Multifocality increases the risk of central compartment lymph node metastasis but is not related to the risk of recurrence and death in papillary thyroid carcinoma

Introduction

Since 2000, thyroid cancer has become significantly more common in China, and in 2022, approximately 22,000 new cases were reported (1). In recent times, the incidence of papillary thyroid carcinoma (PTC) has increased dramatically (2,3). This rise can be partially explained by the advancements in imaging techniques and the enhanced precision in pathological diagnosis (4,5). A common characteristic of PTC is that it typically presents with unilateral or bilateral multifocal tumors. Multifocality is indicative of an increased risk of lymph node metastasis (LNM) and a higher likelihood of advanced staging; however, accurately quantifying the effect of the number of foci on pathological and clinical features of PTC remains challenging.

Reports on the incidence of multifocality in PTC have varied greatly among different studies (range, 18–87%) (6,7). Compared with unifocal PTC, multifocal PTC typically represents a significant increase in the risk of aggressive PTC and also presents with an increased risk of extensive LNM and recurrence (8-10). Current guidelines from the European Society of Endocrinology and the (11,12) British Thyroid Association recommend that total thyroidectomy be performed in patients presenting with multifocal disease. Conversely, the American Thyroid Association (ATA) guidelines suggest that multifocality is a low-risk factor relapse or persistent disease in PTC (13).

Currently, the management of multifocal papillary thyroid microcarcinomas (PTMCs) in which all foci have a diameter of <10 mm presents a clinical challenge. Traditionally, multifocality has been associated with increased risk in PTC. However, there is a growing need to quantify multifocality to better predict outcomes, such as central compartment LNM, recurrence, and overall survival. The current ATA guidelines do not recommend that all patients undergo routine prophylactic central compartment neck dissection; however, concerns related to the presence of insidious LNM that could contribute to the recurrence of PTC remain. This raises the question of whether central compartment neck dissection is necessary in all cases of multifocal PTMCs.

In this study, patients with PTC were retrospectively analyzed to evaluate the ways in which multifocality influences the likelihood of central compartment LNM and to develop a quantifiable method to predict potential insidious LNM, recurrence rates, and overall survival. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2024-505/rc).

Methods

Patients

This study was carried out in the Department of Thyroid and Neck Oncology (with 89 beds) at Tianjin Medical University Cancer Institute and Hospital, which is staffed by a multidisciplinary team of 20 surgeons and 52 nurses. The department manages over 25,000 outpatient visits and performs more than 3,000 surgical procedures annually, with thyroid cancer surgeries comprising over 90% of this total. It plays a leading role in the academic and professional community, serving as the Secretariat of the China Anti-Cancer Association Thyroid Cancer Committee, the Secretariat of the China Cancer Society, and the Chairman of the Tianjin Thyroid Cancer Committee. The department has pioneered the use of standardized surgical techniques, which include total thyroidectomy with central compartment neck dissection, lobectomy, and lateral neck dissection. In addition, innovative, minimally invasive procedures, such as endoscopic thyroidectomy and video-assisted lateral neck dissection (Miccoli technique), are routinely performed, reflecting the department’s commitment to integrating advanced surgical technologies into clinical practice. These practices exemplify the department’s forward-thinking approach, with an aim to optimize patient outcomes while enhancing procedural efficacy.

Patients with classic PTC diagnosed at the Tianjin Medical University Cancer Institute and Hospital between April and October 2013 were included in this study, and their histopathological and ultrasonographic reports and medical records were reviewed. Patients with isthmus as the tumor location and those with a histological variant (trabecular, tall cell, follicular, or others) were not included in the study, and only patients with classical PTC were included. All procedures were aggregated from multiple institutions. The age, sex, bilateral disease, tumor size, cervical LNM, and tumor foci number of each patient were recorded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Research Ethics Board at Tianjin Medical University Cancer Institute and Hospital (approval No. BC2021023). Due to the retrospective design of this study, the requirement of informed consent was waived.

Data collection and verification/definition of parameters

Patient information was gathered from medical records, encompassing demographic details, clinical history, diagnostic findings, treatment strategies, and follow-up results. Surgical volumes were systematically recorded within a centralized electronic medical records (EMR) system, which tracked all surgeries conducted in the department. Each surgery was logged with key details, including the date, procedure type, surgeon, and patient identifiers. The research team routinely reviewed and cross-verified the collected data to ensure its completeness and consistency. A dedicated verification team, comprising medical records staff and research assistants, carried out periodic audits to confirm data accuracy. To validate surgical volumes, the team cross-checked the EMR logs, surgical documentation, and operative reports, ensuring all surgeries were appropriately recorded. Independent audits were regularly conducted by an external committee to ensure adherence to data documentation standards. Any inconsistencies identified during these audits were addressed by cross-referencing the original medical records and consulting with the surgical team for clarification and correction. This database contains no duplicate or overlapping data.

