Therapy with radioactive iodine (I-131) following a total thyroidectomy has been a gold standard in the treatment of differentiated thyroid cancer (DTC) for over 80 years. Over the years, its role has shifted from routine use to a more selective, risk-adapted approach, informed by tumor biology, patient risk stratification and evolving clinical guidelines. This review examines the changing landscape of I-131 therapy, tracing its historical foundations, current indications, and future directions shaped by molecular medicine. We discuss the transition from a standardized, one-size-fits-all treatment approach to an individualized, dynamic stratification model that allows for ongoing risk reassessment and tailored treatment strategies. Key updates in clinical practice, such as the 2015 ATA Guidelines, the 2022 ETA Consensus Statement, and joint SNMMI and EANM nuclear medicine recommendations, are critically examined. We also address ongoing controversies in the management of low- and intermediate-risk patients, including the roles of I-131 whole-body scanning, activity selection, and overall treatment approach. Molecular theranostics is ushering in a new era in DTC management, enabling improved patient selection and more precise treatment. Advances in molecular profiling, imaging, and targeted therapies support a personalized treatment approach that aims to optimize therapeutic decisions while minimizing side effects and enhancing long-term safety.

To date, the survival benefits of multiple radioactive iodine therapies (RAIT) in RAI-avid pulmonary micrometastatic differentiated thyroid cancer (DTC) remain debatable. This study aimed to compare the progression-free survival (PFS) benefits between those received only once RAIT (o-RAIT) and multiple RAITs (m-RAIT) in such patients.

Patients with RAI-avid pulmonary micrometastatic DTC were included and divided into either o-RAIT or m-RAIT group according to the number of RAIT cycles. The response to first RAIT in all patients and last RAIT in m-RAIT were evaluated and classified as partial response (PR), stable disease (SD), and progressive disease (PD). PFS was defined as the time from first RAIT to PD. Logistic regression analysis and Kaplan-Meier survival curves were employed to identify risk factors and estimate PFS, with propensity score matching (PSM) to reduce confounders.

A total of 117 patients with RAI-avid pulmonary micrometastatic DTC were retrospectively included, with 38 (32.5%) from o-RAIT and 79 (67.5%) from m-RAIT. Patients from m-RAIT exhibited younger age at diagnosis, more local persistent disease before RAIT, and more metachronous metastasis compared with o-RAIT group (all P < 0.05). In the comparison of RAIT response, there was no difference in the first RAIT response between the o-RAIT and m-RAIT, while the last RAIT response of m-RAIT is worse not only than o-RAIT (P = 0.005), but also than their own first RAIT response (P = 0.0003). Multivariate analysis revealed age at diagnosis (over 45 years old) (P = 0.006) and local persistent disease before RAIT (P = 0.001) were independent risk factors for PD after RAIT, while number of RAIT cycles was not. To minimize potential confounders, the risk factors for PD and follow-up time were matched by PSM, after which, no significant difference in PFS was observed between the matched o-RAIT and m-RAIT (5-year PFS rate: 83.6% vs. 81.6%, P = 0.808).

In patients with RAI-avid pulmonary micrometastatic DTC, o-RAIT exhibited non-inferior PFS benefits compared with m-RAIT, suggesting the "less is more" management strategy of RAIT towards such patients.

Although papillary thyroid carcinomas (PTC) are usually indolent in nature and clinically controllable, two-thirds of metastatic diseases become radioactive iodine-refractory (RAI-R). This study aimed to determine the role of pathological features, BRAFV600E, TERT promoter (TERT-p), and their combinations on Vietnamese patients with RAI-R recurrent PTC.

This cross-sectional study included 174 cases of locoregional recurrent PTC, including 135 and 39 RAI-R and RAI-avid (RAI-A) cases, respectively. Logistic regression analyses were used to evaluate the associations between pathological features, mutations, and RAI-R with tissues from recurrent lesions.

Loss of polarity/loss of cell cohesiveness (LOP/LCC) component was exclusively observed in recurrent cancers in the RAI-R group. RAI-R was associated with BRAFV600E mutation, TERT-p mutation, BRAFV600E/TERT-p single mutant (Smut), BRAFV600E/TERT-p double mutant (Dmut), tall cell component, and mitosis ≥ 2/2 mm2 in the unadjusted logistic regression analysis. Multivariable logistic regression analysis revealed that BRAFV600E mutation and Dmut were independent predictors of RAI-R. The presence of Dmut (odds ratio [OR] = 6.64) was more significantly associated with RAI-R compared with that of Smut (OR = 2.75). There was a marginal association between tall cell > 5%, mitosis count ≥ 2/2 mm2 and RAI-R. The combination of BRAFV600E/tall cell components was the strongest predictor of RAI-R.

RAI-R PTC cases were independently associated with BRAFV600E, Dmut. The association between Dmut and RAI-R PTC was stronger than that between Smut and RAI-R PTC. Future studies should focus on elucidating the role of mitotic count and LOP/LCC in RAI-R PTC.

Identifying risk factors in papillary thyroid carcinoma (PTC) that warrant more aggressive treatment is paramount. Importantly, the prevalence and clinical significance of BRAF p.V600E mutation in PTC remain debatable. This study aims to determine the association of BRAF p.V600E with demographic and clinicopathologic characteristics, including recurrence. Single institution data from consecutive PTC patients with BRAF p.V600E immunohistochemistry and/or molecular testing was collected between 2018 and 2022, including BRAF status, morphologic subtype, TN category, tumor size, nodal disease burden, tumor multifocality, extrathyroidal extension, treatment, follow-up time, loco-regional and distant recurrence, and mortality. This study included 301 patients, 30% male. The majority had BRAF p.V600E mutation (78.7%), and BRAF p.V600E was associated with morphologic subtype (p < 0.001), with 88% of classic subtype PTCs, 38% of PTCs with extensive follicular growth, and 100% of tall cell subtype expressing BRAF p.V600E. BRAF p.V600E was not associated with tumor size (p = 0.696) or nodal disease burden (p = 0.962). On multivariate analysis using Cox proportional hazard model, large volume nodal disease burden (HR 3.37, 95%CI 1.49-7.64, p = 0.004) and male gender (HR 2.29, 95%CI 1.23-4.26, p = 0.009) were significantly associated with recurrence. BRAF p.V600E (HR 0.71, 95% CI 0.31-1.65, p = 0.4) was not significantly associated with recurrence. In conclusion, presence of BRAF p.V600E in the absence of high risk histologic features does not have an impact on PTC recurrence, and thus, its utility in risk stratification is questionable in the setting of other clinicopathologic risk factors.

