2024 Volume 71 Issue 1 Pages 7-21
Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.
A low-risk papillary thyroid microcarcinoma (PTMC) is a papillary thyroid carcinoma (PTC) measuring ≤10 mm in maximal diameter without high-risk features such as invasion to adjacent organs, clinical node metastasis, or distant metastasis (cT1acN0cM0). In the past, PTMCs have been confirmed in autopsy examinations (latent carcinoma) and in pathological specimens of the thyroid dissected for thyroid diseases other than carcinoma (incidental carcinoma). The incidence of latent PTMC ≥3 among Japanese women was reported as 3%–5.2%, which was more than 1,000 times higher than the prevalence of clinical thyroid carcinoma in Japanese women at that time [1]. A meta-analysis of 42 studies and 12,834 autopsies over six decades found that the prevalence of incidental differentiated thyroid carcinoma (iDTC) among the whole examination subgroups was 11.2% [2], indicating that iDTC is a common event.
Recent advances in ultrasound technology and the development of the ultrasound-guided fine needle aspiration cytology (FNAC) technique have greatly facilitated the detection and diagnosis of PTMC on medical checkup. Surgery has been widely adopted as the first-choice treatment for PTMC, and is not technically difficult. Indeed, in 2012, we reported the excellent postoperative prognosis of PTMC, with 5- and 10-year lymph node recurrence-free survival rates of 99% and 99%, distant recurrence-free survival rates of 100% and 100%, and cause-specific survival rates of 100% and 100%, respectively [3]. Favorable outcomes of PTMC were also reported in other countries. Hay et al. analyzed 900 patients with PTC ≤10 mm (including some high-risk cases) who underwent surgery between 1945 and 2004 (mean follow-up time, 17.2 years). They found that only 3 patients (0.3%) died of thyroid carcinoma, and the 20-year and 40-year tumor recurrence rates were 6% and 8%, respectively [4]. Yu et al. analyzed 18,445 PTMCs in the Surveillance, Epidemiology and End Results (SEER) Cancer Database from 1988 to 2007. They found that the 10-year and 15-year disease-specific survival rates were 94.6% and 90.7%, respectively, and that the significant risk factors for overall survival were age >45 years, male sex, African American or minority race, node metastasis, extrathyroid invasion, and distant metastasis. Forty-nine of the patients in their analysis (0.3%) died of a cancer-related cause and 45 of these had at least 2 risk factors [5].
In 1994, Takebe et al. reported that thyroid carcinoma was detected and cytologically diagnosed in 3.5% of the otherwise healthy women aged ≥30 years who visited their clinic for breast cancer screening, and 75% of their tumors measured ≤15 mm [6]. These findings suggested that (i) a large number of individuals have PTMC without any symptoms, and (ii) only a small portion of the tumors grow and become clinically significant. Therefore, most PTMCs are not unfavorable or life-threatening for most patients. Even though the prognosis is excellent if these lesions are surgically removed, routine performance of surgery for all PTMCs immediately after diagnosis should still be considered an overtreatment, when considering the adverse surgical events that occasionally occur, as described later.
Indeed, Akira Miyauchi at Kuma Hospital (Kobe, Japan) proposed in 1993 that immediate surgical treatment is not the best strategy for almost all PTMC patients, since most PTMCs remain small. In other words, many PTMC patients might be able to avoid unnecessary surgery throughout their lives. In contrast to surgery, the purpose of AS is not to prevent PTMC progression itself but to prevent unfavorable events associated with tumor progression. In 1993, no markers of PTMC progression that could be evaluated for cytological specimens had been identified (in fact, this remains the case today), and Miyauchi speculated that progressive PTMC cases could be identified during active surveillance (AS) by ultrasound. He also thought that conversion surgery (CS) at the time of slight disease progression during AS could provide ideal management for progressive PTMCs, as described later. Based on this reasoning, Miyauchi proposed a clinical trial of AS for low-risk PTMCs at a 1993 Kuma Hospital physicians meeting, and the trial was approved and started that year [1]. The Cancer Institute Hospital (CIH, Tokyo) performed their own investigation into the prognosis of symptomatic and asymptomatic PTC ≤10 mm. In their retrospective analysis, the 10-year cause-specific survival rate of symptomatic tumor was poor, at 74.1%, while that of asymptomatic cases was excellent, at 100% [7]. Based on their own data that the prognosis of PTMC is excellent, they initiated AS for PTMC in 1993.
AS was adopted as a management option in the guidelines issued by the Japan Association of Endocrine Surgeons/Japanese Association of Thyroid Surgery (presently known as the Japan Association of Endocrine Surgery) in 2010 and 2018 [8, 9]. In 2015, AS was also adopted by the American Thyroid Association (ATA) guidelines [10], and thereafter prospective and retrospective studies on the effectiveness of AS have been published from countries other than Japan; these are described in a later section. Consensus statements from the Japan Association of Endocrine Surgery and a position paper from the Japan Thyroid Association were also published in 2021 to contribute to the safe implementation of active surveillance for PTMCs [11, 12].
In the United States, Davies and Welch reported that the incidence of thyroid carcinoma increased by 2.4-fold between 1973 and 2002 and by 2.9-fold between 1975 and 2009 [13, 14], while the thyroid cancer mortality rate remained stable. In the same reports, the authors described that the incidence of PTCs measuring ≤20 mm, including PTMCs, increased with time, while the incidences of larger PTCs remained almost stable, and although the incidence of thyroid cancer increased, mortality from thyroid cancer remained stable. These results suggest that small PTCs were overtreated in the U.S. over these periods. In South Korea, it was reported that the incidence of thyroid carcinoma increased by 15-fold between 1993 and 2011, which was largely because of the national screening program for thyroid carcinoma with ultrasound; during that period, thyroid carcinoma mortality did not change but the rate of surgical complications increased significantly [15].