For patients with suspected metastasis to the lateral cervical lymph nodes identified during preoperative assessment, it is recommended to perform fine needle aspiration (FNA) of the affected lymph nodes for definitive diagnosis. Should the FNA confirm metastasis, simultaneous lateral cervical lymph node dissection is indicated to ensure comprehensive management and improve patient outcomes.

The presence of PTC foci in both lobes of the thyroid gland indicates bilateral disease. The presence of multiple PTC foci indicates multifocal disease. This analysis examined the largest diameter of each PTC tumor.

Determination of tumor size and number of tumor foci

Two independent researchers reviewed the ultrasonographic and histopathological reports of the patients to define the tumor diameter of each tumor and the number of tumor foci. The latter was extracted from histopathological reports, and information on the largest diameter of each tumor was extracted from ultrasonographic reports for each tumor. The largest diameter was recorded only when three-dimensional data were provided by the ultrasonographers.

Follow-up

All patients underwent serum thyroglobulin antibody and thyroglobulin assessments, neck sonography, and physical examination under thyroid-stimulating hormone suppression; in the first year, these tests were conducted every three months, and thereafter, these examinations were conducted annually (2). If the neck sonography revealed any suspicious lesions, the neoplastic nature of the thyroid and/or cervical lymph node were checked by fine-needle aspiration biopsy. Differentiated thyroid cancer patients who had a disease-free period of at least one year before the disease was identified again were diagnosed with disease recurrence. In addition, the patients with lesions identified within a year after surgery were classified as having persistent disease. This diagnosis of disease recurrence applied if the recurrence occurred in the lateral cervical lymph nodes or in the operative region but not if malignant nodules were observed in the contralateral thyroid.

Statistical analysis

IBM SPSS Statistics for Windows (ver. 21, IBM Corp., Armonk, NY, USA) was used for statistical analyses. For univariate analyses, the Student’s t-test was used for normally distributed data, and the Mann-Whitney U-test and Fisher’s exact test were used for non-normally distributed continuous variables and categorical variables, respectively. The covariates with a P value of <0.05 in the univariate analysis were included in the final multivariate regression analysis. For multivariate analysis, logistical regression was used. When the number of individuals in a subgroup was fewer than five, Fisher’s exact test was used to estimate the P value between the two groups. Finally, to assess the effect of multifocality and tumor size (PTMC vs. PTC) on overall survival and disease-free survival, a Kaplan-Meier log-rank analysis was conducted. Notably, a P value of <0.05 was considered statistically significant.

Results

Clinical and pathological features

Herein, we included 1,139 patients (mean age, 46 years; age range, 17–76 years) who were diagnosed as having PTMC or PTC at Tianjin Medical University Cancer Institute and Hospital between April 2013 and October 2013 and had comprehensive follow-up data, ensuring a robust dataset for analysis (Figure 1). The patients had a median tumor size of 7 mm (range, 1–45 mm). Of the 1,139 patients, 261 were men (22.9%) and 878 were women (77.1%). Notably, 517 patients (45.4%) had multifocal cancer lesions. Specifically, 305 (26.8%), 140 (12.3%), 47 (4.1%), and 25 (2.2%) patients had two, three, four, and five or more foci, respectively. In relation to the multifocal PTMCs, 184 (43.7%) were unilateral and 237 (56.3%) were bilateral. The level VI LNM rates for bilateral and unilateral cancer patients were 40.1% (95/237) and 32.1% (59/184), respectively. Table 1 shows the pathological and clinical features of these patients.

Figure 1 Flow diagram of sample selection. PTC, papillary thyroid carcinoma.

Factors associated with central compartment LNM

A univariate analysis was conducted to identify the risk factors for central compartment LNM. Consequently, age, male sex, PTC, bilateral disease, and multifocality were identified as the risk factors in the included patients (Table 2). Notably, in multifocal diseases (i.e., multifocal PTMCs and multifocal PTCs), bilateral disease was not found to be a risk factor. A multivariate analysis was then conducted to identify the independent risk factors for LNM. Consequently, older age (≥55 years), male sex, multifocality, and a tumor diameter of >10 mm were identified as independent risk factors for LNM. Interestingly, bilaterality was not found to be an independent risk factor for LNM (Table 3).

