Tumor Volume Doubling Time in Active Surveillance of Papillary Thyroid Microcarcinoma: A Multicenter Cohort Study in Korea

Abstract

Background:

Some papillary thyroid microcarcinomas (PTMCs) may progress with tumor enlargement or development of new lymph node (LN) metastasis during active surveillance (AS). This study evaluated the relevant predictors of disease progression, especially new cervical LN metastasis.

Methods:

This was a long-term follow-up study conducted using a previous multicenter cohort of AS in Korea. After excluding 54 (14.2%) patients with a short follow-up duration, 326 PTMC patients were evaluated for tumor kinetics, including changes in tumor volume (TV) and TV doubling time (TVDT).

Results:

During a median follow-up duration of 4.9 years, 17 (5.2%, 95% confidence intervals [CI] 2.7–7.6%) patients showed a maximal diameter increase of ≥3 mm after a median of 4.0 years follow-up, while 9 (2.8%, CI 1.0–4.5%) developed new LN metastasis after a median of 2.2 years follow-up. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. The prevalence of new development of LN metastasis was higher in patients with TVDT <5 years (7.4%) than in those with TV ≥50% (3.2%). Furthermore, only TVDT <5 years was significantly associated with LN metastasis (p = 0.002). In univariate and multivariate analyses, TVDT <5 years was an independent risk factor for disease progression with respect to new development of LN metastasis (hazard ratio [HR] = 6.51, CI 1.73–24.50; p = 0.002) and tumor enlargement (HR = 20.89, CI 5.78–75.48; p < 0.001). Finally, 86 (22.6%) patients underwent delayed surgery, and the most common reason was patient anxiety.

Conclusions:

TVDT <5 years is a predictor of disease progression during AS in terms of new LN metastasis development as well as tumor enlargement. Determination of TVDT in the early phase of AS could help in predicting disease progression, tailoring follow-up intensity of AS and in determining if early surgical intervention is needed.

Introduction

Most papillary thyroid microcarcinomas (PTMCs) have an indolent nature and excellent clinical outcomes. Therefore, active surveillance (AS) instead of immediate surgery is a safe and effective alternative (1 –5). Since the incidence of disease-specific mortality and distant metastasis is extremely low (6), disease progression in the form of tumor enlargement or new lymph node (LN) metastasis are important clinical outcomes during AS.

Although their progress is usually very slow, some PTMCs may progress during AS. In a study conducted at the Kuma Hospital, 5- and 10-year cumulative rates of tumor enlargement, defined as maximal diameter increase of ≥3 mm, were 4.9% and 8.0%, respectively (2,7), and for newly developed LN metastasis were 1.7% and 3.8%, respectively (2). Based on this study, physicians have traditionally considered a maximal diameter increase of ≥3 mm as tumor growth. However, the fundamental question exists whether the tumor size enlargement is a clinically relevant sign of disease progression (7 –9). Furthermore, performing thyroid surgery immediately after maximal diameter increase of ≥3 mm remains debatable (10). In contrast, new LN metastasis development during follow-up requires management conversion from AS to immediate surgery. Therefore, it is crucial to investigate the factors that can predict disease progression, especially the development of new LN metastasis in the early phase of AS. This would help in tailoring the follow-up intensity of AS and determining if early surgical intervention is needed.

In a previous study, we found that tumor volume (TV) change is a more sensitive marker for evaluating tumor growth as compared with maximal tumor diameter increase for disease progression in the early stage (8). In addition, TV doubling time (TVDT) is a dynamic marker for the prediction of thyroid cancer growth. In this single-center study, TVDT <5 years was a good indicator of disease progression of PTMCs during AS, especially for tumor enlargement (11). Both TV ≥50% and TVDT <5 years are sensitive predictors of tumor enlargement, but it is unclear whether they can predict the development of new LN metastasis or which one is a better predictor of LN metastasis. Currently, there is limited literature regarding new cervical LN metastasis during AS of PTMCs (2,8 –13). Furthermore, the median follow-up duration in most previous studies was relatively short, and a long-term follow-up study is needed.

This study analyzed the follow-up data of a previous multicenter cohort of AS in Korea (8) and evaluated the most relevant predictors of disease progression during AS, especially new cervical LN metastasis. Various tumor and patient factors, including tumor kinetics, were evaluated.