A significant increase in the incidence of thyroid carcinoma but stable thyroid carcinoma mortality was also reported in Italy, France, England, Scotland, Australia, Spain, and Nordic countries [12, 16]. Due to the continued spread of the use of imaging methods such as CT, MRI, and ultrasound examinations, the likelihood of the detection of small thyroid nodules has increased, and the widespread availability of ultrasound-guided FNAC has made the diagnosis of small PTCs much easier, resulting in unnecessary surgical interventions for small carcinomas.
A fundamental first step when considering AS is to determine whether or not a patient’s PTMC is suitable for AS. Tumors with high-risk features such as clinical node metastasis, clinical distant metastasis (very rare), or aggressive cytology (very rare) are inappropriate for AS, and immediate surgery (IS) is strongly recommended for them. Tumors that may cause vocal cord paralysis by invasion to the recurrent laryngeal nerve and those showing obvious invasion to the trachea are also strong candidates for IS. In addition, the evidence supporting the choice of AS for pediatric patients is not sufficient.
3.1.2 Should the M factor be investigated?Clinical distant metastasis is very rare in PTMC. A meta-analysis study published in 2008 showed that only 35 of the 9,313 included patients (0.4%) showed distant metastases at diagnosis [17]. In 2011, Yu et al. demonstrated that, among patients in the SEER database of 18,445 patients with PTMC, only 0.5% were positive for distant metastasis [5]. In 2016, A single-institution study from Korea revealed that only 12 of the 8,808 patients (0.14%) with PTMC had distant metastasis. Of the 12 patients, 10 were classified as cases of cN1, and the remaining 2 as having pN1 (cN0) [18]. Kawano et al. reviewed chest CT scans of 1,000 patients with PTMC who underwent the chest CT examination as a routine preoperative practice and then had immediate surgery for their PTMC; none of the patients showed pulmonary metastasis [19]. Therefore, we currently conclude that investigation of the M factor is not necessary before AS for PTMC.
3.1.3. Risk assessment of the suitability of AS for PTMC by imaging studies: ideal, appropriate and inappropriateRisk assessment with neck ultrasound is the key for picking up patients with PTMC suitable for AS. A solitary tumor buried in the thyroid is ideal for AS (Fig. 1a). Multiple tumors (Fig. 1b) and tumors suspected of minimal invasion to the thyroid capsule anteriorly are considered appropriate for AS (Fig. 1c) [20]. Nagaoka et al. clearly demonstrated that multiplicity was not a significant risk factor for PTMC progression [21]. For a detailed evaluation of the relationship between the tumor location and the trachea and/or the recurrent laryngeal nerve, a CT examination may provide better information. Regarding PTMCs attached to the trachea, it is important to evaluate the angles formed by the tumor surface and the tracheal cartilage. If the angle is acute, the tumor is appropriate for AS, but if it is obtuse, IS is strongly recommended (Fig. 1d, e). In a series of PTMCs ≥7 mm attached to the trachea, 19% of those forming obtuse angles between the tumor surface and tracheal cartilage showed significant invasion to the trachea requiring a resection of tracheal cartilage with or without resection of the tracheal mucosa, whereas none of the tumors forming right or acute angles showed such a significant tracheal invasion [22].
a: A solitary papillary thyroid microcarcinoma (PTMC) buried in the thyroid (Ideal). b: Multiple PTMCs in thyroid tissue (see arrows) (Appropriate). c: PTMC suspected of anterior invasion (Appropriate). d: PTMC attached to the trachea with an acute angle (arrows) (Appropriate). e: PTMC attached to the trachea with an obtuse angle (arrow) (Inappropriate). For this case, a CT examination was better for the evaluation than ultrasound. f: PTMC located at the dorsal side but with normal thyroid tissue (arrow) along the course of the recurrent laryngeal nerve (Appropriate). g: PTMC located at the dorsal side, without normal thyroid tissue along the course of the recurrent laryngeal nerve (Inappropriate).
The positional relation between the tumor and the recurrent laryngeal nerve is also important. If the tumor has normal thyroid tissue to the course of the recurrent laryngeal nerve, it is appropriate for AS (Fig. 1f), but if not, IS should be considered (Fig. 1g). Our research group has also demonstrated that among PTMCs ≥7 mm, 9% of the tumors that have no normal thyroid tissue between the tumor surface and the course of the recurrent laryngeal nerve showed significant invasion requiring a partial layer resection or a complete nerve dissection with reconstruction using the ansa cervicalis, and otherwise, no significant invasion was detected [22]. More recently, Newman et al. demonstrated that, in small well-differentiated PTC ≤2.0 cm, recurrent laryngeal nerve invasion was a rare event (0.8%), but tumors ≥0.9 cm and located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions ran a risk of recurrent laryngeal nerve invasion and were thus unsuitable for AS [23].
3.1.4. The rarity of aggressive cytology in PTMCWe regard the cases with aggressive cytology as a contraindication of AS. Gamboa-Domintuez et al. showed that 19 of the 229 patients with PTC were pathologically determined to have the tall cell variant and 6 cases had aspirates with tall cells [24]. Lee et al. demonstrated that 4.9% and 6.0% of PTCs in their series were cytologically diagnosed with the tall cell variant, and classic PTC with tall cell features, respectively [25]. As a setting for PTMC, however, aggressive cytology is extremely rare. Miyauchi et al. reported that 2 of 5,646 PTMCs had cytological reports suggestive of poor or aggressive types and were treated with immediate surgery; however, the final pathological reports of the two cases were conventional-type PTC [26]. The indication of cytology for PTMC is discussed in Section 3.2.
