The indolent nature and excellent prognosis of papillary thyroid microcarcinoma (PTMC) have contributed to the emergence of active surveillance (AS) as a viable treatment approach for low-risk thyroid cancer (1). AS for low-risk PTMC was introduced in Japan, and the American Thyroid Association guideline also recommended AS as an applicable management strategy in selected cases of low-risk thyroid cancer (2). A Korean study revealed a good prognosis, including 1.5% recurrence rate during a median follow-up of 7.7 years and 0.1% distant metastasis rate among 8,808 patients with PTMC (3). However, physician- and patient-related barriers to accepting AS in patients with PTMC still exist, and one of the main barriers is the fear of cancer progression, even though the risk of disease progression is low. Therefore, appropriate candidate identification for AS, especially the exclusion of cases with high risks of disease progression, is important.

Many studies have evaluated the prognostic factors of PTMC, including old age, male gender, larger tumor size, extrathyroidal extension (ETE), lymph node (LN) metastasis, multifocality, BRAF mutation, and coexistence of chronic thyroiditis, with varying or inconclusive results (4–8). The majority of prognostic factors can be ascertained through postoperative pathological results, which makes their utilization challenging for patients under consideration for AS. However, all patients diagnosed with PTMC undergo ultrasonography (US) before the AS decision to identify high-risk features, such as invasion and LN metastasis. Distant metastasis in patients with PTMC was rarely observed, but it could be fatal and all patients with PTMC with distant metastasis had synchronous cervical LN metastasis at the time of the first diagnosis (3). In particular, lateral LN metastasis is a prognostic factor of recurrence in patients with PTMC (9). Most of the lateral LN metastases in patients with PTMC progress sequentially from the initial central LN metastasis to the ipsilateral lateral LN metastasis (10). However, skip metastasis with a discontinuous lymphatic spread pattern has been reported in up to 21.8% of cases and PTMC (less than 1 cm) is a risk factor of skip metastasis among patients with papillary thyroid carcinoma (PTC) (11, 12).

Hence, the primary objective of this study is to assess potential risk factors associated with the development of lateral LN metastasis in patients with PTMC. This will be achieved by analyzing US findings in conjunction with clinicopathological factors among patients with lateral LN metastasis (N1b) and comparing them to age- and sex-matched patients without LN metastasis (N0). Additionally, we analyzed risk factors for skip metastasis in patients with PTMC with lateral LN metastasis.

This study focused on identifying risk factors for lateral LN metastasis in patients with PTMC. We evaluated clinicopathologic features and US findings not only in the main thyroid tumor but also in the background thyroid gland. Additionally, this study aimed to evaluate predictors of skip metastasis in patients with PTMC. The results revealed that ETE, tumor multifocality, upper lobe tumor location, and non-parallel tumor shape were independent predictors for lateral LN metastasis in patients with PTMC. Importantly, all these predictors can be assessed non-invasively using US, making it a valuable tool for risk stratification before the decision of AS.

PTC, the most common type of differentiated thyroid cancer, has seen a significant increase in incidence over the last few decades (22), resulting in considerable economic and emotional burden. As a result, AS is increasingly recommended as a suitable management option for low-risk PTC, particularly PTMC, given its favorable prognosis (23). The most important part of AS is to find appropriate criteria for AS, which could reduce the possibility of disease progression during observation. The definition of disease progression under AS is divided into two sections: tumor size growth and the emergence of new LN metastasis (14). The lower frequency of LN metastasis and the lack of significant benefit from prophylactic central LN dissection have supported lobectomy and even AS strategies in patients with PTMC. However, the presence of lateral LN metastasis can alter the treatment approach, with reported rates of up to 39.5% when prophylactic LN dissection is performed (24). This distinction can significantly impact the management strategy choice between AS and immediate surgery (IS) for patients with low-risk PTC. Moreover, LN metastasis has been linked to distant metastasis and recurrence in PTC patients, further emphasizing the importance of detecting and addressing LN involvement in the disease management (3, 25, 26). Our study demonstrated that patients with PTMC without LN metastasis (N0) at diagnosis showed no structural recurrence during an average follow-up period of 94.6 months, which could be safe candidates for AS.

In a Korean study analyzing 5,656 patients with PTMC, male gender was identified as one of the independent predictors for lateral LN metastasis, with the difference of loco-regional recurrence according to nodal stage (27). Similarly, a Japanese AS cohort study revealed that young age (<40 years) was an independent risk factor for newly developed LN metastasis among low-risk patients with PTMC (28). Young age and male gender are well-known predictors in patients with PTC; however, a Korean study demonstrated higher recurrence rates and mortality in male patients compared to female patients with PTC, but male gender was not an independent prognostic factor for recurrence in propensity score-matched patients with PTMC (29). In this study, we performed the PSM for age and sex among patients with PTMC; thus, the age and sex variables for the risk of LN metastasis could not be analyzed. Nevertheless, special attention is warranted to identify lateral LN metastasis in patients with young age and male gender.