Materials and Methods

Study design and patients

This study analyzed the long-term follow-up data from a previous multicenter AS cohort in Korea (8). Initially, 383 PTMC patients from three tertiary referral centers were screened: Asan Medical Center (AMC), Samsung Medical Center (SMC), and Seoul St. Mary's Hospital (SMH). Three patients who underwent immediate thyroid surgery instead of AS and 54 with a short follow-up duration (<3 years) were excluded (Fig. 1). Among these 54 patients, 7 died from other causes and other patients were lost to follow-up. Finally, 326 PTMC patients under AS were evaluated. The management and follow-up protocols for PTMC were as described previously (8). The study protocol was approved by the Institutional Review Board of the respective institutions (AMC: 2018-0354; SMC: 2018-02-079; and SMH: KC16OISI0414) (8). The need for informed consent was waived due to the retrospective design of the study.

FIG. 1.

Flowchart of the selection protocol for patients with PTMC during AS. AS, active surveillance; PTMC, papillary thyroid microcarcinoma.

Neck ultrasonography examination and evaluation of the findings

Neck ultrasonography (US) findings were retrospectively reviewed by experienced radiologists or endocrinologists at each center. All nodules were evaluated in the transverse and longitudinal planes for three-dimensional evaluation and TV measurement. US findings of the target nodule, including maximum tumor diameter, location, internal content, echogenicity of the solid portion, shape, margin, calcifications, and subcapsular location, were evaluated (1,14,15). The TV was calculated as follows (16): TV (mm³) = length (mm) × width (mm) × thickness (mm) × π/6. TV change was calculated as follows: [final TV (mm³) − initial TV (mm³)]/initial TV (mm³) × 100%. TVDT was also calculated using a previously described method (11,17). As seen in the equation, TV change was determined only by the initial and final volumes of the nodule, but TVDT was calculated using all available TVs.

Tumor location was classified as upper pole, middle pole, lower pole of the right/left thyroid gland, or isthmus. The internal content of the nodule was categorized according to the ratio of the cystic to the solid portion within a nodule. Echogenicity of the nodule was defined as a hypoechogenic pattern compared with an echogenicity pattern in the thyroid parenchyma and a marked hypoechogenic pattern as compared with that of the strap muscle. The nodule shape was categorized as ovoid to round or irregular, and the orientation was categorized as parallel or nonparallel. The tumor margins were classified as well-defined smooth, spiculated, lobulated, or ill-defined. Calcifications were categorized as microcalcification (calcification foci ≤1 mm), macrocalcification (calcification foci >1 mm), rim calcification (curvilinear or eggshell calcification), or none. When different types of calcification coexisted with microcalcification, the nodule was classified as macrocalcification or rim calcification rather than microcalcification (18). Subcapsular location of the nodule was defined as a nodule that abutted the thyroid capsule, without invading the thyroid parenchyma. Because patients with multifocal PTMCs underwent immediate surgery rather than AS, we did not consider multifocality as a variable in the analysis.

Definition and outcomes

The primary outcome of this study was disease progression during AS. Disease progression was defined as an increase in the maximal diameter of the nodule of ≥3 mm, and the development of new cervical LN metastasis on US. We evaluated the development of new cervical LN metastasis based on maximal diameter increase ≥3 mm, TV increase ≥50%, or TVDT <5 years. In additional analysis, we evaluated the development of new cervical LN metastasis based on TV increase ≥75% and ≥100%. We also evaluated the clinicopathological factors associated with newly developed LN metastasis and maximal tumor diameter enlargement. The secondary outcome was delayed surgery. Patients could undergo delayed thyroid surgery anytime they wanted during the follow-up period. Delayed thyroid surgery was recommended by the attending physician when the patients showed disease progression or when their comorbidities improved enough to be able to tolerate general anesthesia and surgery.

Statistical analysis

The software R, version 3.4.4 (R Foundation for Statistical Computing; www.R-project.org), was used for statistical analyses. Graphs were generated with GraphPad Prism version 5.0 (GraphPad Software, Inc., San Diego, CA). Continuous and categorical variables are presented as median and interquartile range (IQR) and number (percentage), respectively. Wilcoxon rank-sum test and chi-square test were used to compare the continuous and categorical variables, respectively. Survival curves were plotted using the Kaplan–Meier method, and the log-rank test was used to determine significance. The Cox proportional hazard model was used to evaluate risk factors for disease progression, presented as hazard ratios (HRs), 95% confidence intervals (CIs), and p-values. Statistical significance was set at p < 0.05.