3.1.5. The possibility for CS after ASPatients and physicians should note that, even though the PTMC is regarded as being ideal or appropriate for AS, there is always the possibility of surgical removal by CS in the future. Sasaki et al. demonstrated that disease progression was the most likely reason for CS [27]; the management of AS is based on the assumption that CS is required in a small percentage of cases with tumor progression.
3.2. Performing FNAC at the initiation of ASAt Kuma Hospital, we currently perform a cytological examination for suspicious nodules ≥5 mm, because the Japanese Guidebook for Thyroid Ultrasound Diagnosis issued by the Japan Association of Breast and Thyroid Sonology recommends an FNAC for suspicious nodules ≥5 mm [28]. The guidelines conducted by ATA do not recommend FNAC for subcentimeter nodules with a high suspicion sonographic pattern [10] and ETA recommends active surveillance for such nodules, provided that there are no abnormal lymph nodes and the patient is willing to accept regular ultrasound scanning [29]. The guidelines issued by the National Cancer Network, the American College of Radiology and the European Society for Medical Oncology do not recommend FNAC for nodules ≤10 mm in principle [30-32].
However, in our situation, if we do not cytologically diagnose a nodule and do not tell the patient that he or she has PTMC, the patient might visit another facility, undergo an FNAC, and be told that he or she has thyroid cancer. The patient should also be told that Kuma Hospital failed to diagnose the PTMC, and that they underwent surgery unnecessarily. Such an unfortunate situation both for patients and Kuma Hospital should be avoided. Therefore, we perform FNAC and describe the cytological results to the patient as they are. If the nodule is cytologically diagnosed as PTMC, we tell the patient that his or her nodule was highly suspicious for PTC and ask him or her to make constant follow-up visits to our hospital if undergoing AS. Even though no cytological evidence of malignancy is available for a nodule suspected of being a PTMC on ultrasound findings, we always tell the patient that he or she may have PTMC and urge close follow-up at our clinic.
3.3. Recommendations for and the implementation of ASIn the past, patients at Kuma Hospital were informed of the cytological diagnosis of PTMC, then presented with two management options (AS and IS) as equally recommended alternatives, and allowed to choose their preferred option. At present, because of the accumulation of favorable outcomes of patients who chose AS, we recommend AS to patients as an initial management approach. As described in Section 3.1, we do not perform a systemic examination for distant metastasis before starting AS.
At Kuma Hospital, the intervals for the ultrasound checkups for AS are 6 months at the second visit and 12 months thereafter, and these were adopted in the Consensus Statements put out by the Japan Association of Endocrine Surgery [11]. At every visit, an ultrasound evaluation should be performed to check for changes in the tumor size and to determine whether new suspicious enlarged lymph nodes have appeared. A tumor is regarded as enlarged if its maximal diameter has increased by ≥3 mm compared to the value obtained at the initiation of AS. However, if a patient prefers to stay under AS and the tumor is not present at a risky location (especially towards the trachea or the recurrent laryngeal nerve), the patient’s AS could be continued until the tumor size becomes a little larger than 10 mm (e.g., 13 mm). For suspicious nodes, we perform an FNAC and measure the thyroglobulin (Tg) level in the wash-out of the FNAC needles. If the patient is cytologically diagnosed as having PTC metastasis or if the Tg levels in the wash-out are high, we recommend conversion surgery (CS).
The concept of AS was not immediately accepted by all patients and physicians after the initiation of the first clinical trial, even at Kuma Hospital. The proportion of patients who chose AS differed widely among attending physicians and changed over time. Between 1993 and 1997, only 30% of patients at Kuma Hospital chose AS, but the incidence increased to 88% between 2014 and 2016 [33]. At present, approximately 95% of new PTMC patients at Kuma Hospital choose AS (our unpublished data). The accumulation of AS data has enabled physicians to recommend AS with greater confidence than before, which may explain the marked increase in the frequency of PTMC patients who choose AS.
In 2003, the first report of the outcomes of patients who underwent AS was published in Japan: the cases of 162 patients were analyzed, and the results revealed that the enlargement rate (size increase by ≥3 mm compared to the size at the initiation of AS) and nodal metastasis appearance rate (confirmed by cytology) were 10.2% and 1.2%, respectively [34]. The first report from CIH published in 2010 demonstrated that during the AS, 7% of the tumors were enlarged and 1% showed the appearance of node metastasis [35]. Several institutions in other countries published prospective studies thereafter, and all of them showed favorable outcomes as summarized in Table 1 [21, 26, 34-45].
