The differences between unilateral multifocality and bilateral multifocality in papillary thyroid carcinoma: a retrospective cohort study

Introduction

Papillary thyroid carcinoma (PTC) is the prevailing form of thyroid cancer and the most prevalent endocrine malignancy, comprising around 85% of the total cases (1). Its prevalence has risen dramatically in the previous two decades (2-4). It typically follows a favorable trajectory, with a 10-year survival rate that surpasses 90% (5). PTC can manifest as a solitary unifocal tumor or as multifocal PTC, which consists of two or more anatomically distinct foci within the thyroid gland. The occurrence of multifocal PTC is prevalent, with an incidence rate ranging from 18% to 87%, depending on the diagnostic methodology employed (6-8). Studies have indicated that patients with PTC have a higher likelihood of multifocality when Hashimoto’s thyroiditis (HT) is present. (9,10). A specific study shows that patients with concurrent PTC and HT tend to be younger, have smaller tumor foci, and exhibit less extrathyroidal extension, lymph node metastasis, and distant metastasis (11). However, other research has not found this relationship. In recent years, numerous fundamental research reports have been conducted on the prevalence of multifocal PTC. Some studies suggest that multifocal PTC may have a polyclonal origin (12,13), while others propose intraglandular dissemination as a contributing factor (14,15). Depending on where the tumors are, the meaning of multifocality can be broken down into unilateral multifocality (two or more lesions in the same lobe) and bilaterality (one or more lesions in each lobe).

Multifocality as a prognostic marker is a hotly debated topic (16-25). While several studies have reported no correlation between multifocality and disease recurrence (26,27), other investigations have identified multifocality as a significant risk factor for disease recurrence or mortality (28,29). One of the reasons for the variation in the predictive value of multifocality across different studies may be the undifferentiated multifocality types. However, the prognostic significance of multifocality is still unclear, even in the few studies examining unilateral multifocal and bilateral PTC. Polat et al. (30) found no link between bilateral involvement in multifocal PTC and prognosis. A cohort (31) of more than 2,000 patients shows bilateral multifocal PTC (BMPTC) experiences a shorter duration of disease-free survival (DFS) than unilateral multifocal PTC (UMPTC). Another research (12) demonstrates that UMPTC is significantly associated with a higher recurrence risk and poorer DFS than BMPTC.

Based on these existing clinical problems and controversies, we aimed to evaluate the differences between unilateral multifocality and bilaterality in PTC. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-147/rc).

Methods

Patients

Data for pathologically confirmed PTC patients who underwent thyroid surgery in the Department of Thyroid Surgery, West China Hospital (Chengdu, China) were collected and reviewed over the period spanning from 2013 to 2018. There were 2,322 PTC patients who were >18 years old and underwent the first-time total thyroidectomy with central lymph node dissection (CLND) enrolled. After excluding the unifocal PTC patients, 117 unilateral multifocal cases and 386 bilateral multifocal cases were involved in the study. Then, the bilateral multifocal cases were divided into the N1-BMPTC group (one lesion in each lobe) and the N2-BMPTC group (two or more lesions in the same lobe and one or more lesions in the opposite lobe). The patient data that was gathered encompassed several variables such as age, gender, the maximum tumor diameter (MTD), central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), capsular invasion, gross extrathyroidal extension (gETE), and so on from the hospital database. The study received approval from the medical ethics committee of West China Hospital, Sichuan University (No. 2023813). The participants in the study granted informed consent. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Definition

