Clinical significance of level VII lymph node metastasis in medullary thyroid cancer

The American Joint Committee on Cancer Eighth Edition reclassified level VII lymph node metastasis from N1b to N1a in medullary thyroid cancer. However, the prognostic implications of this change remain debated.

Using 1,983 medullary thyroid cancer patients (Surveillance, Epidemiology, and End Results, 2004-2015), participants were categorized into N0, N1a (level VI), N1b (level I-V), and level VII groups. Disease-specific survival was evaluated using hazard ratios and 10-year disease-specific survival. We first evaluated the prognostic impact of level VII lymph node metastasis as a distinct category. We then compared the discriminative ability of the American Joint Committee on Cancer Eighth Edition with a modified N classification that reclassifies level VII into the N1b category, using the concordance index and proportion of variation explained. Sensitivity analyses were conducted using overall survival.

Level VII lymph node metastasis, 4.7% of medullary thyroid cancer patients, exhibited the most aggressive features: poor differentiation, size >40 mm, extrathyroidal extension, and distant metastasis. Level VII group conferred the poorest disease-specific survival (adjusted hazard ratio versus N0: 4.59; 95% confidence interval, 2.95-7.13), significantly worse than N1b (adjusted hazard ratio, 3.29; 95% confidence interval, 2.33-4.64) and N1a (adjusted hazard ratio, 2.46; 95% confidence interval, 1.63-3.71). Adjusted 10-year disease-specific survival was 72.7% (level VII) vs 78.5% (N1b). However, under the American Joint Committee on Cancer Eighth Edition, there was no significant difference in disease-specific survival between N1a and N1b (adjusted hazard ratio, 1.02; 95% confidence interval, 0.79-1.31), whereas the modified system achieved superior stratification: N0 (91.8%), N1a (82.8%), and N1b (77.4%) with enhanced discrimination (concordance index: 0.726 vs 0.715; proportion of variation explained, 0.104 vs 0.096) and improved stage III/IVA separation (adjusted hazard ratio, 1.75; 95% confidence interval, 1.23-2.50 versus American Joint Committee on Cancer adjusted hazard ratio, 1.26; 95% confidence interval, 0.92-1.73).

Level VII lymph node metastasis represents a distinct, highly aggressive medullary thyroid cancer subgroup with the worst prognosis. Reclassifying it into N1b improves prognostic discrimination and optimizes the American Joint Committee on Cancer system.