Results of prospective studies of active surveillance (AS) for small papillary thyroid carcinomas (PTCs)
| Institution, location, year [ref.] |
No. of patients (tumors) |
AS period | Definition of enlargement | Enlargement rate | Node metastasis appearance rate | Predictors of tumor enlargement | Predictors of node metastasis appearance |
|---|---|---|---|---|---|---|---|
| Kuma Hospital (Kobe, Japan) 2003 [34] |
162 PTMC |
18–113 mos. (avg. 46.5 mos.) |
Size increase ≥3 mm | 10.2% | 1.2% | Not listed | Not listed |
| Kuma Hospital (Kobe, Japan) 2010 [36] |
340 PTMC |
18–187 mos. (avg. 74 mos.) |
Size increase ≥3 mm | 5-yr 6.4% 10-yr 15.9% |
5-yr 1.4% 10-yr 3.4% |
Not listed | Not listed |
| Kuma Hospital (Kobe, Japan) 2014 [37] |
1,235 PTMC |
18–227 mos. (avg. 60 mos.) |
Size increase ≥3 mm | 5-yr 4.9% 10-yr 8.0% |
5-yr 1.7% 10-yr 3.9% |
Age <40 yrs | Age <40 yrs |
| Kuma Hospital (Kobe, Japan) 2023 [38] |
2,705 PTMC |
1–15.7 yrs (median 5.5 yrs) |
Size increase ≥3 mm | 5-yr 3.0% 10-yr 5.5% 15-yr 6.2% |
5-yr 0.9% 10-yr 1.1% 15-yr 1.1% |
Age <40 yrs, high TSH level, tumor size ≥9 mm |
Age <40 yrs, male sex |
| Kuma Hospital (Kobe, Japan) 2023 [26] |
3,222 PTMC |
1–29.3 yrs (median 7.3 yrs) |
Size increase ≥3 mm | 10-yr 4.7% 20-yr 6.6% |
10-yr 1.0% 20-yr 1.6% |
Not listed | Not listed |
| CIH/NMS (Tokyo, Japan) 2010 [35] |
300 lesions of asymptomatic PTMC | 1–17 yrs (mean 5 yrs) |
Max. dia. increased by ≥3 mm | 7% | 1% | Not listed | Not listed |
| CIH/NMS (Tokyo, Japan) 2016 [39] |
384 with PTMC (480 tumors) | 1–23 yrs (avg. 4.3 yrs) |
Max. dia. increased by ≥3 mm | 5-yr 6.3% 10-yr 7.3% |
0% | Age <50 yrs, No/micro calcification Rich vascularization |
Not listed |
| CIH/NMS (Tokyo, Japan) 2021 [21] |
571 with PTMC (718 tumors) | 1–26 yrs (median 7.6 yrs) |
Max. dia. increased by ≥3 mm | 10-yr 9.9% 20-yr 18.0% |
10-yr 1.4% 20-yr 3.9% |
Age <40 yrs (either tumor enlargement or node metastasis appearance) | |
| MSKCC (U.S.) 2017 [40] |
291 with low-risk PTC ≤1.5 cm | 6–166 mos. (median 8.2 mos.) |
1. Max. dia. increased by ≥3 mm 2. Tumor volume increased by ≥50% |
1. 2-yr 2.5% 5-yr 12.1% 2. 2-yr 11.5% 5-yr 24.8% |
0% | Age <50 yrs | Not listed |
| MSKCC (U.S.) 2022 [41] |
483 with low-risk PTC ≤1.5 cm | 0.5–17 yrs (median 3.7 yrs) |
1. Tumor volume increase >72% 2. Max. dia. increase by >3 mm |
1. 59 (12%), 5-yr 15.9% 2. 472 (9%) 64 (15.9%) |
7 (1.4%) 5-yr 1.5% |
None | None |
| Multicenter study (South Korea) 2018 [42] |
370 PTMC |
23.6–47.0 mos. (median 34.1 mos.) |
1. Max. dia. increased by ≥3 mm 2. Tumor volume increased by ≥50% |
1. 3-yr 3.2% 5-yr 6.4% 2. 3-yr 17.3% 5-yr 36.2% |
8.6% | Age <45 yrs | Not listed |
| University of Antioqula (Colombia) 2020 [43] |
102 with low-risk PTC ≤1.5 cm | 0.2–112 mos. (median 13.9 mos.) |
1. Max. dia. increased by ≥3 mm 2. Tumor volume increased by ≥50% |
1. 2-yr 10.2% 2. 2-yr 23% |
0% | Not listed | Not listed |
| University of Pisa (Italy) 2020 [44] |
93 with low-risk PTC ≤1.3 cm | 6–54 mos. (median 19 mos.) |
1. Max. dia. increased by ≥3 mm 2. Tumor volume increased by ≥50% |
1. 2.2% 2. 16% (No time sequence analysis) |
1.1% (No time sequence analysis) | Not listed | Not listed |
| Multicenter study (South Korea) 2022 [45] |
755 with PTMC (Multicenter study) | Median 41.4 mos. (mean 41.4 ± 16.0) |
Size increase ≥3 mm in one dia., ≥2 mm in two dias. or appearance of extrathyroid extension and node metastasis | 2-yr and 5-yr progression rate, 5.3% and 14.2% | Age <30 yrs, male sex and tumor size ≥6 mm (independent predictors of progression) | Not listed | |
AS: active surveillance; avg: average; CIH: Cancer Institute Hospital; mos: months; MSKCC: Memorial Sloan Kettering Cancer Center; NMS: Nippon Medical School; PTC: papillary thyroid carcinoma; PTMC: papillary thyroid microcarcinoma; yrs: years.
The most recent study conducted at Kuma Hospital enrolled a series of 3,222 patients with PTMC. The 10-year and 20-year tumor enlargement rates were 4.7% and 6.6% and the 10- and 20-year node metastasis appearance rates were 1.0% and 1.6%, respectively [26]. The most recent study from CIH/Nippon Medical School (NMS) reported 10- and 20-year enlargement rates of 9.9% and 18% and 10- and 20-year node metastasis appearance rates of 1.4% and 3.9%, respectively [21]. None of the patients developed distant metastasis or died of thyroid carcinoma during their AS, although one patient in our series developed a lung metastasis after choosing to undergo CS as described in Section 7.1.
