Revised Perspective on the AJCC Staging System for Medullary Thyroid Cancer: A Study of Two Nationwide Cohorts

Background: The current AJCC TNM staging system for medullary thyroid cancer (MTC) is largely adapted from criteria for differentiated thyroid cancer, which may not fully capture MTC-specific prognostic factors. This study aimed to evaluate the prognostic significance of upper mediastinal lymph node metastasis (LNM) and propose corresponding modifications to the N category and staging system to improve their applicability for MTC. Methods: We conducted a population-based, retrospective study enrolling patients with MTC from 19 Chinese referral centers. Demographics and pathologic characteristics were collected, and patients were categorized into 4 LNM subgroups: no LNM, central cervical LNM, lateral cervical LNM, and upper mediastinal (level VII) LNM. We assessed their prognostic significance using Kaplan-Meier survival curves and Cox regression analysis. Recursive partitioning analysis was then applied to regroup patients with similar overall survival (OS). To validate our findings, we analyzed an independent cohort from the SEER database. Results: Our multicenter cohort included 827 patients with initially treated MTC, of whom 438 (53.0%) were female, with a median age of 50 years (IQR, 40–59). Upper mediastinal (level VII) LNM was present in 12.6% of patients and was significantly associated with worse OS, structural recurrence-free survival, and biochemical response compared with other LNM sites (all P <.05). Based on these findings, we proposed up-classifying level VII metastases from N1a to a new category, N1c, while keeping the T and M definitions unchanged. We then regrouped 4 TNM stages: stage I (T1–2N0–1aM0), stage II (T1–3N1bM0, T3N0–1aM0), stage III (T4N0–1bM0, T1–3N1cM0), and stage IV (T4N1cM0, T1–4N0–1cM1). Our modified staging system demonstrated superior prognostic discrimination and predictive power compared with the current AJCC TNM system, both in our multicenter cohort and the SEER validation cohort. Conclusions: For the first time, we identified the upper mediastinum as the most critical site for regional LNM in MTC. Our proposed adjustments to the N category and TNM staging system could provide better risk stratification for patients with MTC, potentially guiding improved clinical management and treatment strategies.