Clinical Outcomes of the Germline RET M918T Pathogenic Variant in Hereditary Medullary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

Background and Objectives: Hereditary medullary thyroid carcinoma (hMTC) exhibits substantial clinical heterogeneity according to the underlying germline RET pathogenic variant. Although the germline RET M918T pathogenic variant is associated with aggressive disease, its associations with clinical outcomes have not been comprehensively quantified. We aimed to evaluate the associations between the M918T variant and adverse clinical outcomes in patients with hMTC. Materials and Methods: PubMed, Scopus, and Embase were searched from database inception to May 2026 in accordance with PRISMA 2020. Eligible studies compared patients with the germline RET M918T pathogenic variant with those harboring other germline RET pathogenic variants. Random-effects models were used to pool odds ratios (ORs) and 95% confidence intervals (CIs) for lymph node metastasis, metastatic disease, advanced-stage disease, and mortality. Risk of bias was assessed using the Quality in Prognosis Studies tool. The protocol was prospectively registered in PROSPERO (CRD420261377120). Results: Nine cohort studies involving 1485 participants were included, with outcome-specific sample sizes varying. Three studies had a low overall risk of bias and six had a moderate risk. The M918T variant was associated with increased odds of lymph node metastasis (OR 7.86, 95% CI 2.58-23.94), metastatic disease (OR 6.50, 95% CI 3.72-11.37), advanced-stage disease (OR 4.88, 95% CI 2.30-10.33), and mortality (OR 7.32, 95% CI 3.14-17.10). The association was stronger for disease-specific than all-cause mortality, although the subgroup difference was not statistically significant. Conclusions: The germline RET M918T pathogenic variant was associated with adverse clinical outcomes compared with other germline RET pathogenic variants. However, heterogeneous comparator groups and residual confounding preclude causal interpretation.