4.2. Evaluations of tumor enlargementIn our first study, we defined tumor enlargement as an increase of ≥3 mm in the tumor maximal diameter because we regarded ±2 mm as observer variation [33]. Professor Michael R. Tuttle at the Memorial Sloan Kettering Cancer Center proposed that the evaluation be conducted using tumor volume, with a tumor volume increase of ≥50% defined as tumor enlargement [40]. He and his colleagues demonstrated that the 2-year and 5-year maximal diameter increase rates were 2.5% and 12.1% and the 2- and 5-year tumor volume increase rates were 11.5% and 24.8%, respectively [40]. Based on these findings, the use of tumor volumes rather than maximal tumor diameters as an index of tumor enlargement would seem to more precisely reflect carcinoma progression. However, in the case of a 1-mm increase of a 7-mm tumor, this would correspond to a 49% increase in tumor volume. We therefore think that a tumor volume increase of ≥50% is too early to use a cutoff for recommending CS.
A Korean group evaluated PTC enlargement by the tumor volume doubling time (TV-DT). They enrolled 273 PTC patients who underwent AS for more than 1 year and demonstrated that 10.3%, 5.1%, 6.2%, and 6.3% of the patients had a TV-DT of <2 years, 2–3 years, 3–4 years, and 4–5 years (rapid-growing group), with the remaining 71.8% having a TV-DT of ≥5 years (stable group) [46]. They concluded that TV-DT is a good indicator of the growing velocity of PTCs during active surveillance. However, the cutoff at a TV-DT of 5 years between the rapid-growth group and stable group is likely too crude for the accurate evaluation of tumor growth.
The accumulated data show that the growth rate of PTMCs is not uniform. Miyauchi et al. studied the tumor volume kinetics of 169 patients with PTMC during AS by calculating the tumor volume doubling rate (TV-DR), which is an inverse of the TV-DT; they observed that 3%, 22%, 57%, and 17% of the tumors showed moderate growth (TV-DR >0.5), slow growth (0.1–0.5), stable disease (–0.1 to 0.1), and clear shrinkage (<0.1), respectively, indicating that spontaneous disease regression can occur in PTMC during AS [47]. In the same study, Miyauchi et al. also calculated the hypothetical TV-DR of PTMCs before presentation based on the assumption that a single carcinoma cell measuring 10 μm was present at birth and grew at a constant growth rate. They suggested that, in most cases, the tumor growth activity before presentation should have been much higher than that during AS [47]. These findings strongly suggest that the tumor growth activity is generally higher before presentation and decreases thereafter. Ito et al. reported that the TV-DR of PTMCs decreased significantly after enlargement (both by a size increase and a tumor volume increase), which supports the findings described by Miyauchi et al. [48].
4.3. Factors related to the progression of PTMC 4.3.1. AgeAs shown in Table 1, most of the prospective studies demonstrated that young age (<40 years, <45 years, or <50 years) is a significant predictor of PTMC progression. Both of the two Japanese institutions showed that age <40 years independently affected PTMC progression [21, 37, 38]. A systematic review and meta-analysis published in 2020 also demonstrated that the pooled risk ratio for tumor growth of ≥3 mm in maximal diameter in individuals aged 40–50 years compared with younger individuals was 0.51 when adjusted for confounders and the unadjusted risk ratio of this outcome for individuals 40 years or older was 0.55 [49].
Based on the above findings, one might conclude that immediate surgery is more suitable for the management of young PTMC patients. However, Miyauchi et al. estimated the lifetime probabilities of tumor enlargement in age decade-specific enlargement rates [50], and they observed that the lifetime probability of tumor enlargement rates was 48.6% for patients in their 20s (at presentation), 25.3% for the 30s, 20.9% for the 40s, 10.3% for the 50s, 8.2% for the 60s, and 3.5% for the 70s. This indicates that more than half of PTMCs in patients in their 20s (100% minus 48.6%) could be stable throughout their lives. Moreover, the growth rate generally becomes low with advanced age, making it less likely that patients will suffer unfavorable events related to tumor growth. Even though CS is required, it is not technically difficult, and Fujishima et al. showed that the postoperative prognoses of patients who underwent IS and CS after AS were not significantly different [51], as described in Section 5. Taken together, these findings indicate that young adult patients with PTMC could be candidates for AS.
4.3.2. SexSome prospective studies for the active surveillance of PTMC demonstrated that male sex was related to tumor enlargement and the appearance of node metastasis (Table 1) [38, 45].
4.3.3. Serum thyroid-stimulating hormone (TSH) levelsTable 2 depicts the relationship between the TSH levels of patients with PTMC and the outcomes of AS. An analysis of TSH was performed retrospectively in all of these studies. The studies’ conclusions regarding whether the TSH level is related to PTMC progression were conflicting. Two Korean studies published in 2018 and 2023 showed that a high TSH level was significantly related to PTMC progression [52, 53], and the latter study indicated that effective levothyroxine treatment prevented the progression of the PTMC in patients <50 years old [53].