In the study, MTD was the diameter of the greatest tumor focus in multifocal PTC. Unilateral multifocality was defined as two or more lesions in the same lobe. Bilateral multifocality was described as one or more lesions in each lobe. CLNM was defined as tumor metastasis in level VI cervical lymph nodes. Based on the postoperative pathological diagnosis, LLNM was defined as tumor metastasis in lymph nodes of levels II, III, IV, and V in the neck region. Based on the postoperative pathology diagnosis, the capsular invasion was defined as a tumor involving the capsule but not penetrating it. gETE was characterized as the tumor penetrating the thyroid capsule and invading surrounding tissues or organs, for example, esophagus, trachea, vessel, or recurrent laryngeal nerve (RLN). Locoregional recurrence was defined as a recurrent disease of the operated thyroid bed or cervical lymph nodes and confirmed by needle aspiration cytology. Distant metastasis was defined as tumor metastasis to distant tissues and organs, determined by imaging, including computed tomography (CT) and positron emission tomography. DFS was defined as the living period from the date of receiving surgery to the date of locoregional recurrence or distant metastasis. Tumor classification was standardized using the 8th edition of the American Joint Committee on Cancer (AJCC) TNM classification (32).

Surgical strategy

All patients in the study underwent a complete thyroidectomy procedure, removing the two lobes, the isthmus, and the pyramidal lobe. Prophylactic central lymph nodes dissection (PCLND) was performed on all enrolled patients. The central lymph node compartment was identified by hyoid bone (superior), suprasternal fossa (inferior), carotid artery (lateral), superficial layer of deep cervical fascia (anterior), and esophagus (posterior). The ipsilateral central compartment was defined as the prelaryngeal/pretracheal and paratracheal regions on the same side as the tumor. Bilateral PCLND was performed in cases of bilateral PTC. Individuals found to have LLNM after undergoing fine-needle aspiration biopsy or preoperative imaging were candidates for lateral lymph node dissection from at least level II to level V, sparing the internal jugular vein, spinal accessory nerve, and sternocleidomastoid muscle. The intraoperative frozen sections provided confirmation of this diagnosis. Radioactive iodine therapy was used for intermediate- and high-risk patients following total thyroidectomy.

Statistical analysis

SPSS 26.0 software and GraphPad Prism10 were applied to the data analysis. Continuous variables (confirmed by the Kolmogorov-Smirnov test) with non-normal distribution were presented as the median and interquartile range (IQR). Differences between continuous variables were examined using the Mann-Whitney U test. Categorical variables were presented as the absolute value and relative percentages. Pearson’s χ² test or Fisher’s exact test was used to investigate the heterogeneity between categorical variables. Univariate and multivariate logistic regression analyses were used to identify the risk factors for CLNM and LLNM. Univariate and multivariate Cox regression analyses were used to identify predictors of time-to-recurrence. Survival curves were created by the Kaplan-Meier method. A P value of <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 503 eligible patients were enrolled and categorized into the UMPTC group (n=117) and the BMPTC group (n=386). The N1-BMPTC group had 261 instances, while the N2-BMPTC group had 125 cases. Demographic and clinicopathological characteristics of the patients are presented in Table 1. No significant difference was found between the UMPTC and BMPTC groups (P>0.05), except the BMPTC group had larger MTD [10.00 (8.00–18.00) vs. 10.00 (7.00–15.00), P=0.02]. The N1-BMPTC group [10.00 (8.00–18.50) vs. 10.00 (7.00–15.00), P=0.04] and the N2-BMPTC group [10.00 (9.00–16.50) vs. 10.00 (7.00–15.00), P=0.04] had larger MTD than the UMPTC group. Recurrence was more likely to occur in the N1-BMPTC group than in the UMPTC group (6.1% vs. 0.9%, P=0.02).

Risk factors for CLNM and LLNM in multifocal PTC

We employed univariate and multivariate analyses to identify the risk factors associated with CLNM and LLNM (Table 2). Univariate analysis identified five variables [nodular goiter (NG), MTD, capsule invasion, RLN extension, N1-BMPTC] linked with CLNM. The results of the univariate regression analysis showed a significant association between LLNM and many factors, including sex, NG, MTD, capsule invasion, esophageal extension, RLN extension, tracheal extension, and N1-BMPTC.