In a Korean study analyzing 3,578 patients with PTMC, central LN metastasis, ETE, and multifocality were identified as significant risk factors for lateral LN metastasis (30). Our study also found similar trends, with multifocality and ETE being related to lateral LN metastasis, although central LN metastasis could not be evaluated due to the study’s design comparing N1b with N0. Many studies have shown that multifocality is a risk factor for LN metastasis in PTC and patients with PTMC (7, 31, 32), and there are still controversies regarding its relationship with prognosis. A recent study suggested that minimal ETE is linked to lateral LN metastasis (33), but there is no association between minimal ETE and recurrence among patients with PTMC (34). A future prospective study could explain the relationship between multifocality and clinical outcome in patients with PTMC.

At the time of the decision for AS in low-risk patients with PTMC, many histopathological risk factors are not readily available. However, tumor size, ETE, and multifocality can be evaluated by US with some limitations. For instance, capsular invasion on US can be defined as the percentage of the tumor perimeter in contact with the thyroid capsule, and PTC patients with >50% capsular invasion on US show a higher frequency of lateral LN metastasis (35). Loss of the echogenic capsule has been identified as a reliable US value for evaluating capsular invasion in PTC patients, with 75% sensitivity and 65% specificity, but a false discovery rate of 57.1% (36). US may have some limitations in accurately assessing multifocality due to the possibility of occult tumors with small size, and three patients were excluded because tumor was not observed in preoperative US of our study. Despite these challenges, our study showed the association of ETE and multifocality with lateral LN metastasis; thus, careful US evaluation of ETE and tumor number can provide valuable clues for the risk of lateral LN metastasis.

US findings play a critical role in predicting disease progression, especially lateral LN metastasis, in patients with PTMC considering AS because US should be performed in all patients before the decision of AS. Despite its importance, only a few studies have focused on US features for PTMC. A Chinese study highlighted that US features, such as central LN metastasis in the presence of concurrent HT, upper lobe tumor location, lack of a well-defined margin, and the presence of calcifications, were significantly associated with lateral LN metastasis in patients with PTMC (37). Another study identified upper lobe tumor location, microcalcification, and subcapsular lesions (defined as nodules abutting the thyroid capsule without intervening thyroid tissue) as factors associated with lateral LN metastasis (38). In the present study, we found that upper lobe tumor location and a non-parallel shape of the main thyroid tumor were independent predictors for lateral LN metastasis in patients with PTMC. The association between upper lobe tumor location and lateral LN metastasis has been consistently demonstrated in most studies focusing on patients with PTMC (39). Consequently, meticulous US follow-up is essential with a specific focus on detecting lateral LN metastasis in patients with PTMC with tumors located in the upper lobe. The upper lobe tumor location and PTMC were risk factors of skip metastasis (40, 41). This study evaluated risk factors of skip metastasis in patients with PTMC, and upper lobe tumor location was identified as a risk factor. Furthermore, skip metastasis could suddenly occur without other progressive signs including bilaterality, multifocality, and the expansion of metastatic LNs.

Apart from the main characteristics of the thyroid tumor, the background of the thyroid itself could also influence LN metastasis. The association between DTD and PTC has primarily been evaluated in the context of HT. Previous reports have indicated a higher prevalence of PTC in patients with HT compared to those without HT, and some studies have suggested a potential protective effect of HT in terms of recurrence and disease-related mortality of PTC (42). However, controversies still exist regarding this association. In our study, we found that coexisting HT, as determined by pathological results and US findings, showed no association with lateral LN metastasis in patients with PTMC. Similarly, other studies have shown no significant association between HT and LN metastasis or recurrence rate in patients with PTMC when HT was defined based on thyroid autoantibodies or pathology (43). Furthermore, a meta-analysis reported that there was no relationship between HT and LN metastasis in patients with PTMC and that HT had a negative association with LN metastasis in PTC cases larger than 1 cm (44).

This study has several limitations that need to be acknowledged. Firstly, the retrospective design of the study may introduce selection bias and limit the generalizability of the findings. Secondly, the evaluation of vascularity using Doppler US was not conducted due to the lack of data, which could have provided valuable information on the vascularity of the thyroid tumor and gland. Thirdly, age- and sex-matched data were used as controls (N0 group), which means that the effects of age and sex as potential risk factors were not specifically evaluated in this study. Despite these limitations, this study is valuable as it assessed and analyzed US findings of both the main tumor and the thyroid gland, allowing for the identification of potential candidates for AS without relying solely on pathological findings.

In conclusion, factors including upper lobe tumor location and non-parallel shape, along with ETE and multifocality, were identified as independent risk factors for lateral LN metastasis in patients with PTMC, and skip metastasis is also more commonly observed in tumors of the upper lobe. Therefore, meticulous US examinations to predict LN metastasis that include an assessment of tumor location, number, orientation shape, and the presence of ETE beyond mere detection of LN metastasis are necessary in the decision-making process for AS in especially when primary tumor was found in upper lobe.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The Institutional Review Board of Chonnam National University Hwasun Hospital (No. CNUHH-2020-271) approved this study. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

JY: Data curation, Formal analysis, Investigation, Writing – original draft. JP: Data curation, Methodology, Writing – original draft. AH: Investigation, Software, Writing – review & editing. HK: Supervision, Validation, Writing – review & editing. H-CK: Conceptualization, Supervision, Writing – review & editing.