# Multifocality as a marker of aggressiveness in medullary thyroid carcinoma: a retrospective cohort analysis of lymph node metastasis and recurrence

## TL;DR

This study shows that multifocal medullary thyroid carcinoma is more aggressive, with higher risks of lymph node metastasis and recurrence, suggesting it should be considered in risk assessments.

## Contribution

The study demonstrates a dose–response relationship between tumor foci number and aggressiveness in multifocal medullary thyroid carcinoma.

## Key findings

- Multifocal tumors had higher preoperative calcitonin levels and more capsular invasion compared to unifocal tumors.
- Multifocality independently predicted lymph node metastasis and recurrence with a dose–response relationship based on lesion number.
- Bifocal tumors showed the highest lymph node metastasis risk, and multifocal cases had significantly worse progression-free survival.

## Abstract

The prognostic role of multifocality in medullary thyroid carcinoma (MTC) is controversial. This study evaluated multifocality’s association with aggressiveness, lymph node metastasis (LNM), and survival, focusing on multifocality-related parameters (such as number of tumor foci, tumor diameter).

We retrospectively analyzed 186 MTC cases (136 unifocal, 50 multifocal) with a median 59-month follow-up (95% CI: 52-66). Multivariate logistic analysis and Cox regression models assessed multifocality’s impact on LNM and recurrence, with detailed subgroup analyses. Diagnostic performance of tumor size parameters was evaluated using receiver operating characteristic (ROC) analysis, while survival outcomes were assessed via Kaplan–Meier method.

Multifocal tumors exhibited significantly more aggressive features, including: (1) higher preoperative calcitonin (1226.7 ± 751.9 vs 706.6 ± 704.2 ng/L, P < .001); (2) increased capsular invasion (68% vs 32%, odds ratio [OR] = 5.8, 95% CI: 2.32-14.53); and (3) more frequent intraglandular spread (54% vs 18%, OR = 6.05, 95% CI: 1.47-24.92). Multifocality independently predicted both LNM (OR = 3.35, 95% CI: 1.22-9.25, P = .019) and recurrence (hazard ratio [HR] = 6.59, 95% CI: 2.48-17.53, P < .001). ROC analysis identified optimal LNM cut-offs at 13.5 mm (largest focus) and 16.5 mm (total tumor diameter). Subgroup analyses revealed: (1) bifocal conferred highest LNM risk (OR = 8.51 vs unifocal, 95% CI: 1.74-41.69, P = .008); (2) recurrence risk showed dose–response relationship with lesion number (bifocal: HR = 4.89, 95% CI: 1.88-12.70, P = .001; ≥3 foci: HR = 5.86, 95% CI: 1.54-22.33, P = .01). Survival analysis demonstrated significantly worse progression-free survival in multifocal cases (P < .001), persisting beyond 2 years (P = .001), though overall survival difference was nonsignificant (P = .168).

Multifocal MTC exhibits aggressive behavior with high LNM and recurrence risks, driven by the number of tumor foci, demonstrating a dose–response relationship. These findings support incorporating multifocality into risk stratification for optimized management.