Validation of the International Medullary Thyroid Carcinoma Grading System in Patients with Distant Metastases

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) is a two-tier score that classifies high-grade medullary thyroid carcinoma (MTC) by the presence of at least one of the following features: mitotic index ≥5/2 mm², Ki-67 proliferation index ≥5%, or tumor necrosis. Cases lacking all three features are classified as low-grade. This study aimed to validate the prognostic role of the IMTCGS in patients with metastatic MTC. The prognostic significance of a high proliferative index (Ki-67 index ≥20%) was also investigated. Methods: We conducted a monocentric retrospective study of 99 metastatic MTC patients treated at Gustave Roussy between 2000 and 2024, in whom the IMTCGS was assessed on the primary tumor. Results: IMTCGS high-grade tumors were found in 67 patients (67.7%), who were older (p = 0.009) and had larger primary tumors (p < 0.001) compared with 32 patients with low-grade tumors. Postoperative calcitonin levels, number of metastatic sites/patient, prevalence of synchronous metastases, and RET-M918T mutation were similar between groups. Median overall survival (OS) was shorter in patients with IMTCGS high-grade than low-grade (4.8 vs. 13.9 years; p = 0.01), as was time to systemic treatment initiation (TTI) (1.0 vs. 4.8 years; p < 0.001). However, among the 75 patients who received systemic therapy, OS from treatment initiation was similar between the two groups (2.8 vs. 3.89 years; p = 0.865). RET-M918T mutation was not associated with worse OS. On multivariable analysis, IMTCGS high-grade and bone metastases were independently associated with both shorter OS and TTI (p < 0.05 for both). Patients with Ki-67 index ≥20% had worse OS (2.6 years) compared with those with Ki-67 index <5% (10.5 years; hazard ratio [HR] = 6.11; p < 0.001) and 5-19% (6.5 years; HR = 3.29; p = 0.001). Conclusions: The IMTCGS is a strong independent prognostic factor in patients with metastatic MTC. Patients with IMTCGS high-grade tumors and Ki-67 index ≥20% represent a high-risk subgroup with the poorest prognosis.