Predictive features of central lymph node metastasis in papillary thyroid microcarcinoma: Roles of active surveillance in over-treatment

We appreciate the thoughtful and valuable comments by Dr. Coskun Ali from Turkey for our manuscript. Although papillary thyroid microcarcinoma (PTMC) has an indolent course, the central lymph node metastasis (CLNM) has been found with a high incidence in PTMCs at the time of diagnosis [1–3]. The role of therapeutic central lymph node dissection (CLND) for treatment of CLNM in PTMC is well accepted for cN1 disease by The American Thyroid Association (ATA) guidelines for differentiated thyroid cancer and 2014 updating version [4, 5]. However, given the undetermined effect on long-term survival and related morbidity in PTMC patients, the value of routinely prophylactic CLND for cN0 disease remains unclear. Therefore, we conducted a meta-analysis to investigate the clinicopathologic factors predictive of CLNM for guiding prophylactic CLND in PTMCs with risk factors. As noted from comments, the accurate preoperative imaging doesenable complete clearance of the primary tumor and affected lymph node in PTMC patients. Recently, Yeh et al. have published ‘‘American Thyroid Association Statement on Preoperative Imaging for Thyroid Cancer Surgery’’ and highlighted that ultrasonography (US) remained the most important imaging modality in the assessment for both the primary tumor and all associated cervical lymph node basins preoperatively [6]. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications in US examination [6]. Actually, we had reviewed the clinicopathologic and imaging features in a total of 163 patients with thyroid micro-nodules, diagnosed as Bethesda classification V (44/163, 27.0 %) and VI (119/163, 73.0 %) for papillary carcinoma by preoperative cytology. All of them had received thyroidectomy, and PTMC was confirmed in 162 patients on histology. In the multivariate analysis, the US suspicious images for nodal metastasis (Figs. 1 and 2), as mentioned above, we reproved to be independent predictors for CLNM in PTMCs [7]. In addition, recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers in the management of thyroid nodules [8]. Molecular markers have been reported to enhance the diagnostic sensitivity of fine-needle aspiration (FNA) cytology in detecting malignancy preoperatively [9], such as genetic alterations occur in the MAP kinase (MAPK) and PI3 K/AKT pathways, including BRAF and RAS point mutations, as well as translocations in the RET/PTC and PAX8/PPARc genes [8, 10]. In the latest 2014 ATA guidelines [5], it is pointed out that studies of the BRAF mutation have suggested an association between presence of the mutation and the risk of nodal disease [11–13]. However, BRAF mutation has a limited positive predictive value for recurrence and therefore BRAF mutation status in the primary tumor is not recommended on the decision for prophylactic CLND in the new guidelines [5]. We have reviewed the related studies and found that results across all patients on association between BRAF mutation status and the risk of & Qing-hai Ji jonathan_qn@163.com

e17583 Background: Papillary thyroid microcarcinoma (PTMC) accounts for nearly half of all cases of thyroid papillary cancer. Although PTMC has a good prognosis, lymph node metastasis, especially central lymph node metastasis (CLNM), is the leading cause of local recurrence. The value of central lymph node dissection in PTMC remains controversial. Few studies have focused on the relationship between CLNM and multifocality in PTMC. This retrospective study of a large cohort of patients with PTMC aimed to identify assess the predictive value of multifocality for identifying patients at high risk of CLNM who may benefit from central lymph node dissection. Methods: Patients with PTMC who underwent total or hemi-thyroidectomy with effective unilateral or bilateral central lymph node dissection at Zhejiang Caner Hospital between January 2007 and December 2015 were enrolled ( n = 3543). Number and laterality of PTMC foci, extrathyroidal extension (ETE), tumor size, age, sex, positive/total number of central lymph nodes and other clinicopathological factors were recorded. The chi-square test was used for univariate analysis; logistic regression, for multivariate analysis. Results: Multifocality, age, sex, tumor size, ETE and nodular goiter were significantly associated with central lymph node metastasis (CLNM) in univariate analysis. Multifocality was an independent predictive factor for CLNM in multivariate analysis. Compared to unifocal disease, the odds ratio (OR) for CLNM was 1.447 for patients with ¡Ý 2 tumor foci ( P < 0.001) and 2.978 for patients with ¡Ý 3 tumor foci ( P < 0.001). Conclusions: Multifocality with ¡Ý 3 tumor foci was an independent predictive factor for CLNM in PTMC. Multifocality should be assessed when selecting patients for prophylactic central neck lymph node dissection, and we recommend patients with multifocality should undergo more radical treatment.