Results

Baseline characteristics of PTMC patients undergoing AS

Table 1 shows the baseline characteristics of the 326 PTMC patients undergoing long-term AS. The median follow-up duration was 4.9 (IQR 3.4–6.3) years, median age was 50.6 years (IQR 43.0–58.6), 156 (47.9%) patients were aged ≤50 years, and the majority (76.7%) were female. The median frequency of neck US measurements was six times (IQR 5–8) in each patient. The median maximal tumor diameter and TV at initial diagnosis were 5.6 mm (IQR 4.4–5.6) and 55.4 mm³ (IQR, 29.8–95.2), respectively. Forty (12.3%) patients took levothyroxine during AS, of whom 18 (5.5%) took it for thyrotropin suppression. Hashimoto's thyroiditis was present in 72 (22.1%) patients. AS was selected based on the patient's decision (71.8%) or presence of other comorbidities such as other malignant disease (19.6%), cardiopulmonary disease (4.3%), or other systemic disease (4.3%).

Table 1.

Baseline Characteristics of Patients with Papillary Thyroid Microcarcinoma Under Active Surveillance

	Total, n = 326
Age at diagnosis (years)	50.6 (43.0–58.6)
≤50 years	156 (47.9%)
Female sex	250 (76.7%)
Maximum tumor diameter at diagnosis (mm)	5.6 (4.4–6.8)
Tumor volume at diagnosis (mm³)	55.4 (29.8–95.2)
Levothyroxine replacement	40 (12.3%)
Hormone replacement therapy	22 (6.7%)
Thyrotropin suppressive therapy	18 (5.5%)
Hashimoto's thyroiditis	72 (22.1%)
Reason for active surveillance
Patients' decision	234 (71.8%)
Other comorbidities	92 (28.2%)
Other malignant disease	64 (19.6%)
Cardiopulmonary disease	14 (4.3%)
Other systemic disease	14 (4.3%)

Continuous variables are presented as median (IQR) and categorical variables as numbers (percentages).

IQR, interquartile range.

Supplementary Table S1 shows the baseline characteristics of the 54 excluded patients (median age, 53.2 years [IQR 44.2–63.2]). They were slightly older and had more comorbidities (33.3%) when compared with the study cohort (28.2%), but without statistically significant differences (p = 0.102 and p = 0.545, respectively).

Disease progression according to TV increase and TVDT

Disease progression was confirmed during follow-up in 26 (8.0%, CI 5.0–10.9%) patients: 17 (5.2%, CI 2.7–7.6%) had maximal diameter increase of ≥3 mm and 9 (2.8%, CI 1.0–4.5%) developed new LN metastasis after a median of 4.0 and 2.2 years of follow-up, respectively (Table 2). Two of the patients had lateral neck LN metastasis, and seven had central neck LN metastasis. In terms of TV, 94 (28.8%) patients showed increase of ≥50% during follow-up and 68 (20.9%) had TVDT <5 years.

Table 2.

New Lymph Node Metastasis According to Maximal Diameter, Tumor Volume Increase, and Tumor Volume Doubling Time

	Maximal diameter increase ≥3 mm (n = 17)	Volume increase ≥50% (n = 94)	TVDT <5 years (n = 68)
New LN metastasis (n = 9)	0 (0.0%)	3 (3.2%)	5 (7.4%)

Values are presented as numbers (percentages).

LN, lymph node; TVDT, tumor volume doubling time.

New LN metastasis according to maximal diameter increase, TV increase, and TVDT was analyzed to determine the most relevant predictors during AS (Table 2). None of the patients with maximal tumor diameter increase of ≥3 mm developed new LN metastasis. The Kaplan–Meier curves revealed no difference in cervical LN metastasis between patients with and without maximal diameter increase of ≥3 mm (p = 0.481) (Fig. 2A). Among 94 patients with TV increase ≥50%, 3 (3.2%) developed new LN metastasis. In patients with TV increase ≥50% there was no difference in new LN metastasis development (p = 0.765) (Fig. 2B) when compared with those with <50% increase. In additional analysis, neither TV increase ≥75% nor TV increase ≥100% was associated new cervical LN metastasis (Supplementary Fig. S1). In patients with TVDT <5 years, the rate of developing new LN metastasis (7.4%) was the highest. TVDT <5 years was significantly associated with new LN metastasis (p = 0.002) (Fig. 2C).

FIG. 2.

Time-dependent cumulative incidence of new LN metastasis in patients with PTMC according to tumor maximal diameter changes (A), TV changes (B), and TVDT (C) during AS. LN, lymph node; TV, tumor volume; TVDT, TV doubling time.