This review focus on the controversial benefits of thyroid hormone suppression therapy (THST) in differentiated thyroid carcinoma (DTC) and its associated risks, highlighting the need for individualized strategies to optimize therapeutic outcomes and guide future research.

A systematic literature search on TSH suppression in DTC over the past 10 years was conducted, prioritizing RCTs, large cohort studies, and non-inferiority trials, with additional references identified from retrieved articles.

Tailored postoperative TSH strategies should consider factors such as risk stratification, treatment modality, histologic subtype, and adverse effect risks. In this context, mechanistic studies offer potential insights that could inform personalized TSH management, though further validation is required. Clinical evidence on THST in DTC remains controversial, particularly for high-risk patients, where support for stringent TSH suppression (<0.1 mU/L) is limited. Data for intermediate-risk DTC are insufficient due to cohort heterogeneity, while TSH suppression in low-risk DTC is largely discouraged. The well-documented adverse effects of excessive THST, including cardiovascular complications and osteoporosis, further provide a strong rationale against its routine use. Additionally, achieving and maintaining target TSH levels in real-world practice remains challenging, underscoring the need for refined approaches.

Current evidence provides limited support for the TSH targets recommended by the 2015 ATA guidelines. Optimizing postoperative TSH management should account for individualized factors, including risk stratification, treatment modalities, histologic subtypes, and susceptibility to adverse effects. Future research should prioritize well-designed studies with clearly defined suppression levels and appropriate confounder adjustments, emphasizing personalized approaches to balance therapeutic benefits and adverse effects.

Surgery is the mainstay of therapy for thyroid cancer. A rising number of patients decline recommended surgical intervention. This study aimed to identify factors associated with the decision to decline surgery for well-differentiated thyroid cancer.

Patients with papillary or follicular thyroid cancer diagnosed between 2004 and 2017 were identified from the National Cancer Database. Patients were grouped based on patient-documented refusal of recommended surgery and patients who successfully completed surgery. Baseline characteristic comparison, univariable and multivariable logistic regression, and survival analyses were performed.

A total of 221,664 patients met inclusion criteria: 565 (0.3%) patients declined and 221,099 (99.7%) underwent recommended surgery. Patients who declined surgery were older, male, Black or Asian, and not privately insured. They more frequently had Charlson-Deyo scores ≥3, were diagnosed at academic centers, and presented with larger tumors and advanced clinical stage. Multivariable modeling demonstrated that older age, Black or Asian race, diagnosis at an academic center, no insurance or lack of private insurance, clinical N stage ≥1a, and clinical M stage >0 were associated with higher odds of declining surgery (P < .001). A mean survival of 10 years was found among patients who declined surgery versus 16 years among patients who underwent surgery (P < .0001).

Most patients diagnosed with well-differentiated thyroid cancer undergo physician-recommended surgical intervention. Declining surgery is associated with worse overall survival and is more likely in older, male, Black, or Asian patients with socioeconomic disadvantage. This study underscores the importance of understanding barriers to thyroid cancer surgery and opportunities to optimize outcomes and reduce disparities for these populations.

We describe an extremely rare papillary thyroid carcinoma metastasic to the paranasal sinuses and our surgical management. A 39-year-old patient with a history of papillary thyroid carcinoma diagnosed five years earlier who presented with symptoms of chronic sinusitis. Medical imaging demonstrated opacification of the frontal sinuses and the anterior ethmoid sinus without signs of angiogenesis, bone destruction or calcification. Biopsy under general anesthesia revealed presence of papillary thyroid carcinoma cells. Treatment consisted in sinus endoscopic surgery with Draf III procedure followed by 131I therapy. To our best knowledge, this is the first described case of papillary thyroid carcinoma metastatic to the frontal sinus and frontal recess.

Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. While PTC generally has a favorable prognosis, a subset dedifferentiates into aggressive forms. However, the molecular mechanisms responsible for aggressiveness and dedifferentiation are still poorly understood. We previously showed that HMGA2, a non-histone architectural transcription factor overexpressed in PTC, is involved in cell invasion. This study aimed to further analyze the role of HMGA2 in PTC tumorigenesis by exploring the expression of thyroid-specific and EMT-related genes following HMGA2 knockdown in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. HMGA2 silencing did not modulate the expression of EMT related genes but led to the increased expression of thyroid differentiation genes. Our data also suggest that the MAPK pathway induces thyroid cell dedifferentiation through HMGA2. On the other hand, forskolin, promoting thyroid differentiation, decreased HMGA2 expression. The negative correlations between HMGA2 and thyroid-specific gene expressions were confirmed in a transgenic mouse model of PTC and in human PTC. Finally, we showed that HMGA2 inhibition by suramin reduced cell invasion and induced differentiation expression in vitro, indicating a new therapeutic strategy for treating thyroid cancer.

Thyroid cancer remains a significant public health concern, with disparities in mortality rates observed across racial/ethnic groups. We quantified the extent to which socioeconomic, clinicopathologic, and treatment variations explain racial/ethnic disparities in thyroid cancer mortality.

We studied a cohort of 109,981 thyroid cancer patients diagnosed from 2006 to 2018 using the United States Surveillance, Epidemiology, and End Results database. We used multivariable logistic regression to assess the association of race/ethnicity with treatment status. We also performed mediation analyses to estimate how much the racial/ethnic differences in thyroid cancer-specific mortality were explained by variations in treatment and clinicopathologic and socioeconomic factors.