Objective To analyze the risk factors for cervical lymph node metastasis in patients with papillary thyroid microcarcinoma (PTMC). Methods The clinical data of 289 patients with PTMC from January 2013 to December 2014 were analyzed retrospectively. All patients underwent thyroidectomy and thyroid isthmectomy/total thyroidectomy plus central (and lateral) cervical lymph node dissection. Results In 289 patients, postoperative pathology confirmed that the central lymph node metastasis was in 118 cases (40.8%); 64 of them performed central and lateral cervical lymph node dissection, and the rate of lateral cervical lymph node metastasis was 42.2% (27/64). The smooth curve fitting chart showed that the risk of central cervical lymph node metastasis was significantly increased when the tumor diameter >6 mm. Univariate analysis result showed that central cervical lymph node metastasis was associated with gender, number of primary lesions, unilateral and bilateral tumor, capsule invasion, tumor diameter and Hashimoto thyroiditis (P 6 mm was the independent risk factor for central cervical lymph node metastasis (OR= 2.036, 95% CI 1.160-3.573, P= 0.013). Univariate analysis result showed that lateral cervical lymph node dissection was associated with central cervical lymph node dissection (P < 0.05); multivariate Logistic regression analysis result showed that central cervical lymph node dissection was the independent risk factor for lateral cervical lymph node dissection in patients with PTMC (OR= 9.630, 95% CI 1.150-80.628, P= 0.037). Conclusions PTMC patients with central or lateral cervical lymph node metastasis is very common, and central lymph node metastasis risk increases significantly when tumor diameter > 6 mm; the risk of lateral cervical lymph node metastasis also significantly increases in patients with central cervical lymph node metastasis. Key words: Thyroid neoplasms; Carcinoma, papillary; Neoplasm metastasis; Risk factors; Retrospective studies

Analysis of risk factors for lymph node meta-stasis in papillary thyroid microcarcinoma

Simple SummaryThe present study focused on patients affected by stage pT1a papillary thyroid micro-carcinomas that were treated with surgery and central lymph node dissection. In this study, male sex, low age, and sub-capsular carcinoma localization resulted as independent predictive factors for central lymph node metastases.Papillary thyroid micro-carcinomas are considered relatively indolent carcinomas, often occult and incidental, with good prognosis and favorable outcomes. Despite these findings, central lymph node metastases are common, and are related to a poor prognosis for the patient. We performed a retrospective analysis on patients treated with surgery for stage pT1a papillary thyroid micro-carcinomas. One hundred ninety-five patients were included in the analyses. The presence of central lymph node metastases was identified and studied. A multivariate analysis employing binary logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals of possible central lymph node metastases risk factors. In the performed multivariate analysis, male gender, younger age, and histopathological characteristics, such as a tumor sub-capsular localization, were significantly associated with central lymph node metastases in pT1a patients. Central compartment lymph node metastases are present in a non-negligible number of cases in patients with papillary thyroid micro-carcinoma undergoing surgical resection. Studying these factors could be an effective tool for predicting patients’ central lymph node metastases in papillary thyroid micro-carcinomas, defining a tailored surgical treatment in the future.