Clinical and US features associated with shorter TVDT of <5 years

Supplementary Table S2 describes the initial US features of the 326 target nodules in the 326 patients. Table 3 compares the clinical and US features between patients with TVDT <5 years and ≥5 years. Patients with TVDT <5 years were significantly younger and predominantly female compared with those with TVDT ≥5 years (p = 0.001 and p = 0.001, respectively). There was no significant difference in levothyroxine treatment, coexistence of Hashimoto's thyroiditis, maximal tumor diameter, TV at diagnosis, and baseline thyrotropin values between the groups. In terms of US features of the target nodule, marked hypoechogenicity was more prevalent in patients with TVDT <5 years than in those with TVDT ≥5 years (p = 0.040). There were no other significant differences in the US features between the groups.

Table 3.

Clinical Features of Patients with Papillary Thyroid Microcarcinoma Under Active Surveillance According to Tumor Size Change

	TVDT ≥5 years (n = 258)	TVDT <5 years (n = 68)	p-Value
Age at diagnosis (years)	51.8 (44.1–59.3)	46.2 (38.2–53.5)	0.001
≤50 years	111 (43.0%)	45 (66.2%)	0.001
Female sex	190 (73.6%)	60 (88.2%)	0.018
Thyroxine treatment	28 (10.9%)	12 (17.6%)	0.190
Hashimoto's thyroiditis	54 (20.9%)	18 (26.5%)	0.415
Maximal diameter at diagnosis (mm)	5.6 (4.6–6.7)	5.3 (4.0–6.8)	0.228
≥5 mm	168 (65.1%)	36 (52.9%)	0.088
Tumor volume at diagnosis	59.6 (31.6–96.7)	46.7 (22.7–93.1)	0.100
≥50 mm³	143 (55.4%)	31 (45.6%)	0.190
Baseline TSH (μU/mL)^a	2.0 (1.3–2.9)	2.3 (1.3–3.5)	0.452
Tumor location on US			0.092
Upper pole	46 (17.8%)	19 (27.9%)
Nonupper pole	212 (82.2%)	49 (72.1%)
Thyroid nodule content on US			0.885
Solid	257 (99.6%)	67 (98.5%)
Predominantly solid	1 (0.4%)	1 (1.5%)
Thyroid nodule shape on US			0.644
Oval and round	188 (72.9%)	47 (69.1%)
Irregular	70 (27.1%)	21 (30.9%)
Thyroid nodule orientation on US			0.102
Parallel	102 (39.5%)	35 (51.5%)
Nonparallel	156 (60.5%)	33 (48.5%)
Thyroid nodule margin on US			0.161
Well-defined smooth	22 (8.5%)	9 (13.2%)
Spiculated	156 (60.5%)	34 (50.0%)
Lobulated	12 (4.7%)	1 (1.5%)
Ill-defined	68 (26.4%)	24 (35.3%)
Thyroid nodule echogenicity on US			0.040
Marked hypoechoic	38 (14.7%)	17 (25.0%)
Hypoechoic	218 (84.5%)	49 (72.1%)
Isoechoic	2 (0.8%)	2 (2.9%)
Thyroid nodule calcification on US			0.633
Microcalcification	72 (27.9%)	24 (35.3%)
Macrocalcification	30 (11.6%)	6 (8.8%)
Rim calcification	11 (4.3%)	2 (2.9%)
No calcification	145 (56.2%)	36 (52.9%)
Thyroid nodule subcapsular location on US	120 (46.5%)	27 (39.7%)	0.386

Continuous variables are presented as median (IQR) and categorical variables as numbers (percentages). Statistically significant values are shown in bold.

Baseline TSH values were available in 158 patients with TVDT ≥5 years and 46 patients with TVDT <5 years.

TSH, thyrotropin; TVDT, tumor volume doubling; US, ultrasonography.

Clinical and US features associated with disease progression

The clinical and US features associated with developing new LN metastasis during AS were evaluated (Table 4). In univariate analysis, only TVDT <5 years was an independent risk factor (HR = 6.51, CI 1.73–24.50; p = 0.002). Other patient and tumor factors showed no association with developing new LN metastasis. Younger age (≤50 years), marked hypoechoic nodules, nonspiculated margin, and TVDT <5 years were associated with tumor size enlargement (Table 5). In multivariate analysis, only TVDT <5 years was an independent risk factor for tumor enlargement (HR = 20.89, CI 5.78–75.48; p < 0.001).

Table 4.