Non-hispanic (NH) Black patients were more likely to not receive the recommended surgical resection than NH White patients (adjusted odds ratio [aOR] 1.10, 95% confidence interval [CI] 1.02-1.20). NH Black patients had a significantly higher risk of all-cause mortality compared with NH White patients (adjusted hazards ratio [aHR] 1.19, 95% CI 1.07-1.31). Mediation analysis showed that socioeconomic status significantly explained 48.7% (indirect effect HR 1.07, 95% CI 1.01-1.14) of the difference in thyroid cancer-specific mortality between NH Black and NH White patients.

This study found that race/ethnicity was associated with treatment status and the risk of mortality among patients diagnosed with thyroid cancer. Moreover, clinicopathologic and socioeconomic factors were identified as the most crucial mediators that explained the excess mortality among minority groups. These findings provide insight into the pathways through which disparities in thyroid cancer mortality in NH Black and Hispanic thyroid patients could operate.

This study assessed CLDN16 as a potential replacement or improvement biomarker for papillary thyroid cancer (PTC), addressing the limitations associated with the prevalently used BRAF-V600E mutation.

Database analyses, tissue validation, RNA sequencing, and functional assays were conducted to evaluate CLDN16 as a PTC biomarker and its clinical application.

CLDN16 expression was examined in PTC and normal thyroid/para-tumor tissues and compared across various cancer types. We evaluated diagnostic accuracy, stability in primary and metastatic sites, and associations with aggressive features. Knockdown experiments were performed to investigate the impact on PTC cell behavior. Additionally, we developed a support vector machine model for diagnosing malignant and high-risk PTCs.

CLDN16 demonstrated high specificity for PTC, with positive detection rates (88.0% in The Cancer Genome Atlas [TCGA] and 88.3% in our center) significantly surpassing BRAF-V600E (47.5% in TCGA and 74.3% in our center). This resulted in superior diagnostic accuracy (ROC-CLDN16 = 0.922 vs ROC-BRAF-V600E = 0.742 in TCGA). CLDN16 exhibited stable expression across primary and metastatic sites and was associated with aggressive features, including extrathyroidal extension and lymph node metastasis. CLDN16 knockdown inhibited migration, invasion, and iodine uptake in PTC cells. Clinically, CLDN16 effectively identified malignancy in BRAF wild patients (94.2%), and combined with BRAF-V600E, achieved 96.9% accuracy. The incorporation of CLDN16 into PTC molecular typing facilitated precise high-risk identification (92.0% accuracy in the training set and 100% in the validation set).

CLDN16 presents a promising biomarker that could surpass BRAF-V600E, offering effective clinical utility and revolutionizing PTC molecular typing for precise high-risk identification.

Pediatric papillary thyroid carcinoma (PTC) is usually treated with total thyroidectomy followed by radioactive iodine (RAI). Recently, RAI has been used more selectively based on surgical pathology and postoperative dynamic risk stratification (DRS).

To describe patients with pediatric PTC not initially treated with RAI and their disease outcomes.

This was an ambispective study at a tertiary cancer center of patients < 19 years diagnosed from January 1, 1990, to December 31, 2021, with stage 1 PTC who intentionally were not treated with RAI within a year of diagnosis. We assessed clinical characteristics, management, and disease outcomes using DRS.

Of 490 PTC patients, we identified 93 eligible patients (median age at diagnosis 16 years; 87% female), including 46 (49%) with cervical lymph node metastases. Initial management included total thyroidectomy ± neck dissection (n = 69, 75%), lobectomy ± neck dissection (n = 20, 21%), or a Sistrunk procedure for ectopic PTC (n = 4, 4%). After a median follow-up of 5.5 years (range 1-26), most patients (85/93; 91%) remained disease-free with no further therapy. Persistent (n = 5) or recurrent (n = 3) disease was found in 9% of the entire cohort. Four patients ultimately received RAI, of which only 1 clearly benefitted, and additional surgery was performed or planned in 4 patients, 2 of whom had an excellent response at last follow-up.

Selected pediatric PTC patients, even those with lymph node metastases, may not require therapeutic 131I and can avoid the unnecessary risks of RAI while still benefitting from the excellent long-term outcomes that are well described for this disease.

The primary treatment for locoregional recurrent/persistent differentiated thyroid cancer (DTC) is repeated lymph node dissection; however, there are limited reports on the safety and long-term efficacy of multiple operations.

Patients who underwent a cervical lymph node dissection between 1998 and 2022 were included in this study. Demographics, initial thyroid surgery, subsequent lymph node dissections, follow up information, and response to therapy were acquired.

After one, two, three and four re-operations, 112/314 (35.7 ​%), 16/79 (20.3 ​%), 3/25 (12 ​%), and 0/3 (0 ​%) patients (p ​< ​0.001) had an excellent response, respectively, resulting in a cumulative rate of 41.7 ​% (131/314). The risk for permanent hypoparathyroidism (2.9 ​%) or recurrent laryngeal nerve injury (2.2 ​%) was 5.1 ​% (14/272). This was higher in patients undergoing re-operative central neck dissection (CNDx) (8.7 ​%, 10/114) versus those who did not undergo a previous CNDx (2.5 ​%, 4/158, p ​< ​0.02).

Surgery remains the primary treatment for recurrent/persistent DTC, however, the likelihood of an excellent response decreases with additional operations. The risk of permanent complications is low but is more likely to occur during redo CNDx.

When the histological examination indicates papillary thyroid carcinoma (PTC), there is no unanimity on the need to proceed with completion thyroidectomy (CT). This study aims to assess the histologic parameters that influenced the decision to perform CT.

This study included PTC patients who underwent thyroid lobectomy between 2019 and 2022. Group A included patients who underwent thyroid lobectomy without further treatments, whereas Group B included those who underwent CT based on histological findings. Differences in terms of histologic parameters were analyzed.