Multivariate analysis found four variables (MTD, capsule invasion, RLN extension, N1-BMPTC), which were predictors of CLNM, and four variables (NG, MTD, RLN extension, N1-BMPTC), which were predictors of LLNM.

Prognostic analysis of patients with multifocal PTC

We compared the prognostic value of all clinicopathologic features in all multifocal PTCs (Table 3). Univariate analysis revealed that N1-BMPTC was significantly associated with tumor recurrence [hazard ratio (HR), 3.704; 95% confidence interval (CI): 1.238, 11.081; P=0.02]. MTD (HR, 1.028; 95% CI: 1.008, 1.049; P=0.005), esophageal extension (HR, 8.509; 95% CI: 2.641, 27.413; P<0.001), tracheal extension (HR, 9.179; 95% CI: 2.943, 28.632; P<0.001), RLN extension (HR, 7.722; 95% CI: 3.114, 19.145; P<0.001), and LLNM (HR, 6.119; 95% CI: 2.343, 15.984; P<0.001) were also significantly correlated with tumor recurrence. On multivariate analysis, N1-BMPTC (HR, 6.306; 95% CI: 1.777, 22.380; P=0.004), tracheal extension (HR, 5.219; 95% CI: 1.036, 26.302; P=0.045), and LLNM (HR, 5.358; 95% CI: 1.622, 17.700; P=0.006) were identified as risk factors for tumor recurrence. Furthermore, we compared the DFS rates among the UMPTC, N1-BMPTC, and N2-BMPTC groups. The N1-BMPTC group had the lowest survival rate (P=0.04) (Figure 1).

Figure 1 Kaplan-Meier survival curves illustrate DFS for the UMPTC, N1-BMPTC, and N2-BMPTC. The P value was calculated using the log-rank t (P=0.04). DFS, disease-free survival; UMPTC, unilateral multifocal papillary thyroid carcinoma; BMPTC, bilateral multifocal papillary thyroid carcinoma.

Discussion

Multifocality is common in individuals with PTC and is becoming recognized as a prognostic indicator for lymph node metastases and regional recurrence. However, the precise variations in unilateral multifocality and bilaterality have not been investigated extensively. Owing to the scarcity of articles and the predominance of retrospective studies with limited quality of evidence, the clinical and prognostic implications of unilateral multifocality versus bilateral multifocality for PTC patients are still controversial. The current study investigated the differences between unilateral multifocality and bilateral multifocality in PTC.

According to two reports (12,33), it has been observed that the average age of individuals in the BMPTC group is higher than the UMPTC group. However, Qu et al. (34) have reported that younger age is a predictor of bilateral-multifocality. It is also postulated that the BMPTC group has more male patients than the UMPTC group (33). Our study showed no statistically significant disparities in age and gender between the UMPTC and BMPTC patients. This finding contrasts with the outcomes reported in previous studies, suggesting that the observed discrepancies could potentially be attributed to variations in the selection criteria and divergent study methodologies employed across different investigations.

LNM is prevalent among individuals diagnosed with PTC. Previous studies have revealed that LNM occurs in 30% to 90% of PTC patients, predominantly in the central region, emerging as a significant determinant in postoperative recurrence (35,36). Extensive evidence from multiple studies highlights more aggressive clinicopathological features, such as larger tumor size, advanced tumor stage, LNM, and extrathyroidal invasion, characterize BMPTC compared to UMPTC (12,20,37,38). Many reports showed that the BMPTC group was more likely to have CLNM and LLNM. However, most researchers considered all BMPTC to be the same type, except for two papers. Cai et al. (39) demonstrated that in cases of bilateral papillary thyroid microcarcinoma (PTMC) with N1 type, bilateral multifocal PTMC with N2 type, and unilateral multifocal PTMC, the risk of CLNM was highest in N2 type bilateral multifocal PTMC, while the risk was lowest in N1 type bilateral multifocal PTMC. Moreover, N2-type bilateral PTMC, as opposed to unilateral multifocal PTMC or N1-type bilateral multifocal PTMC, was identified as a risk factor for both CLNM and LLNM. The study conducted by Park et al. (40) found that both N1- and N2-BMPTC were identified as independent predictors of CLNM, but no association was noted between unilateral multifocal PTC and CLNM. Our investigation revealed that the N1-BMPTC group exhibited the lowest incidence of CLNM and LLNM. The differences in the results may be related to the specific location of the tumor. Therefore, the tumor’s position should be considered in future studies.