Clinical and Sonographic Features Associated with New Lymph Node Metastasis

	LN metastasis on US
	Univariate analysis
	HR (CI)	p-Value
Age ≤50 years	0.98 (0.26–3.67)	0.98
Female sex	1.15 (0.24–5.53)	0.86
Levothyroxine treatment	1.94 (0.40–9.44)	0.41
Hashimoto's thyroiditis	1.87 (0.47–7.49)	0.38
Upper-pole location	0.82 (0.34–1.96)	0.65
Marked hypoechoic	0.65 (0.08–5.20)	0.68
Irregular shape	0.80 (0.17–3.86)	0.78
Nonparallel	0.86 (0.23–3.21)	0.83
Spiculated margin	0.53 (0.14–1.97)	0.34
Microcalcification	2.07 (0.56–7.72)	0.28
Subcapsular location of the tumor	0.99 (0.27–3.71)	0.99
TVDT <5 years	6.51 (1.73–24.50)	0.002

Statistically significant values are shown in bold.

CI, 95% confidence interval; HR, hazard ratio.

Table 5.

Clinical and Ultrasonographic Features Associated with Maximal Diameter Increase of ≥3 mm

	Maximal diameter increase ≥3 mm
	Univariate analysis		Multivariate analysis
	HR (CI)	p-Value	HR (CI)	p-Value
Age ≤50 years	4.42 (1.43–13.61)	0.01	1.85 (0.57–6.00)	0.30
Female sex	5.26 (0.70–39.8)	0.11
Levothyroxine treatment	0.97 (0.27–3.49)	0.97
Hashimoto's thyroiditis	2.09 (0.77–5.66)	0.15
Upper-pole location	0.80 (0.41–1.53)	0.49
Marked hypoechoic	3.03 (1.12–8.21)	0.03	1.63 (0.54–4.90)	0.38
Irregular shape	1.34 (0.47–3.83)	0.58
Nonparallel	0.91 (0.35–2.39)	0.85
Spiculated margin	0.32 (0.12–0.87)	0.03	0.38 (0.13–1.13)	0.08
Microcalcification	1.40 (0.48–4.12)	0.54
Subcapsular location of the tumor	0.88 (0.33–2.34)	0.80
TVDT <5 years	28.56 (8.16–99.94)	<0.001	20.89 (5.78–75.48)	<0.001

Statistically significant values are shown in bold.

Clinicopathological features of patients who underwent delayed thyroid surgery

During AS, 86 (22.6%) patients underwent delayed surgery (median follow-up duration before surgery, 2.4 years [IQR 1.6–3.6]). Table 6 shows the clinicopathological features of the patients who underwent delayed surgery (median age, 48.0 years [IQR 40.6–53.2]; 81.4% were female). The most common reason for delayed thyroid surgery was anxiety among patients (41.9%), followed by tumor enlargement (34.9%): 11 (19.6%) patients had a maximal tumor diameter increase of ≥3 mm and 19 (22.1%) had TV increase ≥50% without maximal diameter increase of >3 mm. Nine (10.5%) patients underwent thyroid surgery due to developing new cervical LN metastasis. Of the 17 patients who had a maximal tumor diameter increase of ≥3 mm during AS, 6 did not undergo thyroid surgery: 4 refused surgery against their physician's recommendation, and the other 2 continued AS because the tumor had not enlarged since its initial increase.

Table 6.

Clinicopathological Features of Patients Who Underwent Delayed Thyroid Surgery for Papillary Thyroid Microcarcinoma

	Total, n = 86
Age	48.0 (40.6–53.2)
≤50 years	54 (62.8%)
Female sex	70 (81.4%)
Reason for thyroid surgery
Patient anxiety	36 (41.9%)
Tumor enlargement	30 (34.9%)
Maximal diameter ≥3 mm	11 (19.6%)
Volume increase ≥50%	19 (22.1%)
Appearance of LN metastasis	9 (10.5%)
Coexistence of large benign nodule	2 (2.3%)
Improvement of comorbidity disease	9 (10.5%)
Extent of surgery^a
Lobectomy	54 (65.1%)
Total thyroidectomy with CND	27 (31.4%)
Total thyroidectomy with MRND	2 (2.3%)
Pathology^a
Classical type PTC	75 (90.4%)
Follicular variant PTC	6 (7.2%)
Tall cell variant PTC	2 (2.4%)
Tumor size (mm)^a	7.0 (5.0–8.0)
Multifocality (yes)^a	30 (36.1%)
Microscopic extrathyroidal extension (yes)^a	38 (45.8%)
LN metastasis (pN1)^a	23 (27.7%)

Continuous variables are presented as median (IQR) and categorical variables as numbers (percentages).

Data for surgical pathology were available for 83 patients.

CND, central neck dissection; MRND, modified radical neck dissection; PTC, papillary thyroid carcinoma; PTMC, papillary thyroid microcarcinoma.