The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC. PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta-analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted. A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22-1.52, p = 0.001), younger age (<45 years; RR = 1.15; 95 % CI 1.04-1.27, p = 0.006), larger tumor size (>5 mm; RR = 1.51 95 % CI 1.32-1.65, p = 0.001), multifocality (RR = 1.40; 95 % CI 1.27-1.54, p = 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34-2.43, p = 0.001). Meta-regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences [hazard ratio (HR) = 0.95, 95 % CI 0.67-1.22, p = 0.054], and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46-2.01, p = 0.544). Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC.

BackgroundHashimoto’s thyroiditis (HT) is the most common comorbidity in patients with papillary thyroid microcarcinoma (PTMC). The necessity of prophylactic central lymph node dissection (CLND) in clinically node-negative (cN0) PTMC cases remains a topic of debate. This study evaluates the risk of cervical lymph node metastasis (LNM) in PTMC patients with concurrent HT.ObjectivesThis study aims to evaluate the risk of central lymph node metastasis (CLNM) in patients with PTMC concurrent with HT. By synthesizing existing literature and conducting a case–control analysis, we seek to enhance individualized risk assessment and inform surgical decision-making for PTMC patients.MethodsWe conducted a search for studies published before 1 June 2025 that assessed the risk of CLNM in PTMC concurrent with HT on PubMed, Embase, and Web of Science. A total of 17 studies involving 11,873 cases were included in this meta-analysis. Additionally, we performed a case–control study through a retrospective analysis of 303 consecutive PTMC patients who underwent surgery between 2017 and 2024.ResultsThe meta-analysis indicated that HT was present in 3,175 of the 11,873 PTMC cases (26.7%). The rate of positive CLNM was significantly lower in the HT group (32.6%) compared to the non-HT group (38.4%), with an odds ratio of 0.75. The false-negative rate was as low as 27.5% when combining ultrasonography (US) and fine-needle aspiration biopsy (FNAB) to evaluate CLN status. Funnel plots showed no significant publication bias. In the retrospective analysis, the CLN examination rate in the HT group was significantly higher than in the non-HT group, yet the incidence of CLNM was lower in the HT group. ROC curve analysis indicated that the TPOAb cutoff point for CLNM was 17.9, with sensitivity and specificity values of 53% and 68%, respectively.ConclusionHT may reduce the risk of CLNM in patients with PTMC, suggesting a protective role. Predictive, preventive, and reliable preoperative evaluations using ultrasound and FNAB enhance the assessment of lymph node status, with TPOAb serving as an important marker. These insights support the development of personalized strategies for early intervention and improved patient management in PTMC.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251174681.

The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central/lateral lymph node dissection, remains controversial. This study investigated the clinicopathologic factors predictive of lymph node metastasis (LNM) in patients diagnosed with PTMC. Multivariate logistic regression analysis was used for PTMC patients identified from the Surveillance, Epidemiology, and End Results database who were treated by surgery between 2002 and 2012, to determine the association of clinicopathologic factors with LNM. According to the results, a total of 31,017 patients met the inclusion criteria of the study. Final histology confirmed 2,135 (6.9%) cases of N1a disease and 1,684 cases (5.4%) of N1b disease. Our multivariate logistic regression analysis identified variables associated with both central LNM and lateral lymph node metastasis (LLNM), including a younger age (<45 years), male sex, non-Hispanic white and other race, classical papillary histology, larger tumor size, multifocality, and extrathyroidal extension; distant metastasis was also significantly associated with LLNM. The significant predictors identified from multivariable logistic regression were integrated into a statistical model that showed that extrathyroidal extension had maximum weight in the predictive role for LNM. LLNM was validated to be a significant risk factor for cancer-specific death in Cox regression analyses, whereas central LNM failed to predict a worse cancer-specific survival according to our data. Therefore, we suggested that central lymph node dissection could be performed in certain patients with risk factors. Given the prevalence of LLNM in PTMC, a thorough inspection of the lateral compartment is recommended in PTMC patients with risk factors for precise staging; from the viewpoint of a radical treatment for tumors, prophylactic lateral lymph node dissection that aims to remove the occult lateral lymph nodes may be an option for PTMC with risk factors. Multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for cervical nodes in PTMC.

