Prognostic Thresholds for Lymph Node Metastasis in Medullary Thyroid Cancer: A Restricted Cubic Splines Analysis

Area of Science:

• Oncology
• Surgical Oncology
• Cancer Prognostics

Background:

• Current medullary thyroid cancer (MTC) staging lacks quantitative lymph node (LN) assessment.
• American Thyroid Association guidelines recommend incorporating quantitative LN metastasis evaluation.
• Existing studies suggest LN ratio (LNR) and positive LN count as prognostic markers.

Purpose of the Study:

• To identify prognostically significant LN thresholds for MTC.
• To estimate the association of these thresholds with MTC-specific mortality.
• To validate identified thresholds using institutional data.

Main Methods:

• Retrospective cohort analysis of MTC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004-20).
• Cox models with restricted cubic splines to assess LNR and positive LN count association with MTC mortality.
• Markov Chain Monte Carlo and bootstrapping for threshold estimation; multivariable models for association analysis.
• Validation in a single-institution testing cohort (1996-2025).

Main Results:

• Identified thresholds: 7.8 positive LNs and 13.8% LNR (nonlinearity p < 0.001).
• ≥8 positive LNs associated with increased MTC mortality hazard (HR 1.54, p=0.014).
• ≥14% LNR associated with significantly higher mortality hazard (HR 3.308, p < 0.001).
• Both thresholds significantly impacted recurrence-free survival in the testing cohort (log-rank p < 0.001 for both).

Conclusions:

• Robust LN thresholds associated with MTC-specific mortality were identified using population-level data.
• A LNR threshold of ≥14% demonstrated a greater increase in MTC mortality hazard compared to ≥8 positive LNs.
• Quantitative LN assessment, particularly LNR, offers significant prognostic value in MTC staging.