BACKGROUND: Whether inherited in the context of multiple endocrine neoplasia 2B at germline level or acquired in a lifetime, all RET p.M918T (RET c.2753T>
C) mutations should activate the RET tyrosine kinase receptor alike, with similar degrees of medullary thyroid cancer (MTC) progression when disparities in disease onset and multifocal growth are accounted for. METHODS: This cross-sectional analysis of RET p.M918T-driven progression of hereditary MTC (33 patients) vs. sporadic MTC (36 patients) sought to explore this hypothesis. RESULTS: Patients with hereditary disease were significantly younger at thyroidectomy (medians of 10 vs. 57 yrs.) and featured significantly more often multifocal growth (69 vs. 14 %) with more thyroid tumor foci (medians of 2 foci vs. 1 focus) than patients with sporadic disease. Although the former had 3.6-fold smaller primary thyroid tumor diameters (medians of 5 vs. 18 mm) and twice as many neck nodes dissected (medians of 66.5 vs. 32 nodes) than the latter, extrathyroid tumor extension (42 vs. 36 %), node metastasis (64 vs. 77 %), distant metastasis (33 vs. 17 %), and biochemical cure rates (45 vs. 35 %) were fairly comparable, as was the number of dissected node metastases (medians of 7 vs. 8 involved nodes). Sensitivity analyses, with breakdown of patients by tumor multifocality and nodal status, corroborated these findings. CONCLUSION: RET p.M918T-driven progression of MTC is similar in hereditary and sporadic disease, barring earlier development and more frequent multifocal growth of hereditary MTC. This makes a compelling case for referral of patients with RET p.M918T-driven MTCs to specialist surgical centers.