Objective To analyze the clinical features of lymph node metastasis in papillary thyroid microcarcinoma(PTMC). Methods 198 patients with PTMC who have underwent total thyroidectomy and at least one 131I treatment were divided into two groups according to the occurrence of lymph node metastasis. The clinical features of lymph node metastasis in PTMC were retrospective analyzed, and independent risk factors of the central and lateral lymph node metastasis in PTMC patients were further analyzed. Results Clinical features of PTMC patients with cervical lymph node metastasis: (1)Most of them were<45 years old(63.4% vs 44.9%, P=0.012); (2)More patients with cancer in bilateral lobes and extrathyroidal extension in lymph node metastasis groups(56.7% vs 42.0%, P=0.043; 63.6% vs 36.4%, P=0.034); (3)The average tumor size of the patients of lymph node metastasis was larger than that of the patients without lymph node metastasis[(0.71±0.25 vs 0.64±0.24)cm, P=0.047]; (4)Preoperative thyroglobulin antibody(TgAb)level of PTMC patients with cervical lymph node metastasis was higher than the control group[(65.27±139.179 vs 36.36±95.647)IU/L, P=0.03]; (5)After the 131I treatments and by 1-6 years of follow-up, it is found no statistically significant difference in cure rate between patients with cervical lymph node metastasis after total thyroidectomy and its control group. But the frequency of 131I treatment required in patients with cervical lymph node metastasis was higher than that of the control group(1.77±0.77 vs 1.49±0.74, P=0.006). Univariate analysis revealed that central lymph node metastasis was correlated with age, tumor size and other factors. There were more patients with cancer in bilateral lobes and extrathyroidal extension in lymph node metastasis group. And lateral lymph node metastasis was correlated with Hashimoto′s thyroiditis. Multivariate analysis showed that age, tumor size, involvement of bilateral glandular lobes and extrathyroidal extension were independent risk factors for central lymph node metastasis. Conclusion The risk factors of lymph node metastasis should be fully evaluated to carry out individualized treatment for the first operation of PTMC patients. (Chin J Endocrinol Metab, 2016, 32: 900-905) Key words: Papillary thyroid microcarcinoma; Lymph node metastasis; Clinical feature; Risk factors

Papillary thyroid microcarcinoma (PTMC), one specific subtype of papillary thyroid carcinoma (PTC) which measures less than 10 mm in maximum dimension, presents with a high risk of insidious lymph node metastasis escaping from preoperative examinations (cN0). Given the complications of lymph node dissection (LND) and metastasis risk, proper stratification of PTMC for performing prophylactic LND bears great importance. From June 2015 to December 2017, 338 PTMC patients undergoing thyroidectomy were included in the present study. Potential risk factors, including age, gender, maximal tumor size, etc. were collected and analyzed for association with thyroid lymph node metastasis. Among the 338 patients, 87 patients (25.7%) presented with right central lymph node metastasis (CLNM) and 28 patients (8.3%) had posterior right recurrent laryngeal nerve lymph node metastasis (PRRLN-LNM). The maximal tumor was prone to occur at the middle part of the lower pole (35.3%) in patients with right CLNM, while the proportion of tumors located in the middle part of the upper pole (17.2%) was highest in PRRLN-LNM patients. Ages younger than 45 years old, male gender, and a tumor size of more than 0.5 cm were correlated independently with right CLNM and PRRLN-LNM. Presence of capsular invasion also had a significant association with the occurrence of PRRLN-LNM. Ages younger than 45, male gender, and a maximal tumor size larger than 0.5 cm, in addition to capsular invasion, were independent risk factors for stratification of PTMC patients. PTMC patients with these clinical characteristics were suggested to receive prophylactic LND in their initial thyroid surgeries.