Group A included 291 patients (68.3 ​%), whereas Group B 135 patients (31.7 ​%). Multivariate analysis identified associations between CT and tumor size (p ​< ​0.001), aggressive variant (p ​= ​0.009), and vascular invasion (p ​< ​0.001). ROC curve analysis established a tumor size cut-off of 21 ​mm for CT. At ROC curve analysis, the cut-off number of aggressive factors required for CT was 2.

A thorough comprehensive assessment encompassing all pathological characteristics might be necessary in case of PTC with aggressive histologic features after thyroid lobectomy.

Radiofrequency ablation (RFA) is a minimally invasive treatment modality used as an alternative to surgery in patients with benign thyroid nodules, recurrent thyroid cancers (RTCs), and primary thyroid microcarcinomas. The Korean Society of Thyroid Radiology (KSThR) initially developed recommendations for the optimal use of RFA for thyroid tumors in 2009 and revised them in 2012 and 2017. As new meaningful evidence has accumulated since 2017 and in response to a growing global interest in the use of RFA for treating malignant thyroid lesions, the task force committee members of the KSThR decided to update the guidelines on the use of RFA for the management of RTCs based on a comprehensive analysis of current literature and expert consensus.

To assess the prevalence of psychological distress (PD) among thyroid cancer patients (TCPs) and identify clinical, demographic, and socioeconomic factors associated with PD.

Retrospective population-based cohort study.

2016 to 2018 National Health Interview Survey.

Adults with cancer were included. The primary outcome measure was moderate-to-severe psychological distress (MSPD), defined as a respondent score ≥5 on the validated K6 Psychological Distress Scale. χ2 tests were used to assess differences in MSPD by cancer type. Weighted multivariable logistic regression was used to elucidate factors associated with MSPD among TCPs.

The majority of TCPs (n = 684,674) were white (75.4%), female (78.5%), and on average 55.65 years old (SD = 13.2). 28.4% reported MSPD. On weighted analysis, TCPs were more likely to have MSPD than prostate (14.9%, P < .001), bladder (16.4%, P = .011), and nonmelanoma skin cancer (16.3%, P < .001) patients but less likely than pancreatic cancer (30.0%, P = .030) patients. TCPs who were older when surveyed (odds ratio [OR], 0.93; 95% confidence interval [CI, 0.88-0.98), previously drank alcohol (OR, 0.23; 95% CI, 0.06-0.91), and saw a general physician (GP) in the past year (OR, 0.14; 95% CI, 0.03-0.56) were less likely to have MSPD. Female sex (OR, 8.12; 95% CI, 1.61-40.89), increased number of medical comorbidities (OR, 1.46; 95% CI, 1.00-2.14), and functional limitations (OR, 4.55; 95% CI, 1.33-15.74) were associated with increased likelihood of MSPD.

Nearly 30% of TCPs have MSPD, especially younger patients who do not regularly see GPs. Future work to identify the most at-risk patients is needed to improve prevention and develop meaningful psychosocial interventions.

ESTIMABL2, a multicentre randomised phase 3 trial in patients with low-risk differentiated thyroid cancer (ie, pT1am or pT1b, N0 [no evidence of regional nodal involvement] or Nx [involvement of regional lymph nodes that cannot be assessed in the absence of neck dissection]), showed the non-inferiority of a follow-up strategy without radioactive iodine (131I) administration compared with a postoperative 131I administration at 3 years post-randomisation. Here, we report a pre-specified analysis after 5 years of follow-up.

Patients treated with total thyroidectomy with or without prophylactic neck lymph node dissection, without postoperative suspicious findings on neck ultrasonography, were randomly assigned to the no-radioiodine group or to the radioiodine group (1·1 GBq-30 mCi after recombinant human thyrotropin-stimulating hormone). Follow-up consisted of annual thyroglobulin and thyroglobulin antibody determinations during levothyroxine treatment and neck ultrasonography in odd-numbered years. An event was defined as abnormal foci of 131I uptake on the post-treatment whole-body-scan requiring subsequent treatment, abnormal neck ultrasonography, elevated thyroglobulin levels, increasing titres or appearance of thyroglobulin antibody (using the same laboratory assay), or a combination of these definitions. Non-inferiority of the proportion of patients without an event in one group compared with the other at 5 years after randomisation was shown if this proportion and its CI did not differ by more than -5%. This study was registered on ClinicalTrials.gov (NCT01837745) and is completed.

Of the 776 patients (n=642 [82·7%] female and n=134 [17·3%] male, median age 52·9 years [IQR 42·6-63·1]) enrolled, 698 were evaluable at 5 years. The proportions of patients without events were 93·2% in the no-radioiodine group and 94·8% in the radioiodine group, for a difference of -1·6% (90% CI -4·5 to 1·4). Events consisted of structural or functional abnormalities (n=11) and biological abnormalities (n=31).

The non-inferiority of a follow-up strategy compared with postoperative 131I administration in low risk differentiated thyroid cancer was confirmed at 5 years. There is no loss of opportunity in following these patients without postoperative ablation.

Programme de Recherche Hospitalier Clinique.

A unique case of papillary carcinoma of the thyroid with an extensive tumor thrombus extending into the right ventricle is presented. The patient was a known case of solid variant of papillary carcinoma of thyroid, post three cycles of radioiodine therapy, had reported for a diagnostic 131 I-NaI scintigraphy as a part of the workup for planning the next 131 I therapy. Clinically, the patient was asymptomatic. 131 I-NaI scintigraphy showed an arcuate pattern concentration of tracer in the upper mediastinum, which descended up to the lower mediastinum. A 131 I-NaI single photon emission computed tomography/computed tomography (SPECT/CT) showed a tracer avid tumor with an extensive tumor thrombus extending from the left brachiocephalic vein to the right ventricle. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) and magnetic resonance imaging (MRI) demonstrated similar findings. The patient was decided to be managed with tyrosine kinase inhibitors as surgical intervention was not deemed possible due to the involvement of major vessels and the high risk of bleeding.

