Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was introduced after two Japanese institutions, Kuma Hospital and the Cancer Institute Hospital, initiated clinical trials [1,2]. Since then, several prospective cohort studies and uncontrolled treatment series have reported outcomes of AS for patients with low-risk PTMC [3-9]. These studies suggest that AS can be considered as a treatment option for the disease. As a result, many countries have specified in their thyroid cancer treatment guidelines that AS can be considered for low-risk PTMC [10-15]. We conducted a Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) that enrolled 1,177 patients with low-risk PTMC from 2016 to 2020 [16]. Our study reported on various outcomes, including the progression rate of PTMC, sonographic features associated with progression, quality of life (QoL), surgical outcomes, and cost, comparing AS to surgery [6,17-22]. We continue to monitor and observe relevant indicators.

Current guidelines from most professional societies recommend applying AS primarily to PTMCs measuring 1 cm or less. This is because AS was initially introduced in Japanese studies for low-risk PTMCs under 1 cm, and subsequent research has built upon this foundation. However, the use of the 1 cm size criterion was based on the belief at the time that the prognosis of T1a (≤1 cm) and T1b (1–2 cm) tumors was different. Recently, several studies have reported that when adjusting for factors including treatment range, there is no difference in prognosis between T1a and T1b tumors [23-27]. These studies suggest that tumor size should not be the sole determinant. Other factors, such as more aggressive histological features or evidence of extrathyroidal extension (ETE), may play a more significant role in patient outcomes than size alone. Therefore, the focus is shifting towards a more comprehensive evaluation of tumor characteristics beyond just size [24,26-28]. Based on this evidence, the American Thyroid Association recommends thyroid lobectomy as sufficient treatment for low-risk, unifocal, intrathyroidal papillary and follicular carcinomas ≤4 cm. This perspective has also influenced the criteria for AS, and recently, studies on AS for low-risk papillary thyroid carcinoma (PTC) larger than 1 cm are underway [5,8,29-34]. This expansion of size criteria is based on the hypothesis that the comprehensive risk assessment of ‘low-risk’ is a more important factor than the absolute size of 1 cm in determining the immediate need for surgery for PTC. In studies that include PTC up to 1.5 cm as candidates for AS, initial tumor size (<1.0 cm vs. 1.0–1.5 cm) was not associated with the tumor progression of thyroid cancer during AS [7], and the results of studies published to date indicate that the progression rate of thyroid cancer is not different when comparing studies that observed PTMC (≤1.0 cm) with those that observed PTC up to 1.5 cm [7,30]. Furthermore, studies observing the natural course of PTC have reported that the growth rate of tumor may significantly slow down after reaching a size of approximately 1.0 to 1.5 cm, compared to the initial stages of development [33,35]. Taking this into consideration, if the criterion for applying AS is restricted to the conventional tumor size of 1 cm, there is a risk of performing surgery in cases of low-risk PTC which were detected too early during the initial phase of rapid growth, and show an increase in size during the subsequent follow-up period. To avoid such situations, there is a growing need to expand the size criteria.

Therefore, the aim of the second phase of the MAeSTro (MAeSTro-EXP), is to expand the inclusion criteria, to include tumors up to 1.5 cm and to clarify unclear aspects of the protocol from the original MAeSTro study. This phase will enable a comprehensive evaluation of progression free survival, surgical outcomes, risk factors for disease progression, QoL, medical costs, and factors influencing treatment decisions in patients with low-risk PTCs. The findings from this study may provide the clinical evidence needed to potentially expand the size criteria in current guidelines, which currently recommend AS for low-risk PTMCs measuring 1.0 cm or less. Additionally, MAeSTro-EXP plans to compare outcomes not only between institutions but also based on racial and socio-cultural differences, with participation from four institutions in South Korea and five institutions in Australia as part of this multinational, multicenter study.

In MAeSTro-EXP, the inclusion criteria for AS has expanded tumor size from MAeSTro, a previously conducted multicenter prospective cohort study, to include low-risk PTC with maximum diameter of 1.5 cm. Additionally, we clarified previously ambiguous inclusion criteria. Specific criteria for evaluating the US feature of ETE have now been outlined. ETE to the strap muscle is defined as the presence of strap muscle replacement on US. This definition stems from previous research, where the diagnostic accuracy of determining gross ETE to the strap muscle using a US finding of strap muscle replacement, was found to be higher compared to using US findings such as capsular abutment, disruption, and contour bulging [43]. According to the findings reported by Ito et al. [44], invasion into the trachea or recurrent laryngeal nerve was not observed in low-risk PTC cases with a size of less than 0.7 cm. Additionally, even in cases where the tumor size is 0.7 cm larger, tracheal invasion was not observed when the tumor interfaces with the tracheal wall at an acute or right angle. Therefore, in this study, tumors with a size equal to or greater than 0.7 cm and interfacing with the tracheal wall at an obtuse angle are defined as high-risk features and excluded from consideration for AS. To minimize or exclude the risk of invasion into the recurrent laryngeal nerve, stricter criteria were established. In cases where the tumor is located in the TE groove, it is excluded from consideration for AS regardless of its size if there is no intervening thyroid parenchyma between the tumor and the thyroid capsule. For tumors located near the thyroid dorsal capsule, exclusion from AS is implemented if the tumor is 0.7 cm or larger and exhibits the US finding of dorsal capsule abutment.