The relationship between Hashimoto's thyroiditis (HT) and papillary thyroid microcarcinoma (PTMC) is controversial. These include central lymph node metastasis (CLNM), which affects the prognosis of PTMC patients. This study aimed to establish a predictive model combining ultrasonography and clinicopathological features to accurately evaluate latent CLNM in PTMC patients with HT at the clinical lymph node-negative (cN0) stage. In this study, 1102 PTMC patients who received thyroidectomy and central cervical lymph node dissection (CLND) from the First Affiliated Hospital of Shandong First Medical University from January 2021 to December 2022 and the 960th Hospital of PLA from January 2021 to December 2022 were jointly collected. The clinical differences between PTMCs with HT and those without HT were compared. A total of 373 PTMCs with HT in cN0 were randomly divided into a training cohort and a validation cohort. By analyzing and screening the risk factors of CLNM, a nomogram model was established and verified. The predictive performance was measured by the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA). The ratio of central lymph node metastasis (CLNMR) in PTMCs with HT was 0.0% (0.0%, 15.0%) and 7.7% (0.0%, 40.0%) in the non-HT group (P<0.001). Multivariate logistic regression analysis showed that age, gender, calcification, adjacent to trachea or capsule, and TPOAB were predictors of CLNM in PTMCs with HT. The areas under the curve (AUC) of the prediction models in the training cohort and the validation cohort were 0.835 and 0.825, respectively, which showed good differentiation ability. DCA indicates that the prediction model also has high net benefit and clinical practical value. This study found that CLN involvement was significantly reduced in PTMC patients with HT, suggesting that different methods should be used to predict CLNM in PTMC patients with HT and without HT, to more accurately assist preoperative clinical evaluation. The actual CLNM situation of PTMCs with HT in cN0 can be accurately predicted by the combination of ultrasonography and clinicopathological features.

Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?

To investigate the incidence and the risk factors for occult ipsilateral or contralateral central neck lymph node (LN)metastasis in patients with unilateral papillary thyroid carcinoma (PTC) and a clinically negative neck. Elective central lymph node dissection (CLND) in patients with PTC remains controversial. There have been few prospective studies assessing accurate histopathologic information and predictive factors for the presence of metastasis to the ipsilateral or contralateral central compartment of the neck in patients with PTC and clinically negative neck nodes. We reviewed a prospective protocol of 111 unilateral PTC patients with clinically node-negative necks who have received total thyroidectomy and elective bilateral CLND from 2005 to 2007. The relationships between LN metastasis to the ipsilateral or contralateral central neck compartment and clinico-pathologic factors such as age, sex, size of primary tumor, perithyroidal invasion, lymphovascular invasion, and capsular invasion were analyzed. Occult central neck LN metastasis was present in 54.1% (60/111). Of these patients, bilateral central LN metastases were present in 50% (30/60), unilateral ipsilateral central LN metastasis in 43.3% (26/60), and unilateral contralateral central LN metastasis in 6.7% (4/60). In the univariate analysis, the rate of ipsilateral central LN metastasis was significantly higher in male patients, high risk MACIS score, carcinoma with a maximal diameter of greater than 1 cm, and carcinoma with lymphovascular invasion (P < 0.05). The rate of contralateral central LN metastasis was significantly higher in cases of carcinoma with a maximal diameter of greater than 1 cm, lymphovascular invasion or histologically proven metastasis to the ipsilateral central LN (P < 0.05). Multivariate analysis showed that the tumor size was an independent risk factor for the presence of ipsilateral central LN metastasis, and the presence of ipsilateral central LN metastasis was the only independent predictor for the presence of contralateral central LN metastasis. Unilateral PTC with a maximal diameter of greater than 1 cm is associated with a high rate of ipsilateral central neck LN metastasis. Moreover, ipsilateral central LN metastasis is a potential independent predictor of synchronous contralateral central LN metastasis. These findings suggest that contralateral as well as ipsilateral elective CLND, performed during the initial thyroid operation, may be effective in the management of patients with unilateral PTC having a maximal diameter of greater than 1 cm and ipsilateral central LN metastasis.