In 2015, the ATA updated the guidelines to advocate for a lobectomy for tumors <1.0 ​cm and total thyroidectomy for tumors >4.0 ​cm. Treatment for tumors of intermediate size 1.0-4.0 ​cm is dependent on high-risk characteristics. There is limited research comparing the impact of the updated ATA guidelines on clinical practice on intermediate-sized tumors. In this study, the impact of the 2015 ATA guidelines on the surgical treatment of intermediated-sized FTC will be evaluated using the Surveillance, Epidemiology, and End Results (SEER) database. A total of 9983 patients were included; 7769 patients (74.1 ​%) were diagnosed pre-ATA guidelines and 2709 patients (25.9 ​%) post-ATA guidelines. The mean rate of lobectomy for intermediate-sized tumors was 22.1 ​% which increased to 33.4 ​% post-ATA updates. The results of the logistic regression showed the rate of lobectomy increased significantly in the post-ATA changes period (p ​< ​0.001). Future research could benefit from evaluating how these trends impact patient outcome measures.

Background: The current dogma is a life-long follow-up for patients treated for follicular-derived differentiated thyroid cancers (DTC). Our primary objective was to determine the time to recurrence in a series of DTC patients with an excellent response to therapy 6 months after total thyroidectomy and radioiodine therapy. The secondary objectives were to determine the time to suspicion of recurrence and to identify factors associated with recurrence. Methods: This retrospective cohort study included patients treated for DTC between 2008 and 2012 and in remission 6 months after total thyroidectomy and radioiodine treatment. The criteria for remission were negative imaging and suppressed thyroglobulin (Tg) <0.2 ng/mL or rh-TSH-(recombinant human TSH) stimulated Tg <1 ng/mL according to the 2015 ATA (American Thyroid Association) guidelines. Recurrence was defined by cytologically and/or histologically proven cervical lymph node metastasis or the administration of a second radioiodine treatment. Results: Among 721 patients treated for DTC, 158 were excluded because of persistent disease at 6 months, 71 because of missing follow-up data, and 492 were included. The mean and median follow-up time were 7.0 and 7.9 years (interquartile range IQR [2.1-11.3]). Recurrence occurred for 7 patients (1.4%), 1 initially classified as high recurrence risk, 3 as intermediate, and 3 as low risk according to the 2015 ATA guidelines. All relapses occurred within 10 years after initial management (4 within the first 5 years). For patients with recurrence, rise in Tg and/or suspicious lymph nodes were detected in six out of seven cases in the first 8 years and for the last case 10 years after initial surgery. Conclusion: Low and intermediate recurrence risk DTC patients with excellent response 6 months after total thyroidectomy and radioiodine and in remission 10 years later have an extremely low recurrence risk. Follow-up might be undertaken by primary care providers from this time point. These discharge recommendations should be confirmed by further prospective studies.

The rapid evolution of ultrasound (US) technology has dramatically changed the medical field. Ideally suited for evaluation of anatomic disorders of the thyroid, coupled with its ease of use at the bedside, US has become an essential tool for endocrinologists over the last 50 years. This noninvasive technology provides a sensitive and specific instrument for malignancy risk prediction of thyroid nodules, surveillance for recurrent thyroid cancer, and diagnosis of autoimmune thyroid disorders. While US has proven invaluable for such diagnostic purposes, its extensive use also has resulted in important negative consequences. This review will discuss the evolution of US equipment for the evaluation of thyroid disorders, its use in interventional procedures, and the unintended outcomes from the widespread adoption of this technology. Finally, this article will explore the potential future applications for US technology and its related advancements.

We introduced selpercatinib prior to radioactive iodine therapy prior to radioactive iodine therapy (RAI) for pediatric papillary thyroid cancer (PTC) to enhance the tumorical effects of RAI.

PTC has an excellent prognosis but is commonly associated with local and distant metastases. Successful complete response to the current standard of care, thyroidectomy with lymph node resection and RAI, is achieved in only a small minority of cases with metastases. The direct effect of tyrosine kinase inhibitors (TKIs) on tumor regression has been confirmed in several randomized controlled studies, while the increased RAI uptake has been reported in small case series, but typically TKIs are currently reserved third-line. Selpercatinib is a TKI that specifically has a durable effect in RET-fusion positive malignancies. We describe a 10-year-old Hispanic girl with metastatic PTC treated with total thyroidectomy and extensive lymph node resection. Evaluation for relevant genetic drivers of the malignancy revealed a strong overexpression of the RET tyrosine kinase domain indicative of a RET gene fusion. Selpercatinib 120 mg twice daily given orally was initiated prior to the initial dose of RAI to achieve further tumor regression by a direct cytostatic effect and then secondarily enhancement of RAI uptake. Minimal side effects occurred, specifically intermittent mild skin rashes that resolved. Resolution of distal lung metastases was noted on CT imaging. RAI was then administered 9 months afterward, with ultimately achievement of a low thyroglobulin level 1.0 ng/mL 11 months after RAI.

In conclusion, selpercatinib given prior to the initial dose of adjunctive RAI for RET-fusion positive PTC is a well-tolerated intervention that further reduces tumor burden and potentially enhances the tumorcidal effects of RAI.

Managing locally advanced, or metastatic radioactive iodine-refractory differentiated thyroid cancers (RAIR-DTC) poses substantial challenges, with few available treatment options. The aim of this study was to evaluate clinical outcomes of patients receiving sorafenib as first line treatment. In addition, prognostic markers affecting progression-free survival (PFS) were identified. This retrospective, 6 centers study included 62 patients with locally advanced or RAIR-DTC treated 2008-2023. The median PFS was 16.5 months. The presence of liver metastases was strongly associated with a lower PFS (3.1 months (p < 0.001)). The use of sorafenib as initial treatment resulted longer PFS compared to chemotherapy, with a median of 25.5 vs 4.7 months respectively (p = 0.01). Increased neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were associated with worse outcomes (p = 0.01; p = 0.009, respectively). In conclusion, sorafenib has demonstrated significant PFS benefits when used as first-line treatment. It has been shown that the presence of liver metastases and higher levels of NLR and PLR are associated with a more unfavorable prognosis.

