Predicting papillary thyroid carcinoma cervical lymph node metastases: an algorithm using the American College of Radiology Thyroid Imaging,Reporting and Data System

Abstract

Background

It is important to predict lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) preoperatively; however, the relationship between the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) score and cervical LNM remains unclear.

Purpose

To evaluate the association between the ACR TI-RADS score and cervical LNM in patients with PTC.

Material and Methods

This retrospective study consisted of 474 patients with 548 PTCs. Cervical LNM including central LNM (CLNM) and lateral LNM (LLNM) were confirmed by pathology. Univariate and multivariate analyses were performed to investigate the risk factors of CLNM and LLNM.

Results

Multivariate logistic regression analyses indicated that younger age and multifocality were risk factors for CLNM in PTCs with TR5. In addition, younger age, larger tumor size, and Hashimoto’s thyroiditis (HT) were risk factors for LLNM in PTCs ≥ 10 mm with TR5. In PTCs with TR4, ACR TI-RADS scores 5–6 conferred risks for LNM. In PTCs ≥ 10 mm with TR5, ACR TI-RADS scores ≥9 were risk factors for LLNM.

Conclusion

A higher ACR TI-RADS score is a predictor for cervical LNM in PTCs with TR4 and PTCs ≥ 10 mm with TR5.

Keywords

Papillary thyroid carcinoma central lymph node metastasis lateral lymph node metastasis ACR TI-RADS ultrasound

Introduction

Papillary thyroid carcinoma (PTC) is the main type of thyroid carcinoma with a favorable prognosis (1,2). However, the incidence of cervical lymph node metastasis (LNM) has been reported to be in the range of 20%–90%, which was related to higher recurrence, distant metastasis, and mortality rates (3 –5); therefore, it is crucial to predict LNM. High-resolution ultrasound (US) is an important tool for detecting PTC (6). In 2017, a committee of the American College of Radiology (ACR) recommended guidelines, Thyroid Imaging, Reporting and Data System (TI-RADS), for the classification and management of thyroid nodules (7). Many previous studies have investigated risk factors for LNM in PTCs, and there were some studies evaluating the utility of US features as a predictor of LNM (8 –10). Although there have been previous studies on the associations between LNM and the 2015 ATA guidelines or other version of TI-RADS in PTCs, there is no research on the relationship between the ACR TI-RADS score and cervical LNM in PTCs. The aim of the present study was to assess the value of the ACR TI-RADS score in predicting cervical LNM in PTCs.

Material and Methods

Study population

This retrospective study was approved by our institutional review board and the requirement for informed consent was waived. From April 2018 to December 2019, we enrolled 474 patients with 548 thyroid nodules who underwent total or near-total thyroidectomy at our hospital. The inclusion criteria were as follows: (i) thyroid nodules were diagnosed with PTC; (ii) PTC and LNM confirmed by pathology of surgical specimen; and (iii) complete US image data. The exclusion criteria were previous thyroid surgery and other head and neck cancers. All patients were treated with central compartment neck dissection. Bilateral central compartment neck dissection was performed on bilateral or isthmic PTC. Lateral compartment neck dissection was performed in patients with positive or suspicious findings in the lateral lymph node detected by palpation or radiological examination. The clinical pathological features, including age, tumor size, sex, numbers of tumors (multifocality or unifocality), and Hashimoto's thyroiditis (HT), were recorded.