Among the 86 patients who underwent delayed thyroid surgery, 54 (65.1%) underwent lobectomy and the others underwent total thyroidectomy, of whom 2 (2.3%) underwent total thyroidectomy with modified radical neck dissection and 27 (31.4%) underwent central neck dissection. In patients who had surgery, 90.4% cases were classical-type papillary thyroid cancer (PTC), 7.2% were follicular variant of PTC, and 2.4% were tall cell variant of PTC. Two patients with tall cell variant of PTC underwent delayed surgery because of anxiety rather than disease progression. LN metastasis on pathology was found in 23 patients (27.2%).

Discussion

This study analyzed the follow-up data of a previous multicenter cohort study wherein the median follow-up duration increased from 2.7 to 4.9 years (8). Compared with previous data, the number of patients who underwent delayed thyroid surgery increased from 58 (15.7%) to 86 (22.6%), mainly due to disease progression. In this study, 9 (2.8%) patients had new cervical LN metastasis during AS, but none of them showed a maximal diameter increase of ≥3 mm. The incidence of primary tumor enlargement was noted in 17 (5.2%) patients, and this rate was consistent with that observed in a previous meta-analysis (19). The incidence of new cervical LN metastasis was slightly higher in this study than in the previous meta-analysis; this might be due to the small numbers of events (19). Among the tumor kinetic factors, TVDT <5 years was the most relevant predictor of developing new LN metastasis and the only independent risk factor. Furthermore, 17 (5.2%) patients had maximal diameter increase ≥3 mm; TVDT <5 years was also an independent risk factor for tumor enlargement.

Relevant predictors of disease progression would be useful for timely decision-making regarding surgical intervention and determination of the follow-up intensity of AS. Our study used TV increase of at least 50% as a marker to detect tumor progression, consistent with other studies (9,20). This could be because PTMCs, which are initially vertically slender in many cases, tend to become globular with time, causing the TV to change without a change in the maximal diameter (21). Although the use of TV change as a predictive marker helps to identify progressing tumors at an early stage, it was determined by the first and last US finding and lack of time-dependent dynamics. In addition, there is a risk of error because the TV change itself is too sensitive. TVDT based on data from at least three US follow-up data points might be more relevant than TV change and was recently introduced as a PTMC growth indicator (12,13,22). PTMCs show linear growth up to 5 years in terms of TV (9,23), and there was no difference between the TVDT that was calculated using the initial four times US measurements and that calculated by using all US measurements during AS in this study (p = 0.97, data not shown). We addressed TVDT <5 years as a point for tumor growth classification in a previous study (11). However, these findings focused on tumor enlargement and not on newly developed LN metastasis due to low incidence and short follow-up time.

Development of new cervical LN metastasis can occur concurrently or subsequent to tumor enlargement. Cervical LN metastasis is a critical sign of disease progression, which determines the extent of surgery during AS. Therefore, it is important to determine the early predictor(s) of new cervical LN metastasis. In this study, TVDT <5 year was a significant predictor of both tumor enlargement and new LN metastasis. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. This finding suggests that some PTMCs with rapid TV changes can spread before significant tumor enlargement occurs. Other unknown tumor characteristics that determine the tumor fate with rapid TV changes might be involved, and further studies are needed in this regard. Nevertheless, our results suggest that PTMCs with TVDT <5 years might need early surgical intervention.

Age is a well-known predictor of tumor enlargement in PTMCs (2,8,24). Younger age tends to lead to rapid tumor enlargement; for example, in a previous study, the disease progression rates were 37% and 3.5% for patients in their 20s and 70s, respectively, after 10 years of AS (25). Ito et al. reported that PTMC patients <40 years had a higher rate of cervical LN metastasis than those 40–59 years and >60 years (2). However, in this study, only TVDT <5 years was associated with tumor size enlargement in multivariate analysis. This could be because TVDT is a comprehensive indicator of tumor enlargement, including patient factors, and younger patients tend to have a shorter TVDT. For developing new LN metastasis, TVDT was the only risk factor, and younger age (≤50 years) showed no significant association. This could be due to the difference in age classification or the relatively small sample size in our study.

Sasaki et al. recently reported that the incidence of patients who underwent conversion surgery >12 months after initiating AS was 7.1% (26). It is markedly lower than the incidence (22.6%) noted in our study. The marked discrepancy in delayed surgery rates was due to patients' anxiety and physicians' choice: One possible reason is the physicians' preference for surgery for patients whose TV increased without a maximal diameter increase of ≥3 mm. Another reason may be the lack of confidence by the treating physician to continue AS when patients have anxiety.