With the inclusion of low-risk PTC up to 1.5 cm in size as candidates for AS, determining the appropriate time to transition to surgery when the tumor size increases poses a challenge. Previous prospective cohort studies, including our original study MAeSTro [1,2,16,34], adopted identical criteria for disease progression and the transition from AS to surgery. This creates a dilemma where low-risk PTCs of the same size can become candidates for AS or targets for surgical removal based on the timing of their discovery. Most previous studies that considered low-risk PTMC as AS candidates focused on tumors with sizes ranging from 0.5 to 1.0 cm. In our original study, MAeSTro, the baseline tumor size in the AS group was 0.6±0.2 cm. Similarly, other studies reported an initial tumor size in the range of 0.6–0.8 cm [1,2]. Consequently, applying the widely recognized progression criteria for tumor size, which is an increase of 3 mm or more in the maximum diameter, indicates that most tumors requiring surgical removal are larger than 1 cm. This aligns well with the criterion for applying AS to tumors with a size of ≤1 cm. However, in MAeSTro-EXP, which allows low-risk PTC with a 1.5 cm size as AS candidates, a PTC starting at 0.8 cm and growing to 1.2 cm during AS may qualify for surgery if the criteria for progression and transitioning to surgery remain the same. Conversely, if the same low-risk PTC is initially found at a size of 1.2 cm, it could be considered eligible for AS. Therefore, in the MAeSTro-EXP protocol, two-step surgical indications are established as relative and absolute indications for surgery.

In this study protocol, we incorporated widely accepted progression criteria, including a 3 mm increase in the maximum diameter of the tumor, LN metastasis, distant metastasis, and the occurrence of new PTC, enabling comparability with other studies. We also included the criteria a 2 mm increase in at least two diameters of the tumor, which is one of the progression criteria adopted in our previous study, MAeSTro. The absolute indications for transitioning from AS to surgery align with the progression criteria for LN and distant metastasis, applying the same criteria. However, we have included tumor size and newly occurring PTC in the relative indications for surgery, allowing for a more flexible transition from AS to surgery. Meanwhile, invasion into cervical structures has been included in the absolute indications for surgery, leading to a more stringent approach. This approach ensures that surgery is not pursued merely based on progression but is reserved for cases where surgery is deemed necessary. Kinetic analyses of low-risk PTMC under AS conducted in Japan showed a significant decrease in growth activity after enlargement, and many cases entered a stabilized stage [35,45]. Therefore, Japan groups applying AS for low-risk PTMC do not immediately transition to surgery based solely on tumor size increase. AS can be maintained based on patient preference until the tumor reaches 1.3 cm. To date, when applying these criteria, there have been no reports of life-threatening recurrences or deaths from thyroid carcinoma [45]. Based on these research results, The consensus statements from Japan Associations of Endocrine Surgery indicated that AS could be allowed to continue until the tumor diameter reached 1.3 cm [10]. Additionally, a prospective study from Italy includes low-risk PTC up to 1.3 cm in size in AS on the basis of significant variations in US measurements and the contraction of paraffin-fixed tissue, which typically results in an underestimation of the actual histological size. Building on these previous studies and guidelines, the MAeSTro-EXP protocol allows for the continuation of AS for low-risk PTC until it reaches 1.3 cm. For tumors 1.3 cm or larger, if they do not stabilize and show rapid growth, we transition to surgery. However, if the growth rate is not rapid and does not meet other absolute indications for surgery, AS can be maintained until the tumor reaches 2.0 cm. If the tumor size surpasses 2.0 cm, we opt for transitioning to surgery, even if it does not meet the criteria for other surgical indications. This decision is based on ongoing prospective studies that set 2.0 cm as the maximum size for applying AS to low-risk PTC [29,32]. The criterion for rapid tumor growth rate was a 50% or more increase in volume change over a 6-month period. Previous studies suggested that changes in the maximum diameter were more useful than volume due to reported fluctuations [46]. However, this observation was made for small tumors with an average diameter of around 5 mm, where the baseline volume is very small. If the sum of the three axes is 1.5 cm or more, volume fluctuation is relatively small [46]. Therefore, we apply volume change when the maximum diameter is 1.3 cm or larger, ensuring no issues with this criterion.

The potential limitation of this study protocol is selection bias. Randomly assigning the treatment strategy for low-risk PTC for a clinical study could raise ethical concerns, as decisions regarding the treatment plan involve a shared decision-making process between patients and the medical team. Therefore, selection bias is unavoidable, and the outcomes of MAeSTro revealed that treatment decision was influenced by factors such as the patients’ baseline QoL and the attitudes of the consulting medical team towards AS. In this study, to conduct a more in-depth analysis of these influencing factors, we have prepared a more detailed patient and medical team survey than in previous studies.

Despite the aforementioned limitations, MAeSTro-EXP will be the first multinational prospective study of AS in patients with low-risk PTCs. It is a multidisciplinary study involving endocrinologists, thyroid surgeons, radiologists, and preventive medicine specialists from eight specialized referral hospitals in Korea and Australia. As a multinational study, MAeSTro-EXP provides a unique opportunity to investigate how socio-cultural backgrounds and racial characteristics influence management decisions for low-risk PTC. The outcomes of MAeSTro-EXP will contribute to the development of more optimal management strategies for low-risk PTC, aligning with the clinical, socioeconomic, and radiologic characteristics of the affected patients. Moreover, the results will offer definitive evidence that could validate the role of AS in the management of low-risk PTCs.

In conclusion, we have initiated a multinational, multicenter prospective cohort study, named MAeSTro-EXP, focusing on low-risk PTCs in Korea and Australia. This study compares AS with surgery. The outcomes from this prospective study will validate the role of AS and contribute to the development of personalized management approaches for low-risk PTC patients.