Relationship between TSH levels and PTMC progression during AS (all were retrospective studies)
| Institution, location, year [ref.] |
No. of patients (tumors) | AS period | Definition of progression | Classification of TSH levels | Effect of TSH to PTMC progression |
|---|---|---|---|---|---|
| Samsung Medical Center (Seoul, South Korea) 2018 [52] |
127 tumors in 126 patients | 17.0–37.0 mos. (median 26.0 mos.) | Volume increase >50% Max. dia. increase ≥3 mm Novel appearance or metastatic nodes |
Tertiles of time-weighted TSH: lowest, middle, and highest | 1. PTMC progression was detected in 28 patients (19.8%). 2. The PFS rate of PTMCs of patients with TW-TSH >2.50 was lower (p < 0.001) than that of the patients with TW-TSH ≤2.50. 3. The HR for PTMC progression of highest TSH tertile was 3.55 (95%CI, 1.22–10.28; p = 0.020) in a multivariate analysis. |
| Samsung Medical Center (Seoul, South Korea) 2022 [53] |
234 patients 1,061 person-yrs | 43.0–59.0 mos. (median 51.0 mos.) | Volume increase >50% Max. dia. increase ≥3 mm Novel appearance or metastatic nodes |
Tertiles of time-weighted TSH; lowest, middle, and highest | 1. Ninety-three patients showed PTMC progression. 2. The PFS rates differed significantly (p = 0.031) among the lowest, middle, and highest TW-TSH tertiles. 3. The highest TW-TSH was the risk factor strongly associated with PTMC in patients <50 yrs old. 4. For patients <50 yrs old, the PTMC progression rate successively increased in the order of effective, no, and ineffective LT4 treatment groups. |
| Cancer Institute Hospital (Tokyo, Japan) 2014 [54] |
415 tumors in 322 patients | 2–22 yrs (mean 6.5 yrs) | Max. dia. increase ≥3 mm | Baseline TSH concentration; <0.50 (18 tumors), 0.50–1.99 (260 tumors), 2.00–3.99 (126 tumors), or ≥4.00 mIU/L (11 tumors) | 1. Zero, 15 (6%), 10 (8%), and 0 tumors were enlarged in baseline TSH concentration <0.50, 0.50–1.99, 2.00–3.99, and ≥4.00 mIU/L, respectively. 2. Tumor size-PFS rates did not differ between patients with baseline TSH <2.0 and ≥2.0 mIU/L. 3. A logistic regression model analyzing the association between baseline TSH and PTMC growth showed an odds ratio of 1.01 (95%CI, 0.66–1.29). 4. No significant correlations were detected between the mean TSH during follow-up and the change in the PTMC volume (r = 0.019, p = 0.70). |
| Kuma Hospital (Kobe, Japan) 2023 [37] |
2,705 patients | 1.0–15.7 yrs (median 5.5 yrs) | 1) Max. dia. increase ≥3 mm 2) Novel appearance of metastatic nodes |
Detailed TSH score >3 (within the normal range and lower than the mean of the normal range), and ≥3. | 1. Ninety-two (3.4%) and 22 patients (0.8%) showed tumor enlargement and novel appearance of node metastasis. 2. In the subset of patients <40 yrs old, a TSH score ≥3 was an independent predictor of tumor enlargement, but not in patients ≥40 yrs old. 3. The TSH score was not related to the appearance of metastatic lymph nodes. |
| Kuma Hospital (Kobe, Japan) 2023 [55] |
2,509 patients; 1,935 did not receive LT4 during AS (group IA), 252 started LT4 during AS (group IB), and 322 were administered LT4 before or at diagnosis (group II) | Group IA: 12.2–211.2 mos. (median 78.8 mos.) Group IB: 16.1–200.4 mos. (median 89.2 mos.) Group II: 14.5–179.8 mos. (median 78.7 mos.) |
Evaluated by the change in the tumor volume doubling rate (TVDR) (/yr) | Same as above. | 1. In group IB patients, the detailed TSH score significantly decreased after LT4 administration (p < 0.01), and TVDR also decreased after LT4 administration (p = 0.08). 2. The proportions of group IB patients with rapid or moderate growth significantly decreased after LT4 administration (p < 0.01). |
AS: active surveillance; CI: confidence interval; HR: hazard ratio; LT4: levothyroxine; mos: months; PFS: progression-free survival; PTMC: papillary thyroid microcarcinoma; TSH: thyroid-stimulating hormone; yrs: years.
A Japanese study published in 2014 found no significant relationship between TSH levels and PTMC progression [54]. However, a 2023 study demonstrated that a TSH level higher than the lower normal limit was an independent predictor of tumor enlargement (but not of the appearance of node metastasis) for patients <40 years old [37]. Yamamoto et al. demonstrated that the PTMC growth activity of patients for whom levothyroxine treatment was initiated in the mid-course of active surveillance was reduced after the treatment [55]. Taken together, these findings suggest that a suppression of TSH to a mildly subnormal level by levothyroxine treatment (three months after treatment initiation as a guide) might be effective for preventing tumor enlargement (especially in young patients), but prospective studies are mandatory before conclusions can be made.
4.4. Ultrasound findingsThe CIH/NMS research group showed that a lack of calcification and the presence of rich vascularity are markers of PTMC progression [39]. However, they also reported that calcification appeared and vascularity waned during AS. Thus, PTMCs can undergo AS regardless of these ultrasound findings.
4.5. PregnancyPregnancy may cause an enlargement of thyroid nodule(s) because of the structural similarity between TSH and human chorionic gonadotropin, and one might expect that AS for the PTMCs of pregnant patients and patients who might become pregnant in the future is unfavorable. In the first report on such cases from Kuma Hospital, 4 of 9 patients (44.4%) showed PTMC enlargement during pregnancy [56]. However, in a second report the authors re-checked the entire series and corrected the results; only 4 PTMCs (8%) of the 50 pregnant patients showed a size increase ≥3 mm during pregnancy [57]. Two of these patients underwent surgery after delivery, and no postoperative recurrences have been detected. The remaining 2 patients are continuing the AS because the tumor size increase stopped after delivery. In our experience, most PTMCs are stable during pregnancy, and even in cases where they progress, CS can still be safely and effectively performed after delivery. The purpose of AS is to prevent unfavorable events associated with tumor progression rather than to prevent progression itself. Therefore, it is currently concluded that PTMCs in pregnant women and women of reproductive age can still be candidates for AS.
