International Initiative on a Refined Staging System for Medullary Thyroid Cancer: A Multinational Multicenter Study

PURPOSE To refine the suboptimal prognostic discrimination of the American Joint Committee on Cancer (AJCC) 8th edition TNM (TNM-8) staging system for medullary thyroid carcinoma (MTC). METHODS This retrospective study enrolled patients with MTC from 43 centers across 15 countries under the framework of the International Medullary Thyroid Cancer Staging Consortium (IMTCSC). Pooled data were analyzed with disease-specific survival as the primary end point. With M1 disease fixed in stage IVC, we redefined the schema for stages I to IVB in M0 patients. Using exhaustive enumeration, all possible TN combinations were fitted into multivariable Cox models, with the lowest Akaike information criterion (AIC) defining the proposed system. Prognostic discrimination was assessed using adjusted hazard ratios (aHRs) and the concordance index (C-index). RESULTS The IMTCSC cohort included 2,573 patients with MTC (female-to-male ratio: 1.25; median age 52 years [IQR, 41-62]; median follow-up 76.3 months [IQR, 37.3-121.0]). Level VII metastasis correlated with poorer survival, supporting its upgrade to N1c. Exhaustive search of 116,284 admissible stage-grouping schemas identified the optimal model (lowest AIC) defining stages I to IVB: I (T1N0-N1a/T2N0), II (T1N1b/T2N1a/T3N0), III (T1N1c/T2N1b/T3N1a/T4aN0-N1a), IVA (T2N1c/T3N1b-N1c/T4aN1b), and IVB (T4aN1c/T4b any N). Compared with AJCC TNM-8 (stage I as reference; stage II aHR, 0.84, P = .652; stage III aHR, 1.48, P = .172; stage IV aHR, 7.95, P < .001), the proposed system showed a clearer monotonic increase in disease-specific death risk (stage II aHR 2.22; stage III aHR, 4.81; stage IV aHR 15.75; all P ≤ .001) and a higher C-index (0.892 v 0.856, P < .001), which was also evaluated in the SEER cohort (N = 1,909). CONCLUSION The proposed MTC staging system confers an improved schema for prognostic stratification compared with AJCC TNM-8.