Participant inclusion and tumor progression

A total of 1177 participants were enrolled, 755/1177 (64.1%) who were self-assigned to AS and 422/1177 (35.9%) who were self-assigned to immediate surgery. Of the 755 AS subjects, 59/755 (7.8%) were excluded due to poor image quality. Additionally, 3/422 (0.7%) participants who underwent surgery had more than 2 US exams before their operation. Thus, 699 participants were included in our analysis. The baseline clinical characteristics of participants and US features of tumors are summarized in Table 1.

Table 1: Participant and tumor characteristics at baseline

At the median period of 41.4 months (range, 4-60.2 months), 68/699 (10%) participants (mean age, 49 years ± 12 [SD]; 40 females, 28 males) showed tumor progression. Among these participants, 56/68 (82.4 %) were classified as having tumor enlargement, with a ≥3 mm increase observed in 18/68 (26.5%) participants, a ≥2 mm increase in at least two dimensions observed in 16/68 (23.5%) participants, and both ≥3 mm and ≥2 mm increase in two dimensions observed in 22/68 (32.4%) participants. Additionally, 3/68 (4.4%) participants developed extrathyroidal extension and 8/68 (11.8%) participants developed LNM. One participant (1/68, 1.5%) demonstrated an increase in tumor size (≥3 mm) simultaneously with LNM. 

Baseline Clinical characteristics and US features associated with PTMC progression

In the multivariable analysis, US-DTD (HR, 2.27; [95% CI: 1.39, 3.69]; P =.001) and presence of intratumoral vascularity (HR, 1.74 [95% CI: 1.01, 2.99]; P =.04) were independently associated with tumor progression along with male sex (HR, 2.82 [95% CI: 1.72, 4.62]; P <.001), age < 30 years (HR, 2.90 [95% CI: 1.24, 6.81]; P =.01), and TSH level ≥7 µU/mL (HR, 6.88 [95% CI: 2.72, 17.4]; P <.001) (Table 2).

Table 2: Univariable and multivariable Cox proportional Hazards Analysis to assess variables associated with tumor progression

Progression rates in subgroups stratified by US features

Using participants without US-DTD and intratumoral vascularity as reference, the tumor progression HR was 3.5 for participants with US-DTD and intratumoral vascularity (95% CI: 1.32, 9.23), 2.2 for participants with intumoral vascularity without US-DTD (95% CI: 0.97, 5.14), and 2.2 for participants with US-DTD without intratumoral vascularity (95% CI: 1.26, 3.89). These US-feature-based subgroups accurately stratified risk of tumor progression (log rank, P =.001, Figure 1).

Fig 1: Time dependent cumulative incidence of tumor progression in patients with papillary thyroid microcarcinoma stratified by US features of diffuse thyroid disease (US-DTD) and intratumoral vascularity.

Clinical characteristics and US features associated with tumor progression 

Tumor enlargement of ≥3 mm were associated with male sex (HR, 3.25 [95% CI: 1.72, 6.15]; P <.001), age<30 years (HR, 3.48 [95% CI: 1.21, 10.0]; P = .02), US-DTD (HR, 2.69 [95% CI: 1.43, 5.07]; P = .002), and TSH ≥ 7 µU/mL (HR, 10.66 [95% CI: 3.72, 30.55]; P <.001), (Table 3).

Table 3: Multivariable Cox proportional hazards analysis to assess participant and tumor characteristics associated with specific tumor progression criteria

Male sex (HR, 1.95 [95% CI: 0.99, 3.84]; P = .05), US-DTD (HR, 2.0 [95% CI: 1.05, 3.8]; P <= .04), and TSH ≥ 7 µU/mL (HR, 9.16 [95% CI: 2.79, 30.07]; P <.001) also showed an association with tumor enlargement ≥2 mm in at least two dimensions. For new LNM, only intratumoral vascularity showed independent association (HR, 5.01 [95% CI, 1.29, 19.43]; P =.02). Representative US images at baseline and follow-up from a participant who developed LNM and a participant with tumor enlargement are shown in Figures 2 and 3, respectively.

Fig 2: US images in a 64-year-old man with papillary thyroid microcarcinoma. (a-c) Baseline US images (a) Transverse grey scale image shows a solid hypoechoic thyroid nodule measured as 7mm in the maximal diameter. (b) Color Doppler image reveals hypervascularity. (c) A small probably benign lymph node (LN) was noted in left level IV (arrow). (d) Transverse US images after 12 months demonstrated a suspicious LN (arrow) with increased short diameter and punctate echogenic foci (arrowhead). Subsequent FNA revealed a metastatic thyroid papillary carcinoma.

Fig 3: US images in a 47-year-old female with papillary thyroid microcarcinoma (PTMC) (a-c) Baseline US images (a) Transverse and (b) longitudinal images of right thyroid gland shows a solid hypoechoic nodule measured as 4mm in the maximal diameter. Thyroid parenchyma shows scattered hypoechoic nodular lesions. (c) Color Doppler images showed hypervascularity of thyroid gland and was classified as diffuse thyroid disease (US-DTD) positive. (d-e) US images 18 months after. (d) Transverse and (e) longitudinal US images after 18 months demonstrated size increase of the tumor to 8mm. Background thyroid parenchyma shows mild diffuse hypoechogenicity. On US and CT, no suspicious LNs were noted. Subsequent lobectomy and ipsilateral central neck dissection showed PTMC with lymphocytic thyroiditis. Two metastatic LNs were diagnosed out of 5 dissected LNs.