Comment on “Multicenter analysis of radioactive iodine therapy outcomes after total thyroidectomy for T1-T2 stage papillary thyroid carcinoma with cervical lymph node metastasis in China”

Dear Editor, We reviewed with interest the study by Wang et al[1], which reported no additional benefit of postoperative radioactive iodine (RAI) therapy on structural or biochemical incomplete response in T1–T2 papillary thyroid carcinoma with cervical lymph node metastasis. Their propensity score-matched analysis offers relevant real-world evidence, yet several aspects merit further consideration to support clinical interpretation. 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[2]. First, papillary thyroid carcinoma encompasses histologically distinct subtypes, from indolent encapsulated or follicular variants to aggressive forms such as tall-cell, columnar-cell, hobnail, and solid subtypes[3]. Even within the T1–T2 nodal-positive intermediate-risk category, these aggressive variants may differ from classical PTC in tumor behavior, metastatic propensity, RAI avidity, and recurrence risk. Combining all subtypes could mask a potential RAI benefit in certain high-risk subgroups or overstate its lack of efficacy in low-risk classical cases. Furthermore, the co-occurrence of BRAF V600E and TERT promoter mutations has been associated with reduced efficacy of radioactive iodine therapy in papillary thyroid carcinoma[4]. The present study did not include molecular profiling; therefore, the potential differential response to RAI across molecularly defined subgroups could not be evaluated. Second, the efficacy of RAI relies on adequate functional TSH stimulation to maximize iodine uptake in residual thyroid tissue and metastatic lesions. In clinical practice, TSH elevation is primarily achieved through either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) administration. Evidence suggests that these two approaches may yield differential outcomes in terms of RAI therapeutic effectiveness[5]. The present study did not document, report, or analyze the specific TSH stimulation protocol employed. This omission introduces a potential for non-differential misclassification of RAI treatment exposure. Furthermore, variations in stimulation protocols across different centers and over time may act as an unmeasured confounder or effect modifier, the impact of which remains unassessed in the current analysis. Third, while all participants received at least 60 months of surveillance, details on a standardized monitoring protocol were not provided. Inconsistent application of stimulated thyroglobulin testing, diagnostic whole-body scans, or operator-dependent ultrasonography could lead to surveillance bias, affecting recurrence detection and between-group comparability. Fourth, in the presented multivariable Cox models (Tables 4 and 5), parameters specific to RAI treatment – such as the number of courses, administered activity, and treatment intervals – were included together with the primary exposure variable “RAI administration.” For patients who did not receive RAI, these parameters are inherently undefined. Their concurrent inclusion may yield unstable statistical estimates and complicate clinical interpretation. An alternative analytical approach would be to first evaluate the effect of RAI administration in the full matched cohort, and subsequently, among only those who received RAI, examine the influence of treatment-specific variables. Despite these considerations, the authors provide a clinically relevant contribution by challenging routine RAI use in intermediate-risk papillary thyroid carcinoma with nodal metastasis. Their findings support a more individualized treatment approach and may help reduce overtreatment in this population.