Some patients are undergoing CS after AS for various reasons, e.g., the progression of PTMC or coexisting thyroid or parathyroid disease, a change in the patient’s wishes, or a physician’s recommendation. At Kuma Hospital, Sasaki et al. investigated the difference in the incidence of CS by dividing the whole cohort into two periods: a first-half period (February 2005 to November 2011) and second-half period (December 2011 to June 2017). The cumulative incidence of CS performed for any reason at 5 years fell significantly from 12.3% in the first-half period to 4.2% in the second-half period, which may have occurred because the accumulation of favorable outcomes of this management strategy contributed to the confidence of physicians, as well as the higher trust and better knowledge of PTMC on the part of their patients [58].
At Kuma Hospital, patients who had undergone a CS because of disease progression had larger tumors, were more frequently pathological node-positive, and had higher cell-proliferating activity (evaluated by the Ki-67 labeling index) compared to the patients who had undergone IS; however, the postoperative prognosis did not significantly differ between these two groups [51]. These findings suggest that AS efficiently selected progressive PTMCs requiring surgical treatment. Sasaki et al. showed that the incidence of unfavorable surgical events such as transient/permanent vocal cord paralysis and hypoparathyroidism did not differ significantly between patients who underwent CS after AS and those who underwent IS [58]. These findings are important and support the validity of AS as the initial management for PTMCs.
Miyauchi et al. compared the prognosis of 5,646 PTMC patients between those who underwent AS (3,222 patients) and those who underwent IS (2,424 patients) [26]; the 10-year and 20-year lymph node metastasis occurrence/recurrence rates of the AS group were 1.1% and 1.7%, and those of the IS groups were 0.4% and 0.7%, respectively. The lymph node occurrence/recurrence rates of both groups were excellent, although the IS group showed a slightly better prognosis (which may have occurred because 10.3% of the IS group in this series underwent prophylactic lateral neck dissection at their initial surgery). The 10-year and 20-year remnant thyroid recurrence rates of the IS patients who underwent a hemithyroidectomy were 1.0% and 2.7%, respectively [26]. The proportion of the patients who underwent one or more surgeries was significantly higher in the IS group (100%) than in the AS group (12.3%) (p < 0.01), and the incidence of patients who underwent two or more surgeries was also significantly higher in the IS group (26/2,424; 1.07%) than in the AS group (3/3,222; 0.09%) (p < 0.01) [26]. In addition, the overall mortality rate did not differ significantly between the AS and IS groups [58]. Taken together, these data demonstrated that (i) the oncological outcomes of patients in the AS and IS groups were not meaningfully different, and (ii) the IS group had a higher incidence of surgical interventions than the AS group.
6.2. Unfavorable eventsOda et al. reported that permanent vocal cord paralysis and permanent hypoparathyroidism occurred in 0.2% and 1.6% of their patients, respectively [59]. However, these incidences were the results of surgical treatments being performed by specialists in thyroid surgery. If the surgeries had been performed by non-specialists, the incidence of unfavorable surgical events would have been much higher. We must also note that such events would not have occurred in patients who chose AS and did not undergo surgery.
Sasaki et al. recently reviewed larger cohorts and confirmed that the patients who underwent IS had significantly higher incidences of unfavorable events than the patients who chose AS [58]; they also reported the following data for IS and AS: levothyroxine administration after diagnosis, 65.2% vs. 25.2%; permanent vocal cord paralysis, 0.9% vs. 0%; and permanent hypoparathyroidism, 1.4% vs. 0.2%.
6.3. Medical costsSince the costs for examinations, surgical treatments, and medical prescriptions vary according to regions and countries, discrepant results have been reported regarding the medical costs of AS and IS for PTMC [60-64]; AS was more economical in Hong Kong and in young patients in the U.S., whereas surgery was preferred economically for older patients in the U.S. and in Korea for long-term follow-up. In Japan, most clinical practices are covered by the national health insurance system. Our calculations based on our practice at Kuma Hospital showed that the total cost of immediate surgery and postoperative care for 10 years (including prescription medicines such as L-thyroxine) was USD 68,437/person, which was 4.1 times the total cost of 10 years of active surveillance (62,052/person) in the year 2017 [65].
6.4. Quality of life (QoL)Several studies have compared the QoL of patients between those who underwent AS and those with IS [66-70], as summarized in Table 3. All studies demonstrated that physical complaints such as neck discomfort and weak voice were less severe in the AS group than in the IS group. In contrast, the results concerning psychological impacts were incongruous: of the three reports from Japan, one study showed that the severity of anxiety was greater in the AS group than the IS group [67], but in the other two studies the anxiety severity was greater in the IS group [68, 70]. In our institution, the incidence of patients who chose AS differed highly depending on the physicians [33], probably because of differences in the attitudes of attending physicians regarding AS. Thus, we conjecture that the attitude of physicians toward their patients with PTMC also reflects the anxiety, worries and psychological problems of PTMC patients under AS.