The most important criterion for the safety and success of AS is regular follow-up (27,28). Two previous studies from Japan reported very low rates of losses to follow-up, accounting for 0% and 3% over 74 months and 11 years of follow-up, respectively (4,29). In our study, 54 (14.2%) patients with short follow-up duration (<3 years) were excluded. Except for the 7 patients who died due to other diseases, the reasons for the short follow-up in the other 47 (12.4%) are unknown. This emphasizes the need of educating patients regarding regular visits and the importance of having a tracking/reminder program to ensure proper follow-up (28).

This study has several limitations. First, due to its retrospective design, there may have been a selection bias. Second, there could be interobserver variations in tumor size and volume measurements on US examination. Third, as 54 patients with short follow-up duration were excluded, the study population was not entirely representative of the total population and the study sample size is relatively small.

In summary, we found that TVDT <5 years is the most relevant predictor of PTMC disease progression during AS. Determination of TVDT in the early AS phase may be essential for the prediction of disease progression in terms of tumor enlargement and developing new LN metastasis. This could enable early decision-making regarding surgical intervention. Further large cohort prospective studies are warranted to validate our findings.

Footnotes

Authors' Contributions

Investigation, formal analysis, writing original draft, data curation, and visualization by M.J. and H.I.K. Investigation, validation, data curation, and visualization by J.H. Methodology, validation, formal analysis, resources, review, and editing by M.J.J. Methodology, validation, formal analysis, and resources by W.G.K. Methodology, validation, resources, review, and editing by D.-J.L., T.Y.K., J.H.C., and Y.K.S. Conceptualization, funding acquisition, methodology, and supervision by T.H.K. and W.B.K.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HC19C0215).

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

References

Haugen

, Alexander

, Bible

, Doherty

, Mandel

, Nikiforov

, Pacini

, Randolph

, Sawka

, Schlumberger

, Schuff

, Sherman

, Sosa

, Steward

, Tuttle

, Wartofsky

. 2016. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26:1–133.

Ito

, Miyauchi

, Kihara

, Higashiyama

, Kobayashi

, Miya

. 2014. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid, 24:27–34.

Ito

, Uruno

, Nakano

, Takamura

, Miya

, Kobayashi

, Yokozawa

, Matsuzuka

, Kuma

, Miyauchi

. 2003. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid, 13:381–387.

Ito

, Miyauchi

, Inoue

, Fukushima

, Kihara

, Higashiyama

, Tomoda

, Takamura

, Kobayashi

, Miya

. 2010. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg, 34:28–35.

Kim

, Shong

. 2017. Active surveillance of papillary thyroid microcarcinoma: a mini-review from Korea. Endocrinol Metab (Seoul), 32:399–406.

Jeon

, Kim

, Choi

, Kwon

, Lee

, Sung

, Yoon

, Chung

, Hong

, Kim

, Shong

, Song

, Kim

. 2016. Features predictive of distant metastasis in papillary thyroid microcarcinomas. Thyroid, 26:161–168.

Ito

, Miyauchi

. 2020. Active surveillance of low-risk papillary thyroid microcarcinomas. Gland Surg, 9:1663–1673.

, Ha

, Kim

, Lim

, Kim

, Shong

, Chung

, Baek

. 2018. Active surveillance of low-risk papillary thyroid microcarcinoma: a multi-center cohort study in Korea. Thyroid, 28:1587–1594.

Tuttle

, Fagin

, Minkowitz

, Wong

, Roman

, Patel

, Untch

, Ganly

, Shaha

, Shah

, Pace

, Li

, Bach

, Lin

, Whiting

, Ghossein

, Landa

, Sabra

, Boucai

, Fish

, Morris

LGT

. 2017. Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg, 143:1015–1020.

10.

Ito

, Miyauchi

, Kudo

, Higashiyama

, Masuoka

, Kihara

, Miya

. 2019. Kinetic analysis of growth activity in enlarging papillary thyroid microcarcinomas. Thyroid, 29:1765–1773.

11.

, Kwon

, Song

, Jeon

, Kim

, Lee

, Kim

, Shong

, Chung

, Baek

, Kim

. 2019. Tumor volume doubling time in active surveillance of papillary thyroid carcinoma. Thyroid, 29:642–649.

12.

Kasahara

, Miyauchi

, Ito

, Kudo

, Masuoka

, Higashiyama

, Ito

, Kihara

, Miya

. 2020. Tumor volume kinetic analyses might explain excellent prognoses in young patients with papillary thyroid carcinoma. J Thyroid Res, 2020:4652767.

13.