HT, also known as chronic lymphocytic thyroiditis (CLT), is classified as an autoimmune thyroid disease (AITD) alongside Graves’ disease. It is one of the common thyroid disorders, characterized by thyroid gland enlargement, parenchymal lymphocytic infiltration, and the presence of specific antibodies against thyroid antigens. In recent years, a notable increase in the incidence of HT has led to increased attention to its association with multifocal PTC. Since Dailey et al. first reported this association in 1955 (41), numerous studies have investigated their relationship (42,43). The role of HT in the development of PTC and the underlying mechanisms remain uncertain. Three prevailing hypotheses exist: HT may promote the formation of PTC; HT and PTC may share common etiological factors; or HT might represent an immune response in PTC patients. Evidence suggests an increased incidence of PTC among patients with HT (44-46), with other studies indicating that PTC associated with HT is more likely to be multifocal (9,10). A report (47) indicated that 50% of patients with multifocal PTC had a history of HT. Among the presented patient cases, nearly 22% had a history of HT, with no significant differences observed among the three groups. The association between HT and different kinds of multifocal PTC requires further investigation.

The use of multifocality as a predictive marker is a topic that continues to generate significant controversy in the academic literature (16-25). The probability of structural disease recurrence in unifocal PTMC ranges from 1% to 2%, whereas in multifocal PTMC, which still belongs to the low-risk category, it ranges from 4% to 6%, as indicated by the 2015 American Thyroid Association (ATA) management guidelines (48). Meanwhile, according to a consensus report published by the European Society of Endocrine Surgeons (16), multifocality has been proposed as a potential prognostic indicator in cases with overt PTC and would not serve as a useful predictive tool for PTMC. Several meta-analytic studies have examined the correlation between multifocality and recurrence rates (18,49-52). Guo et al. (51) presented evidence suggesting that there was no significant correlation between multifocality and recurrence. Conversely, previous meta-analyses (18,49,50,52) reported a positive link between multifocality and the likelihood of recurrence. The divergent findings in the existing body of literature may be ascribed to the contrasting clinical characteristics of unilateral and bilateral cancers. Some retrospective investigations (31,33,34) have indicated that the BMPTC group has a greater recurrence rate compared to the UMPTC group. However, another study (12) has demonstrated that unilateral multifocality can serve as a predictive factor for recurrence. The present retrospective study indicates that BMPTC has a greater recurrence rate than UMPTC.

There are certain constraints in this study. First, the study was limited in exploring the link between recurrence and various clinicopathological variables because of the relatively short median follow-up time and the low number of recurrence cases. Second, the retrospective design is subject to selection bias due to the inclusion of patients depending on their characteristics. It is imperative to carry out additional validation studies using a larger cohort and a long-term follow-up.

Conclusions

In summary, this study presents preliminary evidence indicating that patients with N1-BMPTCs have a higher recurrence rate than those with other kinds of multifocal PTC. However, the relationship between the LNM and different types of multifocal PTC remains unclear. A subsequent investigation with a bigger group of participants, a longer duration of observation, and more detailed data on molecular features could offer a better understanding of the progression of multifocal PTC and aid in determining the most effective therapy and follow-up approaches.

Acknowledgments

We thank all patients who participated in this study for their cooperation.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-147/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-147/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-147/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-147/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 medical ethics committee of West China Hospital, Sichuan University (No. 2023813) and informed consent was taken from all individual participants.

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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