[18F]FDG PET/CT has been widely used as a diagnostic tool in detection and localization of recurrent non-avid radioiodine lesions in post-operative differentiated thyroid cancer (DTC) patients with elevated serum thyroglobulin but negative radioiodine whole-body scan (TENIS) syndrome. The aim of our study was to evaluate the role of [18F]FDG PET/CT in prediction on outcomes of these DTC patients.

Post-operative DTC patients with TENIS syndrome were collected in the department of nuclear medicine, Hospital 108 from 2019 to 2023. Patients underwent [18F]FDG PET/CT with standard protocol following EANM guideline for tumor imaging version 2.0. The qualitative [18F]FDG PET/CT imaging characteristics were classified into three categories: (i) negative [18F]FDG PET/CT, (ii) minimal [18F]FDG PET/CT volume of lesions, (iii) extensive [18F]FDG PET/CT volume of lesions. Progression-free survival (PFS) and overall survival (OS) were the end point of the study. The prognosis of qualitative [18F]FDG PET/CT in predicting PFS and OS was illustrated by Kaplan-Meier survival analysis. The independent factors predicting PFS and OS were determined by univariate and multivariate analysis using logistic regression.

There were 164 consecutive patients, 51.2% female and 48.8% female. The most common histopathological type was papillary accounting for 91.5%. The median time of follow-up was 33.3 months, (range 6.57 - 82.5). There was 70 (36.6%) progressions and 12 (7.35%) deaths. Negative [18F]FDG PET/CT uptake patients had median PFS with median 57.1 months which was higher than that of minimal category (46.2 months), and extensive category (37.6 months) (p < 0,001). 1-year OS and 5-year OS in extensive PET/CT category was 97.8% and 86.2% respectively which were significantly lower than that of negative and minimal categories (p = 0.053). In multivariate analysis, age at the time of diagnosis, pulmonary, bone metastases and extensive [18F]FDG PET/CT volume of lesions were the independent factor predicting PFS. Bone metastasis was only the factor could predict OS in multivariate analysis.

The minimal and negative [18F]FDG PET/CT categories had better prognosis than extensive category in PFS and OS. Extensive [18F]FDG PET/CT category was an independent factor for predicting PFS. Bone metastasis was only the independent factor that could predict both PFS and OS.

Differentiated thyroid cancer (DTC), comprising papillary and follicular thyroid carcinoma, is the most common thyroid malignancy and typically has a favourable prognosis when detected early. Positron emission tomography/computed tomography (PET/CT) has emerged as a valuable imaging modality, integrating metabolic and anatomical data. Although PET/CT is not usually part of the initial diagnostic process due to DTC's indolent nature and low metabolic activity, it plays an essential role in selected clinical scenarios. This includes identifying recurrence in patients with elevated thyroglobulin (Tg) levels and negative radioactive iodine (RAI) scans, evaluating metastatic disease, and guiding treatment in advanced cases. As the use of PET/CT evolves in oncology, this review explores its application in regard to staging, detection of recurrence, and follow-up in terms of managing DTC while also evaluating potential challenges that may occur in the future. The review also considers emerging radiotracers and the theragnostic potential of PET/CT.

Optimal management of indeterminate nodules remains a controversial area of endocrine surgery. The purpose of this study is to compare observation, molecular testing, and immediate thyroid surgery for the management of Bethesda Classes III and IV nodules in patients age 50 to 90 years.

A decision analysis was performed from April 22, 2021, to September 29, 2023, using a Markov model constructed with TreeAgePro 2023. Model variables and ranges were selected based on literature review data.

TreeAgePro.

A 1-way sensitivity analysis was performed to evaluate the age threshold at which each management pathway, immediate thyroid surgery, additional molecular testing, or observation, would be favored. A Monte Carlo probabilistic sensitivity analysis was performed 5 times with model patients assigned starting ages of 50, 60, 70, 80, and 90 years to assess how age at diagnosis would impact model results. Outcomes were measured with quality-adjusted life-years and accounted for perioperative complications including permanent recurrent laryngeal nerve injury, permanent hypoparathyroidism, and medical complications.

In the study models, molecular testing was more beneficial than surgery and observation across all ages. The age threshold at which observation became more beneficial than surgery as the next best option was 83.1 years. However, the clinical difference between all 3 treatment algorithms was relatively minimal.

Decision-making regarding indeterminate thyroid nodules is complex. Given the clinically similar results across all 3 treatment algorithm, this study reinforces that treatment modalities should be individually tailored and based on shared physician-patient decision making.

Age is a significant predictor of papillary thyroid carcinoma (PTC). At present, the available evidence shows that age at diagnosis has an important impact on the recurrence of PTC. The objective of our investigation was to examine the relationship between age at diagnosis and recurrence in patients with PTC.

The medical records of patients with PTC who were treated between January 2010 and December 2018 at a single institute in a cancer referral center in China were retrospectively reviewed. The hazard ratios (HRs) and 95 % confidence intervals (CIs) for recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) were assessed using Cox proportional hazard models and restricted cubic splines (RCSs).

A total of 13758 patients were included in the study. With a median follow-up of 60 months (range 12-277), a total of 687 patients experienced recurrence, and 90 patients died. The 5-year RFS, LRRFS and DMFS rates were 95.0 % (95 % CI 94.6%-95.4 %), 95.8 % (95 % CI 95.4%-96.2 %) and 98.8 % (95 % CI 98.6%-99.0 %), respectively. The adjusted smooth RCS curves revealed a U-shaped association between age at diagnosis and RFS, LRRFS, and DMFS. After adjusting for potential confounding variables, both younger (≤30 years) and older (≥55 years) patients exhibited significantly lower RFS and LRRFS rates than did middle-aged patients (31-54 years). Older patients had significantly lower DMFS rates.

This study confirmed a U-shaped association between age at diagnosis and the risk of both locoregional recurrence and distant metastasis.