Difference in quality of life (QoL) between patients who underwent active surveillance (AS) and patients who underwent immediate surgery (IS)
| Institution, location year [ref.] |
Study design | Instruments of measurement | Observation period | Summary of the results |
|---|---|---|---|---|
| University of Ulsan College of Medicine (South Korea) 2019 [66] |
QoL was evaluated for 74 and 148 patients who underwent AS and IS (lobectomy), respectively using SF-12 and THYCA-QoL | SF-2, THYCA-QoL, and FoP | Median 29.6 mos. for the AS group and 38.0 mos. for the IS group | 1. SF-12: Physical health, social functioning, and emotional problems scores were lower in the IS group than in the AS group. 2. THYCA-QoL: In the univariate and multivariate analyses, the neuromuscular, throat/mouth, and problems with scar scale scores were stronger in the IS group than in the AS group. |
| Tokyo Women’s Medical University (Tokyo, Japan) 2020 [67] |
Cross-sectional study for 20 and 30 patients who underwent AS or IS, respectively | STAI and an originally established system (VAS) | 0–8.36 yrs (median 4.1 yrs) | 1. Patients in the AS group showed higher scores in both state anxiety and trait anxiety. 2. Regardless of whether AS or IS was selected, the trait anxiety score was positively associated and the observation time was negatively associated with the state anxiety score. 3. Discomfort in the neck, weak voice, and nervousness about neck appearance were less frequent complaints in the AS group compared to the IS group. |
| Kuma Hospital (Kobe, Japan) 2020 [68] |
QoL was evaluated for 298 and 49 patients who underwent AS and operation | THYCA-QoL and HADS | Median 56.5 mos. (32–88 mos.) for the AS group and 84 mos. (64–130 mos.) for the OP group | 1. THYCA-QoL: The OP group had more complaints about voice, psychological problems with a scar, and weight gain than the AS group. 2. HADS: The AS group had significantly better anxiety, depression, and total scores than the OP group. |
| Multicenter study (South Korea) 2021 [69] |
QoL surveys for 674 and 381 patients who chose AS and IS, respectively | A Korean version of a thyroid-specific QoL questionnaire | Median 24.4 mos. | 1. Of 817 subjects who completed baseline QoL surveys, 2-year QoL was good in order of AS (n = 500), IS (hemithyroidectomy) (n = 238) and IS (total thyroidectomy) (n = 79) groups. 2. Among 101 subjects who underwent CS, 35 who underwent CS due to disease progression had better QoL than 66 who showed no disease progression. |
| Nippon Medical School (Tokyo, Japan) 2023 [70] |
Patients with low-risk PTC (<15 mm) who completed the PRO survey. The AS and surgery groups had 249 and 32 patients, respectively. | STAI, SF-36v2, VAS | After matching, median 4.0 yrs (0.96–16.1 yrs) for the AS group and 4.0 yrs (0.97–16.1 yrs) for the surgery group | 1. After matching, the AS group showed significantly better trait anxiety and mental component summary scores than the surgery group. 2. The surgery group had better role-social component summary scores. 3. In the AS group, trait anxiety and the time from the onset were significant predictors of state anxiety. |
AS: active surveillance; FoP: fear of progression; HADS: Hospital Anxiety and Depression Scale; IS: immediate surgery; MCS: mental component summary; OP: operated; mos: months; PTMC: papillary thyroid microcarcinoma; SF-12: Short-Form Health Survey Questionnaire; SF-36v2: Short-Form 36 version 2; STAI: State-Trait Anxiety Inventory; THYCA-QoL: the thyroid cancer-specific quality of life questionnaire; VAS: visual analog scale; yrs: years.
AS is a treatment plan that involves closely watching a patient’s condition but not giving any treatment unless there are changes in test results that show the condition is getting worse. In this section, current limitations of AS are described.
7.1. Lack of markers predicting PTMC progressionAll advanced PTCs were once PTMCs, indicating that, although very rare, PTMCs can grow rather rapidly and metastasize to distant organs. Our most recent study demonstrated that one of the 2,424 patients (0.04%) who underwent IS developed recurrence to the lung 12 years after the surgery, and one of the 3,222 AS patients (0.03%) who underwent a CS after 2 years of AS (at the behest of the patient) showed pulmonary metastasis 12 years after the diagnosis; these 2 patients were alive 18.8 years and 18.4 years after the initial diagnosis, respectively [26]. Indeed, in the future it would be ideal if physicians could know the future clinical course of a PTMC in advance. If rapid growth and dire prognosis (if not resected) were expected, surgery in the early phase could be the best strategy.
To date, however, no pathological or molecular markers have been identified that can predict aggressive growth of a PTMC at the time of an FNAC. Hirokawa et al. reported that PTMCs that were surgically removed due to tumor enlargement had significantly higher Ki-67 labeling index values than those without tumor enlargement [71], but this cannot be applied for cytological specimens. Although previous studies found that TERT mutations were related to poor prognosis in clinical PTCs [72, 73], these are very rare events in PTMCs and are not associated with patient prognosis [74-78]. The identification of predictive markers would be a great help for the identification of potentially progressive PTMCs indicated for immediate surgery and careful follow-up.
7.2. It remains unknown when AS can be discontinuedAs can be seen in Table 1, some studies showed that the growth activity of PTMC decreases with age, but in clinical PTC, old age is a very significant predictor of poor prognosis [79], indicating that if a PTMC becomes clinically significant, the older patient may have a dire prognosis. Tuttle et al. studied 482 patients with PTMC and reported that only one of the 482 patients began to show rapid PTMC-growth after being under AS for >4 years [41]. The patient underwent a CS and was diagnosed with poorly differentiated carcinoma based on a pathological examination. Taking the results of these investigations together, we have to conclude—at least at present—that AS should be continued for as long a term as possible. However, this would not be considered a drawback of AS, since most patients who undergo surgery require lifetime follow-up and, as necessary, levothyroxine (and vitamin D) treatment.
Active surveillance is an ideal and beneficial management for PTMC, and if appropriately implemented, it is suitable for the initial management for cT1aN0M0 patients.
Yasuhiro Ito is a member of Endocrine Journal’s Editorial Board. None of the authors have any potential conflicts of interest associated with this research.