The central compartment LNM rate was related to multifocality

In relation to PTCs, multifocal PTCs had a significantly higher LNM rate than unifocal PTCs [65.6% (63/96) vs. 60.8% (59/97), P<0.001]. Notably, the LNM rates of the unilateral and bilateral multifocal PTCs were comparable [79.2% (19/24) and 61.1% (44/72), respectively; P=0.11]. The results for the PTMC patients were similar. The LNM rates for unifocal and multifocal PTMCs were 27.8% (146/525) and 41.8% (176/421), respectively, and the LNM rates for unilateral and bilateral multifocal PTMCs were comparable [38.6% (71/184) and 44.3% (105/237), respectively; P=0.24; Table 3].

The number of foci increased the LNM rate

The above results revealed that multifocality was a risk factor for an increased LNM rate regardless of whether the patients had bilateral or unilateral disease. Thus, multifocality should be considered in the context of individual thyroid lobes rather than the thyroid gland as a whole. We also explored how central compartment LNM was affected by the number of PTC foci. Table 4 shows that among all patients with unilateral PTMC, level VI LNM was observed in 146/525 (27.8%) patients with unifocal PTMC. Conversely, LNM was observed in 55/142 (37.3%) patients with two PTMC foci. Notably, the proportion of level VI LNM-positive patients further increased in patients with three PTMC foci with 14/35 (40%) patients showing LNM, and this increase continued in patients with four foci, with 4/7 (57.1%) patients showing level VI LNM (Figure 1). Among the patients with bilateral PTMC, 41/112 (36.6%) with two PTMC foci had level VI LNM. Conversely, in patients with three, four, five, six, and seven PTMC foci, LNM was observed in 41/78 (52.6%), 13/30 (43.3%), 6/11 (54.5%), 2/3 (66.7%), and 2/3 (66.7%) patients, respectively.

The number of unilateral PTC patients LNM with one, two, and three PTC foci was 59/97 (60.8%), 16/21 (76.2%), and 3/3 (100%), respectively. Similarly, the number of bilateral PTC patients LNM with two, three, four, five, and six foci was 15/30 (50%), 15/24 (62.5%), 7/10 (70%), 5/6 (83.3%), and 2/2 (100%), respectively (Table 4) (14).

LNM rates for multifocal PTMC were comparable to those for unifocal PTC

To further explore the relationship between multifocality and LNM in patients with PTMC, a stratified analysis was conducted based on tumor size, dividing patients into three distinct groups: Group A (<5 mm), Group B (6–10 mm), and Group C (>10 mm). This classification allowed for a detailed assessment of how multifocality and tumor size independently and interactively influence the likelihood of LNM. In Group A, the LNM rates observed were as follows: unilateral unifocal PTMC, 18.7% (37/198); unilateral multifocal PTMC, 27.1% (16/59); and bilateral multifocal PTMC, 31.3% (15/48). In Group B, the LNM rates were higher: unilateral unifocal PTMC, 33.3% (109/327); unilateral multifocal PTMC, 44.0% (55/125); and bilateral multifocal PTMC, 47.6% (90/189). These results suggest that both multifocality and larger tumor size contribute significantly to the incidence of LNM, with bilateral multifocal PTMCs demonstrating a consistently elevated risk across all groups. The LNM rates in Group C were as follows: unilateral unifocal PTC: 60.8% (59/97); unilateral multifocal PTC: 79.2% (19/24); and bilateral multifocal PTC: 61.1% (44/72). Notably, for both unilateral multifocal PTMCs and PTCs, the LNM rates of groups A, B, and C were 27.1% (16/59), 44.0% (55/125), and 79.2% (19/24), respectively. For unilateral and bilateral multifocal PTMCs and PTCs, the LNM rates of groups A, B, and C were 29.0% (31/107), 59.0% (161/273), and 65.6% (63/96), respectively (Table 5).

Interestingly, on comparing the risk of LNM in patients with multifocal PTMCs, the LNM rate was found to be comparable to that of patients with multifocal PTMCs in Group B (largest diameter: 6–10 mm) and unilateral unifocal PTCs [55/125, 44.0% vs. 59/97, 60.8%; P=0.43 (95% CI: 0.42–0.93)], indicating that multifocal PTMCs and unifocal PTC have the same risk of LNM.

The risk of recurrence did not increase in multifocal PTCs

The median follow-up period postoperatively was 116.42 months (range, 15.24–158.69 months). Notably, 32 patients (2.8%) developed recurrent disease during the follow-up period [23 patients (2.0%): cervical lymph node recurrence; 8 patients (0.7%): thyroid bed recurrence; and 1 patient (0.09%): distant metastasis] (Table 6).

