Thyroid cancer is the ninth most common cancer worldwide, and its prevalence has increased significantly over the last 40 years (1). In 2020, there were 586,202 new cases of thyroid cancer, with papillary thyroid carcinoma (PTC) accounting for more than 80% of all thyroid cancers (1). In general, PTC is regarded as a disease with a favorable prognosis. However, some PTCs with specific clinicopathological characteristics are aggressive and have poor prognoses (2). Tumor multifocality is a frequent observation in PTC, occurring in 18–87% of documented cases (3). Multifocality in thyroid cancer is the concurrent existence of multiple tumor foci within the thyroid gland (4). 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), bilateral multifocality (two or more lesions in the same lobe and one or more lesions in the opposite lobe), or bilaterality (one lesion in each lobe). And a report showed that unilateral multifocality and bilaterality could be two different multifocal entities in patients with PTC (5).

Multiple studies have shown that multifocality is associated with high-risk characteristics of PTC, such as an aggressive histologic subtype, extrathyroidal extension, lymph node involvement, distant metastasis, and recurrence (6, 7). However, the current staging system still defines the size of multifocal tumors in the same manner as that of unifocal tumors, concentrating on the maximum tumor diameter (MTD) (8). In recent years, many studies have also reported the concept of total tumor diameter (TTD) (9–11). Some demonstrated that TTD could reflect a tumor’s biological characteristics and aggressiveness more accurately than MTD (12).

However, the previous researchers took the unilateral multifocality and bilaterality as the same multifocality in their studies (5, 11). The purpose of the present study was to evaluate the association between TTD and unilateral multifocal PTC using the propensity score matching (PSM) method to provide an updated and more comprehensive assessment of the risk for unilateral multifocal PTC.

The impact of TTD in multifocal tumors has been reported on diseases like breast cancer and kidney cancer (13–15). Additionally, TTD’s significance in thyroid cancer has been documented in prior researches. They found that TTD was associated with lymph node metastasis and may represent the tumor biological traits and aggressiveness more accurately than MTD (9, 11, 12, 16). However, the researchers treated unilateral multifocality and bilaterality as the same multifocality types. The current study used a PSM method to investigate the association between TTD and clinicopathological characteristics in unilateral multifocal PTC based on thyroid cancer patients in our center.

The AJCC TNM classification determines the primary tumor (T) stage according to the largest tumor size and ETE (17), even in the multifocal PTC. The impact of other smaller tumor foci on aggressiveness has not been well investigated. Evaluating the largest tumor size and neglecting the smaller foci in multifocal tumors may underestimate the clinicopathologic aspects of malignancies, impacting tumor staging and treatment. In our study, we did two different types of PSM, matching the MTD and TTD respectively, to explore which diameter could represent the tumor biological characteristics and aggressiveness more accurately. We found that the lymph node metastasis rate had significant differences between unilateral multifocal PTC and unifocal PTC after PSM matching the MTD. However, no difference was found after PSM matching the TTD. In other words, the tumor biological traits of the unilateral multifocal PTC were similar to the unifocal PTC with approximate TTD. This result was identical to the previous study (11), which mainly focused on papillary thyroid microcarcinoma (PTMC), showing that micro-PTC tended to behave like the macro-PTC once the TTD exceeded 1.0 cm.

LNM was common among PTC patients. According to earlier research, LNM was present in 30% to 90% of PTC patients, particularly in the central region (18–20), which was one of the major factors that contributed to postoperative recurrence. Although reoperation could still result in a favorable prognosis, patients were more probably to suffer surgical complications (21, 22). Therefore, it was crucial for the patient’s overall prognosis that the lymph nodes were managed at the initial surgery. Because the unique anatomical position limited the diagnostic ability of the current imaging techniques (23), the clinical lymph nodes negative (cN0) was unreliable. Whether prophylactic central lymph nodes dissection (PCLND) was appropriate for cN0 PTC patients was still up for debate. PCLND at the time of the initial surgery, according to Guo et al. (21, 24), may have advantages, including avoiding the significant risk of long-term hypoparathyroidism and RLN damage associated with repeat surgery. Yoon et al. (25), on the other hand, came to the conclusion that the chance of developing permanent hypocalcemia may rise and parathyroid hormone levels may be dramatically lowered following PCLND. In order to direct therapeutic decision-making, it was helpful to identify high-risk variables for LNM. In our study, TTD was significantly correlated with CLNM and LLNM. Also, the ability of TTD to predict CLNM and LLNM was much better than that of MTD in PTC, showing that TTD might be a better predictor of LNM for unilateral multifocal PTC.

In our data, 62.4% of unilateral multifocal PTC presented with CLNM and 31.6% presented with LLNM, significantly higher than unifocal PTC (48.9%&20.2%). Other researches showed the same results (26, 27). In a report by Lombardi et al., multifocal illness increased cervical lymph node recurrence 17.9-fold (28). In another study, the rate of LNM for patients with multifocal PTCs was 55.6%, while it was only 28.6% for those with unifocal illnesses (29). However, the association between LNM and multifocality remained controversial. According to certain studies, multifocality was not independently related to LNM (30). Many other studies have focused on the risk factors of LNM for multifocal PTC patients. For example, Zheng WH proposed that multifocality should be evaluated when selecting patients for PCLND (31). Some reports showed that multifocality was an independent risk factor for CLNM and LLNM (32, 33). As found in previous studies (33–36), our univariate analyses revealed an association between multifocality and LNM. However, on multivariate adjustment for classic clinicopathological risk factors, including MTD and TTD, the association between unilateral multifocality and LNM was lost in PTC. The result demonstrated that unilateral multifocality played no independent role in LNM.

Once, it was thought that multifocality in PTC was caused by the lymphatic spread of tumor cells from one malignant clone. This theory was backed by the fact that tumor cells were often found in lymphatic vessels and that lymph node metastases happened often. But others had the opposite ideas. Bansal et al. found that as many as 60% of multifocal PTCs may have multiple sources, and these origins were generally found in various lobes. The same mutation status was typically shared by multifocality within the same lobe, though (37, 38). A clinical research also showed that unilateral multifocality differed from bilaterality (5). Unlike earlier studies (5, 11), we only included unilateral multifocal PTC in our study to remove the distraction of different types of multifocality and used PSM method to provide an updated and more comprehensive assessment of the risk for unilateral multifocal PTC.

There were some limitations in the study. The inclusion of patients based on their characteristics resulting in a selection bias in this retrospective analysis. Despite the fact that we used PSM, the results could still be influenced by selection bias. Moreover, the participant sample of unilateral multifocal PTC was small. Our data could be hampered by the small sample size. Conducting more validation studies with a bigger cohort and long-term follow-up is necessary.

In conclusion, the current study offers fresh evidence of the connection between TTD and PTC. TTD can more accurately reflect the biological characteristics and aggressiveness of unilateral multifocal PTC than MTD.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by The medical ethics committee of West China Hospital, Sichuan University. The studies were conducted in accordance with the local legislation and institutional requirements.

Author Contributions (I) Conception and design: A-PS, Z-JW (II) Administrative support: A-PS (III) Provision of study materials or patients: A-PS, Z-JW (IV) Collection and assembly of data: Z-JW, Z-WC, B-YX, HG (V) Data analysis and interpretation: Z-JW, MA. All authors contributed to the article and approved the submitted version.