Miyauchi

, Kudo

, Ito

, Oda

, Yamamoto

, Sasai

, Higashiyama

, Masuoka

, Fukushima

, Kihara

, Miya

. 2019. Natural history of papillary thyroid microcarcinoma: kinetic analyses on tumor volume during active surveillance and before presentation. Surgery, 165:25–30.

14.

Shin

, Baek

, Chung

, Ha

, Kim

, Lee

, Lim

, Moon

, Na

, Park

, Choi

, Hahn

, Jeon

, Jung

, Kim

, Kwak

, Lee

, Park

, Sung

. 2016. Ultrasonography diagnosis and imaging-based management of thyroid nodules: revised Korean Society of Thyroid Radiology consensus statement and recommendations. Korean J Radiol, 17:370–395.

15.

Frates

, Benson

, Charboneau

, Cibas

, Clark

, Coleman

, Cronan

, Doubilet

, Evans

, Goellner

, Hay

, Hertzberg

, Intenzo

, Jeffrey

, Langer

, Larsen

, Mandel

, Middleton

, Reading

, Sherman

, Tessler

. 2006. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Ultrasound Q, 22:231–238; discussion 239–240.

16.

Jeong

, Baek

, Rhim

, Kim

, Kwak

, Jeong

, Lee

. 2008. Radiofrequency ablation of benign thyroid nodules: safety and imaging follow-up in 236 patients. Eur Radiol, 18:1244–1250.

17.

Doubling time and progression calculator. Available at www.kuma-h.or.jp/english/about/doubling-time-progressioncalculator/ (accessed August 8, 2003 ).

18.

Fukuoka

, Sugitani

, Ebina

, Toda

, Kawabata

, Yamada

. 2016. Natural history of asymptomatic papillary thyroid microcarcinoma: time-dependent changes in calcification and vascularity during active surveillance. World J Surg, 40:529–537.

19.

Cho

, Suh

, Baek

, Chung

, Choi

, Chung

, Shong

, Lee

. 2019. Active surveillance for small papillary thyroid cancer: a systematic review and meta-analysis. Thyroid, 29:1399–1408.

20.

Kwon

, Oh

, Kim

, Park

, Jeon

, Kim

, Shong

, Song

, Baek

, Chung

, Kim

. 2017. Active surveillance for patients with papillary thyroid microcarcinoma: a single center's experience in Korea. J Clin Endocrinol Metab, 102:1917–1925.

21.

Jeon

, Kim

, Chung

, Baek

, Kim

, Shong

. 2019. Active surveillance of papillary thyroid microcarcinoma: where do we stand?. Eur Thyroid J, 8:298–306.

22.

Sabra

, Sherman

, Tuttle

. 2017. Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma. Cancer, 123:2955–2964.

23.

Kim

, Jang

, Ahn

, Park

, Oh

, Hahn

, Shin

, Kim

, Chung

, Kim

. 2018. High serum TSH level is associated with progression of papillary thyroid microcarcinoma during active surveillance. J Clin Endocrinol Metab, 103:446–451.

24.

, Park

, Kim

, Kwon

, Song

, Sung

, Lee

, Kim

, Shong

, Kim

, Jeon

. 2017. Young age and male sex are predictors of large-volume central neck lymph node metastasis in clinical N0 papillary thyroid microcarcinomas. Thyroid, 27:1285–1290.

25.

Miyauchi

, Kudo

, Ito

, Oda

, Sasai

, Higashiyama

, Fukushima

, Masuoka

, Kihara

, Miya

. 2018. Estimation of the lifetime probability of disease progression of papillary microcarcinoma of the thyroid during active surveillance. Surgery, 163:48–52.

26.

Sasaki

, Miyauchi

, Ito

, Kudo

, Kanemura

, Sano

, Kawano

, Yamamoto

, Fujishima

, Masuoka

, Higashiyama

, Kihara

, Miya

. 2021. Marked decrease over time in conversion surgery after active surveillance of low-risk papillary thyroid microcarcinoma. Thyroid, 31:217–223.

27.

Haser

, Tuttle

, Urken

. 2016. Challenges of active surveillance protocols for low-risk papillary thyroid microcarcinoma in the United States. Thyroid, 26:989–990.

28.

Brito

, Ito

, Miyauchi

, Tuttle

. 2016. A clinical framework to facilitate risk stratification when considering an active surveillance alternative to immediate biopsy and surgery in papillary microcarcinoma. Thyroid, 26:144–149.

29.

Sugitani

, Toda

, Yamada

, Yamamoto

, Ikenaga

, Fujimoto

. 2010. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J Surg, 34:1222–1231.