Figure 2 shows Kaplan-Meier overall survival in terms of multifocality and tumor size (PTC or PTMC). The incidence of recurrence occurring during the follow-up period in patients with unifocal PTC compared to multifocal PTCs and in patients with unifocal PTMC compared to multifocal PTMCs was 3.1% vs. 9.4% (P=0.16, 95% CI: 0.290–27.10) and 1.9% vs. 2.4% (P=0.87, 95% CI: 0.125–11.41), respectively. Figure 3 shows Kaplan-Meier disease-free survival in terms of multifocality and tumor size (for PTC or PTMC). The incidence of mortality during the follow-up period in patients with unifocal PTC compared to multifocal PTCs and in patients with unifocal PTMC compared to multifocal PTMCs was 1.0% vs. 0% (P=0.64, 95% CI: −1.00 to −1.00) and 0% vs. 0.2% (P>0.99, Figure 2), respectively (Table 7).

Figure 2 Kaplan-Meier overall survival analysis of patients with general (A), papillary thyroid microcarcinoma (B), and papillary thyroid carcinoma (C). HR, hazard ratio.

Figure 3 Kaplan-Meier disease-free survival analysis of patients with general (A), papillary thyroid microcarcinoma (B), and papillary thyroid carcinoma (C). HR, hazard ratio.

Discussion

Previous research has shown that multifocality is a key factor in assessing central compartment LNM risk (15,16); however, little is known about how the number of tumor foci influences the LNM risk. In this study, we investigated the risk factors for LNM in PTC and specifically examined the effect of multifocality on LNM in terms of the number of foci. Multifocality is a common feature of PTC; it was observed in 48.5% of our patient cohort and has been reported in 18–87% of PTC cases (6,7,17). Notably, it was found to significantly increase the risk of level VI LNM. Our findings showed that the higher the number of tumor foci, the higher the LNM risk in patients with both larger PTCs (>10 mm in diameter) and PTMCs. Notably, the rate of level VI LNM exceeded 50% (52.6% for bilateral PTMCs and 62.5% for bilateral PTCs) in cases with three or more foci and reached 100% in cases with six foci. In our study, 212 patients (18.6%) had tumors with three or more foci, which is consistent with the reported proportions of patients with tumors with three or more foci in the literature (6–13.7%) (9,18). These findings provide further evidence that multifocality is a critical marker of tumor aggressiveness in PTC and is correlated with an increased likelihood of regional metastasis.

In our study, both multivariate and univariate analyses identified multifocality, PTC, and male sex as significant predictors of level VI LNM in patients with PTC. These findings corroborate previous studies that reported these factors as notable predictors of level VI LNM in PTC (15,16). Interestingly, in this study, diffuse calcification was not found to be a significant predictor of level VI LNM, which is inconsistent with the findings of some previous studies suggesting an association between diffuse calcification and thyroid malignancy (19,20). Notably, in our previous study (14), all three PTC patients with diffuse calcification had level VI LNM, which suggested a strong correlation between ultrasonography-detected diffuse calcification and an increased risk of locoregional metastasis. However, given the small number of patients with diffuse calcification in that study, further research needs to be conducted to examine the relationship between diffuse calcification and central compartment LNM in differentiated thyroid carcinoma.

The LNM rate did not differ significantly between patients with multifocal PTMCs with a diameter of 6–10 mm and patients with unifocal PTC with a diameter >10 mm, suggesting that the likelihood of central compartment LNM is similar in multifocal PTMCs measuring 6–10 mm in diameter and unifocal PTCs measuring >10 mm in diameter.

Similarly, other studies have reported that multifocal PTMCs, particularly those with a larger number of individual foci, carry a heightened risk of LNM, despite not always presenting clinically. Wang et al. and Zhao et al. introduced the concept of aggregate diameter to better gauge the tumor burden, underscoring the importance of considering the cumulative size of all tumor foci (21,22). In addition, Tam et al. showed that the risk of aggressive histopathological behavior in multifocal PTMCs with a total tumor diameter >10 mm was comparable to that of unifocal PTCs with a total tumor diameter >10 mm (18). Tam et al. introduced an innovative metric, the tumor diameter ratio (TDR), which is calculated as the primary tumor diameter divided by the total tumor diameter to predict tumor behavior (18). They found that the average TDR was significantly lower in multifocal PTMC patients with capsular invasion, extrathyroidal extension, and lymphovascular invasion than in patients without these characteristics. Thus, TDR was shown to be a reliable indicator for identifying clinically advanced PTMCs (23).