Differentiated thyroid cancers (DTCs) constitute the primary histological subtype within thyroid cancer. Due to DTCs' distinctive radioiodine (RAI) uptake mechanism, standard treatment involving surgery, with or without adjunctive therapy using RAI and levothyroxine inhibition, typically yields favorable prognoses for the majority of patients with DTCs. However, this favorable outcome does not extend to individuals with decreased RAI uptake, termed radioiodine-refractory thyroid cancers (RAI-RTCs). Recent research has revealed that the genetic mutations and gene rearrangements affecting sites such as RTKs, RAS, BRAF and TERTp lead to structural and functional abnormalities in encoded proteins. These abnormalities aberrantly activate signaling pathways like the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-hydroxykinase (PI3K) signaling pathways, resulting in thyroid cells dedifferentiation, sodium/iodide symporter (NIS) dysfunction, and consequent the RAI-refractory nature of DTCs. Targeted therapy tailored to mutations presents a promising avenue for the treatment of RAI-RTCs. Lenvatinib and sorafenib, multi-kinase inhibitors, represent the standard first-line systemic treatment options, while cabozantinib is the standard second-line treatment option, for this purpose. Furthermore, ongoing clinical trials are exploring selective kinase inhibitors, immune checkpoint inhibitors, and combination therapies. Notably, numerous clinical trials have demonstrated that selective kinase inhibitors like BRAF, MEK and mTOR inhibitors can restore RAI uptake in tumor cells. However, further validation through multicenter, large-sample, double-blinded randomized controlled trials are essential. Enhanced treatment strategies and innovative therapies are expected to benefit a broader spectrum of patients as these advancements progress.

The incidence of follicular-derived thyroid cancers has increased worldwide in recent decades, mainly papillary thyroid cancers at low recurrence risk. A process of de-escalation in the initial management and follow-up of these patients has therefore been implemented in parallel. This article provides the best practice recommendations made by the French learned societies (Société française d'endocrinologie, Société française de médecine nucléaire, Association française de chirurgie endocrine, Société française d'oto-rhino-laryngologie et de chirurgie de la face et du cou), european and international learned societies (European Society for Medical Oncology and the American Thyroid Association), in the management of follicular-derived thyroid cancer without distant metastases. The extent of thyroid surgery and lymph node dissection, strategies of radioiodine ablation, follow-up protocols and the management of excellent prognosis papillary cancers ≤ 10 mm will be addressed.

The widespread use of neck US and other imaging modalities has contributed to a phenomenon of increased detection of differentiated thyroid cancer (DTC). Most of these cancers remain indolent, without requiring surgical intervention. Nonetheless, a subset of patients who require surgical treatment experience subsequent disease recurrence. This most commonly occurs in the cervical lymph nodes and thyroid bed, followed by distant metastasis to the lungs and bones. Because imaging is an integral part of postoperative surveillance, radiologists play a central role in the detection of recurrent tumors and in guiding treatment in these patients. US is the primary imaging modality used for postoperative evaluation. Other modalities such as CT, MRI, radioactive iodine imaging, and PET/CT aid in the accurate diagnosis and characterization of recurrent disease. Therefore, radiologists must have a thorough understanding of the utility of these imaging techniques and the imaging characteristics of recurrent DTC when interpreting these multimodality studies. The interpretation of imaging findings should also be correlated with the clinical status of patients and their biochemical markers to minimize interpretative errors. The authors present a broad overview of the postoperative evaluation of DTC, including its initial primary management, staging, and prognostication; clinical risk stratification for recurrent disease; postoperative surveillance with imaging and evaluation of biochemical markers; and management of recurrent DTC. Published under a CC BY 4.0 license. Supplemental material is available for this article.

BRAF mutations are detected in 30%-80% of papillary thyroid cancer (PTC) cases. DaBRAFenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer.

This was a retrospective study to evaluate the efficacy of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received daBRAFenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of daBRAFenib and trametinib.

Between December 2019 and January 2022, 27 PTC patients including eight patients with poorly differentiated or anaplastic transformation, received daBRAFenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients.

DaBRAFenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low-intermediate subgroup and an intermediate-high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low-intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients' comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm.

Fatty acid-binding protein 4 (FABP4), a fatty acid transporter that coordinates lipid metabolism, is reported to exert a tumorigenic role in certain cancers. We investigated the effects of FABP4 in the carcinogenesis of thyroid cancer. Bioinformatics data about FABP4 in thyroid cancer were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Sixteen paired papillary thyroid cancer (PTC) tissues from Taipei Medical University (TMU) were gathered, and commercial thyroid cancer complementary (c)DNA and tissue arrays were purchased to measure FABP4 messenger (m)RNA and protein levels. By analyzing data from the GEO and TCGA, we showed that FABP4 mRNA was reduced in PTC and follicular thyroid carcinoma (FTC). In addition, a lower FABP4 mRNA level in PTC was associated with poor clinical parameters and outcomes in the TCGA database. Moreover, FABP4 transcripts and proteins were downregulated in PTC and FTC, and its mRNA expression was associated with PTC staging in clinical specimens. In the TCGA database and TMU cohort, FABP4 mRNA levels were associated with thyroglobulin (r = 0.511 and r = 0.656, respectively), thyroid peroxidase (r = 0.612 and r = 0.909, respectively), and sodium iodide symporter (r = 0.485 and r = 0.637, respectively) transcripts. In conclusion, FABP4 mRNA and protein levels were reduced in PTC and FTC, and may be used as a potential indicator for thyroid cancer evolution in clinical settings. Further, well-designed research to dissect the molecular mechanism of FABP4 in modulating thyroid carcinogenesis is needed.

This study aimed to evaluate the long-term prognosis of contralateral central neck dissection (CND) in papillary thyroid cancer (PTC) patients with ipsilateral lateral neck metastasis. We compared the actual recurrence rate according to the extent of CND-ipsilateral and contralateral sides.

A total of 708 PTC patients who underwent total thyroidectomy and concomitant ipsilateral or bilateral CND with ipsilateral lateral neck dissection between January 1997 and December 2022 at Samsung Medical Center were retrospectively analyzed.

