Comment on “Evaluating the necessity of prophylactic lateral neck dissection in medullary thyroid carcinoma based on preoperative calcitonin levels: a multicenter retrospective cohort study”

Dear Editor, Medullary thyroid carcinoma arises from the parafollicular C-cells. While it constitutes only about 1.6% of all thyroid malignancies, it accounts for approximately 13.4% of thyroid cancer-related mortality[1]. At diagnosis, cervical lymph node metastasis is present in up to 50.0% of MTC cases, representing a crucial prognostic factor. The 10-year survival drops dramatically to 21.0–46.0% in stage IV disease, compared to 98.0–100.0% in stage I patients[2]. Our group recently reviewed with interest the multicenter retrospective cohort study by Lee et al in the International Journal of Surgery[3]. The investigation focused on whether prophylactic lateral neck dissection improves long-term outcomes in MTC patients with preoperative calcitonin exceeding 200 pg/ml but without clinically detectable lateral neck metastasis. While providing valuable clinical insights, several methodological aspects merit deeper consideration. This correspondence was developed following the TITAN Guidelines 2025(2) for the declaration and use of artificial intelligence in scholarly publishing. No AI tools were employed in the conception, design, analysis, interpretation, or writing of this work[4]. First, the study reports biochemical cure rates of 95.2% in the prophylactic LND group versus 82.5% in the no-LND group (P = 0.074). It concludes that although prophylactic LND is associated with a higher biochemical cure rate, this does not translate into reduced recurrence rates or improved survival, suggesting routine prophylactic LND may be unnecessary. However, this represents a strongly trending yet statistically non-significant result. The final analysis included only 103 patients, and the low number of events resulted in limited statistical power, increasing the risk of a false-negative finding. Therefore, stating this conclusion without qualification seems premature. The authors should explicitly acknowledge that the difference did not reach statistical significance, potentially due to sample size limitations, and that larger studies are needed for confirmation. In rare disease research, clinical relevance can sometimes outweigh P-values. If this difference persists in larger cohorts, it might hold significant prognostic value. Employing Bayesian analysis or estimating effect sizes (e.g., Relative Risk, Number Needed to Treat) could strengthen the validity of their findings. Second, with merely seven structural recurrence events recorded, the application of a multivariable Cox regression model to assess multiple risk factors raises concerns about model stability and overfitting. The exceptionally wide confidence intervals for certain hazard ratios (e.g., tumor size ≥2 cm: HR = 4.47, 95% CI: 0.73–86.2) indicate substantial statistical uncertainty. Drawing definitive conclusions about independent risk factors from such unstable estimates requires caution. Third, the inclusion criterion of “no clinical evidence of lateral lymph node metastasis” lacked specification regarding minimum preoperative imaging standards. Over the four-decade study period (1980–2022), imaging technology evolved dramatically – from basic ultrasonography in earlier years to contemporary high-resolution CT and PET-CT. This temporal heterogeneity in diagnostic sensitivity likely introduced significant information bias, potentially misclassifying some patients with occult metastases as node-negative. Fourth, among the seven recorded deaths, only one was attributed to MTC itself. When estimating disease-specific survival using Kaplan–Meier methodology, non-disease deaths are typically censored. This approach may overestimate the actual disease-related mortality risk in the presence of competing events. A competing risk analysis would provide a more nuanced perspective on survival outcomes. Notwithstanding these considerations, we genuinely appreciate the authors’ contribution. This study adds meaningful real-world evidence to guide surgical decision-making in medullary thyroid carcinoma, particularly in this clinically challenging patient subgroup.