Given the scarcity of evidence, current risk stratification and staging systems do not incorporate bilaterality or multifocality as risk factors associated with recurrence (13,24). In their study of a large patient population (n=2,095) with PTC, Kim et al. found that multifocality (and not bilaterality) was significantly predictive of persistence/recurrence (25). They found that multifocality resulted in a 1.45-fold increased risk of recurrence/persistence. Parvathareddy et al. found that bilaterality in multifocal PTC was associated with several aggressive clinicopathological markers, including older age, male sex, gross extrathyroidal extension, larger tumor size, and locoregional and distant metastasis (26). This finding is consistent with previous research that found that multifocality in PTC was linked to more aggressive disease characteristics (27,28). Conversely, a previous study has reported that bilaterality or multifocality were not associated with the risk of PTC recurrence (29). A recent multicenter analysis involving 2,638 patients with PTC did not identify multifocal PTC as an independent predictor of overall and recurrence-free survival, and the results were replicated and validated using data of 89,680 patients from the Surveillance, Epidemiology, and End Results database (30). Similarly, Guo et al. conducted a meta-analysis of 13 studies comprising 7,048 patients and did not identify multifocality as a significant risk factor for recurrence (31). Consistent with the findings of Elbasan et al. (32), multifocality did not emerge as a predictor of disease recurrence in differentiated thyroid cancer in our study. Nagaoka et al. conducted a review of an active surveillance cohort in Kuma Hospital, which included 457 unifocal and 114 multifocal PTMC patients, and found no significant differences between the two groups in terms of tumor enlargement (11.4% vs. 14.8%) and LNM (1.1% vs. 2.4%). In addition, another multivariate analysis showed that multifocality was not an independent risk factor for PTMC progression (33). Therefore, in the case of multifocal micropapillary thyroid carcinoma, a more conservative surgical approach may be appropriate, as overly aggressive interventions may not be required to achieve optimal clinical outcomes.

Studies have shown that multifocal PTCs tend to have a higher likelihood of LNM compared to unifocal PTCs. Specifically, the number of tumor foci was found to be a significant predictor of LNM. Multifocal PTCs often present with larger and more numerous lymph node metastases. For instance, a study found that patients with multifocal PTCs had a higher frequency of large-number LNM compared to those with unifocal PTCs (34). The ratio of metastatic to examined lymph nodes was also higher in multifocal PTCs. This suggests that multifocality is associated with a more extensive spread of the disease (35).

Based on the characteristics of retrospective studies, this research has certain limitations. Our retrospective study relied on previously collected data, which may be subject to various biases, such as selection bias and recall bias. In addition, confounding factors that were not accounted for during the original data collection may have influenced the study’s results, leading to inaccurate conclusions. Furthermore, the findings of our retrospective study may not be generalizable to broader populations as the study cohort was selected based on specific criteria and may not reflect the diversity of the population in real-world clinical settings. A significant proportion of surgical cohorts encompass a variety of surgical techniques, with the procedures being carried out by different surgeons, each potentially introducing variability in outcomes. One of the key limitations of a single-center study is the potential for selection bias, stemming from the uniformity of the patient population, which is confined to a single institution with specific demographic characteristics. This lack of diversity can restrict the applicability of the study’s findings to broader, more heterogeneous populations. Moreover, variations in local clinical practices, treatment protocols, and the experience levels of surgeons within a single center can introduce confounding factors that might affect outcomes, complicating efforts to generalize results to other healthcare environments. Furthermore, the limited sample size typical of single-center studies reduces statistical power, potentially masking subtle but clinically significant effects and limiting the robustness of conclusions drawn from the data.

Conclusions

Taken together, our findings showed that compared to unifocal and bifocal PTCs, multifocal PTCs carry an increased risk of LNM, particularly when there are more than four foci. Moreover, the risk of LNM of multifocal PTMCs with diameters of 6–10 mm is similar to that of PTCs with diameters >10 mm. Thus, a cautious approach needs to be adopted in the management of multifocal thyroid PTMCs, as they should not be considered similar to conventional PTMCs and erroneously categorized as low risk.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 82272721 and 82703871), and the Tianjin Key Medical Discipline (Specialty) Construction Project (Nos. TJYXZDXK-012A and TJYXZDXK-009A).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2024-505/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2024-505/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2024-505/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2024-505/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Research Ethics Board at Tianjin Medical University Cancer Institute and Hospital (approval No. BC2021023). Due to the retrospective design of the study, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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