US examination and image analysis

All US images were acquired using a 4–15-MHz linear probe (Aixplorer; Supersonic Imagine, Aix-en-Provence, France), a 6–13-MHz linear probe (MyLab Class C; Esaote, Genoa, Italy), a 5–14-MHz linear probe (Resona7S; Mindray, Shenzhen, PR China), or a 3–12-MHz linear probe (EPIQ 5; Philips Medical Systems, Bothell, WA, USA). Real-time US was performed, interpreted, and recorded preoperatively by one of 20 the board-certified radiologists with >5 years of thyroid US expertise. A board-certified radiologist with five years of experience in thyroid imaging blinded to pathological results retrospectively interpreted US images. The recruitment criterion for each nodule was two interpretation results were consistent. US features of all nodules were assessed according to the 2017 ACR TI-RADS lexicon (7), including composition (0 points = cystic or almost completely cystic, spongiform; 1 point = mixed cystic and solid; 2 points = solid or almost completely solid), echogenicity (0 points = anechoic; 1 point = hyperechoic or isoechoic; 2 points = hypoechoic; 3 points = very hypoechoic), shape (0 points = wider-than-tall; 3 points = taller-than-wide), margin (0 points = smooth and ill-defined; 2 points = lobulated or irregular; 3 points = extra-thyroidal extension), and echogenic foci (0 points = none or large comet-tail artifacts; 1 point = macrocalcifications; 2 points = peripheral (rim) calcifications; 3 points = punctate echogenic foci). Adding the points corresponding to US features, we obtained each nodule's total ACR TI-RADS score, which determined the nodule's ACR TI-RADS level, ranging from TR1 (benign) to TR5 (highly suspicious for malignancy). In addition, radiologists also examined the bilateral cervical lymph nodes of all patients before surgery and recorded the US features of suspected lymph nodes, including location, size, shape, border, echogenicity, internal architecture, and vascular pattern.

Statistical analyses

Data were expressed as the mean and standard deviation (SD) when normally distributed, or as the median and interquartile range (IQR) when non-normally distributed. Categorical variables were tested by the chi-square test. Continuous variables were tested by a Student's t-test or Mann–Whitney U-test as appropriate. Variables with P < 0.15 in the univariate analyses as well as the variable of particular interest for this study (i.e. ACR TI-RADS score) were included in the multivariate logistic regression analyses to identify independent factors associated with LNM. A P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, IL USA).

Results

Among the 474 patients, 305 (64.3%) had LNM, 269 (56.8%) had central LNM (CLNM) and 132 (27.8%) had lateral LNM (LLNM). Of the 548 PTCs, 76 (13.9%) nodules were diagnosed as TR4 and 472 (86.1%) were diagnosed as TR5 by US.

Risk factors for LNM in PTCs with TR4

In univariate analysis, multifocality and ACR TI-RADS score were significantly associated with LNM (Table 1). In multivariate analysis, ACR TI-RADS scores 5–6 were risk factors for LNM (Table 1). There were no significant associations between LNM and age, sex, tumor size, or HT in either univariate or multivariate analyses (Table 1).

Table 1.

Univariate and multivariate analyses for lymph node metastasis in PTCs with TR4.

Parameter	LNM + (n = 40, 52.6%)	LNM – (n = 36, 47.4%)	P value	OR (95% CI)	P value
Age (years)	48.3 ± 12.0	47.3 ± 11.0	0.702*
>48	17 (42.5)	16 (44.4)	0.864	–	–
≤48	23 (57.5)	20 (55.6)		–
Size (mm)	7.0 (5.4–10.8)	6.3 (4.0–9.8)	0.153^†
≤7	22 (55.0)	22 (61.1)	0.590	–	–
>7	18 (45.0)	14 (38.9)		–
Sex
Male	11 (27.5)	9 (25.0)	0.805	–	–
Female	29 (72.5)	27 (75.0)		–
Multifocality
Negative	21 (52.5)	27 (75.0)	0.042	1 (reference)
Positive	19 (47.5)	9 (25.0)		2.108 (0.719–6.180)	0.174
Hashimoto's thyroiditis
Negative	32 (80.0)	22 (61.1)	0.070	1 (reference)
Positive	8 (20.0)	14 (38.9)		0.462 (0.149–1.436)	0.462
ACR TI-RADS score
4	10 (25.0)	17 (47.2)	0.043	1 (reference)
5–6	30 (75.0)	19 (52.8)		2.888 (1.045–7.981)	0.041

Values are given as n (%), mean ± SD, or median (IQR).

*P values were calculated using a Student's t-test.

†

P values were calculated using a Mann–Whitney U-test.

CI, confidence interval; IQR, interquartile range; LNM, lymph node metastasis; OR, odds ratio; PTC, papillary thyroid carcinoma; SD, standard deviation.

