Abstract
KEY POINTS
Not all patients with N1b papillary thyroid carcinoma may derive clear benefit from total thyroidectomy or radioactive iodine therapy.
Recurrence risk is determined by the number and size of metastatic lymph nodes, higher lymph node ratio, and extranodal extension, rather than the extent of surgery or addition of radioactive iodine.
Personalized risk stratification and management are necessary to avoid overtreatment and maximize oncologic outcomes.
SUMMARY
Background
Papillary thyroid carcinoma (PTC) is risk-stratified by the 2025 American Thyroid Association (ATA) guidelines into low-, low-intermediate-, intermediate-high-, and high-risk groups based on clinicopathologic features associated with recurrence. 1 Intermediate-high-risk PTC includes clinically evident lateral neck metastases (cN1b), aggressive histological variants (tall-cell, columnar-cell), large (>3 cm) or multiple metastatic nodes, vascular invasion, or multiple combined adverse risk features. 1 These factors create a heterogeneous cohort of patients with differing tumor and nodal burdens.
Adjuvant radioactive iodine (RAI) therapy is recommended by the ATA guidelines in high-risk PTC with extrathyroidal extension, large nodal metastases (>3 cm), extranodal extension (ENE), or distant metastases, as it improves overall and disease-free survival. 1 RAI may be “considered” in intermediate-high-risk PTC, 1 and its utility remains controversial because long-term survival data are scarce, with often-conflicting results. Fujiwara et al. 2 evaluated oncologic outcomes of three differing treatment approaches with intermediate-high-risk cN1b PTC.
Methods
This multicenter retrospective cohort study included patients with cT1-3N1bM0 PTC who underwent thyroidectomy with lateral neck dissection between 2010 and 2022. The treating clinician conducted chart reviews of the clinical stage, imaging findings, and surgical records, rather than a specific protocol, to inform the decision to treat. Three management approaches were compared: (1) lobectomy with lateral neck dissection (n = 109), (2) total thyroidectomy with lateral neck dissection (n = 170), and (3) total thyroidectomy with lateral neck dissection followed by adjuvant RAI (n = 279). The primary outcomes were recurrence-free survival (RFS) and disease-specific survival (DSS) and were assessed using Kaplan–Meier analysis. Multivariable Cox proportional-hazards regression models were used to compare independent predictors of recurrence, including patient age, primary tumor size, metastatic lymph node size, and the presence of ENE.
Results
The cohort was composed of 593 patients (60.6% female; median age, 58 years) who had a median follow-up duration of 71.5 months. The median primary tumor size was 18 mm, and multifocal disease was present in 242 patients (43.4%), with predominant pathological classical subtype. Extrathyroidal extension was observed in 226 patients (40.5%) and ENE in 144 patients (24.3%). Recurrence was reported in 75 patients (12.6%). Patients who underwent total thyroidectomy followed by RAI demonstrated a trend toward worse RFS, though there was no significant difference in RFS (p = 0.19) or DSS (p = 0.40) among the three treatment groups.
Multivariable analysis identified older age (hazard ratio [HR], 1.024 per year; confidence interval [CI], 1.007-1.041; p = 0.006), larger primary tumor size (HR, 1.026 per mm CI, 1.012-1.041, p < 0.001), larger size of the largest metastatic lymph node (HR, 1.020 per mm CI, 1.003-1.036; p = 0.017), and ENE (HR, 1.741; CI, 1.046-2.898; p = 0.033) as being independently associated with shorter RFS. Conversely, the extent of thyroid surgery and use of RAI were not independent predictors of recurrence.
Conclusions
RAI may improve RFS in selected patients with high-risk features and extensive nodal disease; however, its routine use across all intermediate-high-risk cN1b PTC cases may constitute overtreatment. In those with lower nodal disease burden and favorable tumor characteristics, lobectomy or total thyroidectomy with therapeutic lateral neck dissection without RAI could be appropriate.
COMMENTARY
Contemporary management of PTC with cN1b disease is shifting from uniform treatment protocols toward personalized risk stratification. The study by Fujiwara et al. is influential in this transition, demonstrating no significant difference in RFS or DSS between patients treated with lobectomy, total thyroidectomy, or total thyroidectomy followed by adjuvant RAI (Figure). These findings challenge the assumption that all intermediate-risk cN1b patients require maximal intervention.
The addition of adjuvant radioactive iodine therapy (RAI) to total thyroidectomy with lateral neck dissection does not confer a survival benefit in intermediate-high-risk cN1b papillary thyroid cancer (PTC). Adapted from Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Crucially, recurrence risk was not dictated by nodal status alone. Instead, older age, larger primary tumors, increased size of metastatic nodes, and ENE independently predicted worse RFS. This aligns with the 2025 ATA guidelines, which recommend total thyroidectomy and “consideration” of adjuvant RAI (1.1-3.7 Gbq of 131-iodine) for intermediate-high-risk cases, particularly when aggressive histology, high nodal burden, or ENE are present.1,3 RAI remains indicated for large tumors (>4 cm), bulky metastatic nodes, vascular invasion, or incomplete resection. 1
The survival benefit of adjuvant RAI remains debated, largely owing to heterogeneity within intermediate-high-risk cohorts. Some studies report only a modest 1.3%-2% improvement in 10-year survival, 4 while others document recurrence rates of 1%-12% even after an initial “excellent response.” 5 A meta-analysis of intermediate-high-risk differentiated thyroid carcinoma shows recurrence rates as low as 2% with successful ablation, but up to 14% if ablation fails. 6 Conversely, studies treating differentiated thyroid carcinoma with total thyroidectomy alone report recurrence rates of 0-1.6%,7–9 though these typically represent lower-risk populations. These conflicting data underscore the importance of Fujiwara et al.’s finding of no significant difference between treatment groups, suggesting that RAI may not provide meaningful clinical benefit for some PTC cN1b patients.
For patients with low-volume nodal disease (<5 small nodes), no ENE, and complete resection, RAI after total thyroidectomy may constitute overtreatment. 3 Avoiding unnecessary total thyroidectomy reduces the risks of permanent hypoparathyroidism and recurrent laryngeal-nerve injury. 1 Omitting RAI avoids xerostomia, lacrimal duct stenosis, and the cumulative risk of radiation-induced secondary malignancies. 1 Quality of life declines after thyroid surgery and is worse following more extensive procedures, further supporting conservative approaches when appropriate. 10
Limitations include the study’s retrospective design, relatively short median follow-up, and selection bias, as patients receiving more intensive therapy likely had higher-risk disease despite multivariable adjustment. Favorable oncologic outcomes and lower recurrence rates observed in such cohorts may, in part, reflect management within high-volume endocrine surgical units, where experienced surgeons optimize initial disease clearance and tailor surgical techniques to individual risk. While this is recommended in the latest ATA guidelines, we acknowledge that this may not be feasible in all practice settings, and these findings should be interpreted and applied within the context of local resources and clinical expertise. 1
Ultimately, this study supports a tailored approach to intermediate-high-risk cN1b PTC, showing no survival advantage from adding RAI to total thyroidectomy.