The median follow-up time was 118 months. Locoregional recurrence was observed in 26 patients (7.9%) and 30 patients (7.9%) in the ipsilateral and bilateral CND groups, respectively. There were 6 contralateral recurrence cases (1.8%) in the ipsilateral CND group and 6 cases (1.6%) in the bilateral CND group. There was only 1 contralateral central neck recurrence in the ipsilateral CND group. The incidence of hypocalcemia (P = 0.007) was higher in the bilateral CND group compared to the ipsilateral CND group.

Surgeons may consider performing only unilateral CND-the side where tumor is for therapeutic purposes to reduce surgical complications.

The Bethesda system classifies all fine-needle aspiration specimens into 1 of 6 categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior.

This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology.

A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with a predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs 41 days, P < .001) (Fig. 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62% vs 46%, P < .03), a lower possibility of recurrence (8% vs 24%, P < .001), and a shorter interval to achieve remission (median 1218 vs 1682 days, P = .02) compared to Bethesda V/VI, which did not change after adjusting for age, sex, radioactive iodine therapy, mode of surgery, and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis.

Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

Studies have shown that m6A modification is related to the occurrence and development of papillary thyroid carcinoma (PTC). The disorder of succinic acid metabolism is associated with the occurrence and development of various tumors. However, there are few studies based on m6A and succinate metabolism-related genes (SMRGs) in PTC.

The TCGA-Thyroid carcinoma (THCA), GSE33630, 1159 SMRGs, and 23 m6A regulatory factors were collected from the online databases. Subsequently, the differentially expressed genes (DEGs) were selected between PTC (Tumor) and Normal samples. The overlapping genes among the DEGs, m6A, and SMRGs were applied to screen the biomarkers. Using the 3 machine-learning algorithms, the biomarkers were determined based on the overlapping genes. Next, the biomarkers were evaluated by the ROC curve and expression analysis in TCGA-THCA and GSE33630. Then, the overall survival (OS) differences were compared between the high-and low-expression biomarkers. Finally, immune infiltration analysis, molecular regulatory network, and drug prediction were performed based on the biomarkers.

In TCGA-THCA, there were 2800 DEGs between and Normal samples, and then 7 overlapping genes were obtained. Importantly, ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ were determined as biomarkers with excellent diagnostic efficiency (AUC > 0.7). In PTC samples, ADK and TNFRSF10B were high-expressed while CYP7B1, FGFR2, and CPQ were low-expressed. Especially, the high-expression groups of ADK had a better prognosis, while the high-expression groups of CYP7B1, FGFR2, and CPQ had a worse prognosis. Afterward, immune infiltration analysis found that 16 immune cells had infiltration differences between the Tumor and Normal samples. Finally, transcription factor SP1 could regulate CYP7B1 and TNFRSF10B. Moreover, Navitoclax was a potential drug for PTC patients.

Overall, we described 5 biomarkers associated with adverse prognosis of PTC, including ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ. All these biomarkers were involved in succinate metabolism and m6A modification of RNA. This set of biomarkers should be explored further for their diagnostic value in PTC. Investigations into the mechanistic role of alteration of succinate metabolism and m6A modification of RNA pathways in the pathophysiology of PTC are warranted.

Differentiated thyroid cancer (DTC) is the predominant type of thyroid cancer, with some patients experiencing relapse, distant metastases, or refractoriness, revealing limited treatment options. Chimeric antigen receptor (CAR)-modified Natural Killer (NK) cells are revolutionary therapeutic agents effective against various resistant cancers. Thyroid-stimulating hormone receptor (TSHR) expression in DTC provides a unique tumor-specific target for CAR therapy. Here, we developed an innovative strategy for treating DTC using modified NK-92 cells armed with a TSHR-targeted CAR. The modified cells showed enhanced cytotoxicity against TSHR-positive DTC cell lines and exhibited elevated degranulation and cytokine release. After undergoing irradiation, the cells effectively halted their proliferative capacity while maintaining potent targeted killing ability. Transfer of these irradiation-treated cells into NSG mice with DTC tumors resulted in profound tumor suppression. NK-92 cells modified with TSHR-CAR offer a promising, off-the-shelf option for advancing DTC immunotherapy.

To investigate whether preoperative ultrasonographic (US) features of the index cancer and metastatic lymph nodes (LNs) are associated with level II LN metastasis in N1b papillary rmfthyroid carcinoma (PTC) patients.

We enrolled 517 patients (mean age, 42 [range, 6-80] years) who underwent total thyroidectomy and lateral compartment LN dissection between January 2009 and December 2015. We reviewed the clinicopathologic and US features of the index cancer and metastatic LNs in the lateral neck. Logistic regression analysis was performed to analyze features associated with level II LN metastasis.

Among the patients, 196 (37.9%) had level II metastasis on final pathology. In the preoperative model, larger tumor size (odds ratios [ORs], 1.031; 95% confidence interval [CI]: 1.011-1.051, p = 0.002), nonparallel tumor shape (OR, 1.963; 95% CI: 1.322-2.915, p = 0.001), multilevel LN involvement (OR, 1.906; 95% CI: 1.242-2.925, p = 0.003), and level III involvement (OR, 1.867; 95% CI: 1.223-2.850, p = 0.004), were independently associated with level II LN metastasis. In the postoperative model, non-conventional pathology remained a significant predictor for level II LN metastasis (OR, 1.951; 95% CI: 1.121-3.396; p = 0.018), alongside the presence of extrathyroidal extension (OR, 1.867; 95% CI: 1.060-3.331; p = 0.031), and higher LN ratio (OR, 1.057; 95% CI: 1.039-1.076; p < 0.001).

Preoperative US features of the index tumor and LN may be helpful in guiding surgery in N1b PTC. These findings could enhance preoperative planning and decision-making, potentially reducing surgical morbidities by identifying those at higher risk of level II LN metastasis and tailoring surgical approaches accordingly.