IntroductionThe treatment of papillary thyroid microcarcinoma remains controversial. Central lymph node metastasis is common in papillary thyroid microcarcinoma and it is an important consideration in treatment strategy selection. ObjectiveThe aim of this study was to investigate clinicopathologic risk factors and thyroid nodule sonographic characteristics for central lymph node metastasis in papillary thyroid microcarcinoma. MethodsWe retrospectively reviewed the data of 599 papillary thyroid microcarcinoma patients who underwent surgery from 2005 to 2017 at a single institution. Univariate and multivariate analyses were used to identify the clinicopathologic factors and preoperative sonographic features of central lymph node metastasis. A receiver-operating characteristic, ROC curve analysis, was performed to identify the efficacy of ultrasonographic features in predicting central lymph node metastasis. A nomogram based on the risk factors was established to predict central lymph node metastasis. ResultsThe incidence of central lymph node metastasis was 22.4%. The univariate and multivariate analyses suggested that gender, age, multifocality, extrathyroidal invasion, and lateral lymph node metastasis were independent risk factors for central lymph node metastasis. The univariate and multivariate analyses revealed that nodular shape, margin, and calcification were independently associated with central lymph node metastasis. The ROC curve analysis revealed that the combination of shape, margin and calcification had excellent accuracy in predicting central lymph node metastasis. The nomogram was developed based on the identified risk factors for predicting central lymph node metastasis, and the calibration plot analysis indicated the good performance and clinical utility of the nomogram. ConclusionsCentral lymph node metastasis is associated with male gender, younger age (<45 years), extrathyroidal invasion, multifocality and lateral lymph node metastasis in papillary thyroid microcarcinoma patients. The ultrasongraphic features, such as irregular shape, ill-defined margin and calcification, may improve the efficacy of predicting central lymph node metastasis. Surgeons and radiologists should pay close attention to the patients who have these risk factors. The nomogram may help guide surgical decision making in papillary thyroid microcarcinoma.

Objective: To analyze the risk factors of lymph node metastasis in central region of patients with papillary thyroid microcarcinoma (PTMC). To evaluate the reliability of different risk factors on the prognosis of cervical lymph node metastasis in PTMC patients, and to provide the clinical support for PTMC in the central area. Methods: The clinical data of 700 patients with PTMC treated with surgery from January 2015 to July 2017 were analyzed retrospectively. Risk factors for lymph node metastasis in central region were analyzed by single factor analysis, multivariate Logistic regression analysis and receiver operating characteristic curve (ROC) curve. Results: Central lymph node metastasis (CLNM) rate was 48.29% (338/700). Multifactor analysis indicated that age≤45 years old, male, multifocality, capsule invasion, the tumor calcification and tumor diameter ≥5 mm were independent risk factors for CLNM in patients with PTMC. In the risk prediction of CLNM, the optimal critical value of diameter prediction was 7 mm and the area under the curve (AUC) of ROC=0.647. The optimal threshold for age prediction was 41 years old and AUC=0.597. Single factor analysis for ROC curve showed that gender factor AUC=0.588, tumor number factor AUC=0.627, tumor location factor AUC=0.613. and calcification factor AUC=0.603. The ROC curve of multiple risk factors was analyzed according to age, gender, diameter, location, number of cancer foci and calcification, and AUC=0.768. Conclusions: Age less than 45 years old, male, multiple cancer foci, focal invasion and capsule invasion, calcification, and tumor diameter ≥5 mm are independent risk factors for CLNM of PTMC. With an accumulation of multiple risk factors, CLNM risk increases, and central lymph node dissection should be recommend.