion in correlation with the SEER-based risk table, patients with angioinvasion had a higher average SEER-based score than patients without angioinvasion. Deep sequencing analysis found that 10 out of 20 genes frequently mutated in MTCs belonged to a specific functional class, namely chromatin organization, and function, which may be responsible for the MTC heterogeneity. In addition, the genetic signature identified 3 main clusters; cases belonging to cluster II displayed a significantly higher number of mutations and higher tumor mutational burden, suggesting increased genetic instability, but cluster I was associated with the highest number of negative events. In conclusion, we confirmed the prognostic performance of the IMTCGS and SEERbased risk score, showing that patients classified as high-grade had a lower event-free survival probability. We also underline that angioinvasion has a significant prognostic role, which has not been incorporated in previous risk scores.& COPY; 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Automated summary

Due to the lack of a standardized tool for risk stratification, the International Medullary Carcinoma Grading System (IMTCGS) and risk stratification study using the Surveillance, Epidemiology, and End Results (SEER) database have been validated for medullary thyroid carcinomas (MTCs). The validation study on 66 MTC cases found that high-grade patients had a lower survival probability and angioinvasion was significantly correlated with metastasis and death. Overall, these results confirm the prognostic performance of IMTCGS and SEER-based risk score and emphasize the important role of angioinvasion in prognosis.