Risk factors for LNM in PTCs with TR5

In PTCs ≥ 10 mm, younger age (≤50 years) was significantly associated with CLNM by univariate analysis. The multivariate analysis showed that younger age (≤50 years) and multifocality were significantly related to CLNM (Table 2). In both univariate analysis and multivariate analysis, younger age (≤46 years), larger tumor size (>15 mm), HT, and higher ACR TI-RADS score were significantly associated with LLNM (Table 3).

Table 2.

Univariate and multivariate analyses for CLNM in PTCs ≥10 mm with TR5.

Parameter	CLNM + (n = 182, 72.2%)	CLNM – (n = 70, 27.8%)	P value	OR (95% CI)	P value
Age (years)	44.0 (34.0–52.0)	50.5 (41.8–57.3)	0.006*
>50	58 (31.9)	35 (50.0)	0.008	1 (reference)
≤50	124 (68.1)	35 (50.0)		2.146 (1.200–3.837)	0.010
Size (mm)	15.0 (12.0–23.0)	14.0 (11.4–18.3)	0.099*
≤15	93 (51.1)	43 (61.4)	0.141	1 (reference)
>15	89 (48.9)	27 (38.6)		1.482 (0.821–2.674)	0.191
Sex
Male	54 (29.7)	15 (21.4)	0.189	–	–
Female	128 (70.3)	55 (78.6)		–
Multifocality
Negative	139 (76.4)	60 (85.7)	0.103	1 (reference)
Positive	43 (23.6)	10 (14.3)		2.214 (1.000–4.904)	0.050
Hashimoto's thyroiditis
Negative	140 (76.9)	60 (85.7)	0.122	1 (reference)
Positive	42 (23.1)	10 (14.3)		1.912 (0.871–4.200)	0.106
ACR TI-RADS score					0.078
7–8	49 (27.0)	18 (25.7)	0.070	1 (reference)
9–10	108 (59.3)	34 (48.6)		1.311 (0.648–2.652）	0.451
≥11	25 (13.7)	18 (25.7)		0.555 (0.239–1.290)	0.171

Values are given as n (%) or median (IQR).

*P values were calculated using the Mann–Whitney U-test.

CI, confidence interval; CLNM, central lymph node metastasis; IQR, interquartile range; OR, odds ratio; PTC, papillary thyroid carcinoma.

Table 3.

Univariate and multivariate analyses for LLNM in PTCs ≥10 mm with TR5.

Parameter	LLNM + (n=89, 35.3%)	LLNM – (n = 163, 64.7%)	P value	OR (95% CI)	P value
Age (years)	43.0 (32.5–51.0)	47.0 (40.0–55.0)	0.010*
>46	35 (39.3)	87 (53.4)	0.033	1 (reference)
≤46	54 (60.7)	76 (46.6)		1.788 (1.030–3.105)	0.039
Size (mm)	17.0 (13.0–26.5)	14.0 (11.5–20.0)	0.002*
≤15	38 (42.7)	98 (60.1)	0.008	1 (reference)
>15	51 (57.3)	65 (39.9)		2.059 (1.184–3.583)	0.011
Sex
Male	26 (29.2)	43 (26.4)	0.630	–	–
Female	63 (70.8)	120 (73.6)		–
Multifocality
Negative	69 (77.5)	130 (79.8)	0.678	–	–
Positive	20 (22.5)	33 (20.2)		–
Hashimoto's thyroiditis
Negative	63 (70.8)	137 (84.0)	0.013	1 (reference)
Positive	26 (29.2)	26 (16.0)		2.289 (1.192–4.398)	0.013
ACR TI-RADS score					0.017
7–8	15 (16.8)	52 (31.9)	0.021	1 (reference)
9–10	54 (60.7)	88 (54.0)		2.085 (1.038–4.188)	0.039
≥11	20 (22.5)	23 (14.1)		3.463 (1.459–8.221)	0.005

Values are given as n (%) or median (IQR).

*P values were calculated using the Mann–Whitney U-test.

CI, confidence interval; IQR, interquartile range; LLNM, lateral lymph node metastasis; OR, odds ratio; PTC, papillary thyroid carcinoma.

In PTCs <10 mm, univariate analysis indicated that there were significant relationships between CLNM and younger age (≤48 years), multifocality, and HT (Table 4). In multivariate analysis, younger age (≤48 years) and multifocality were independently associated with CLNM (Table 5). There were no significant associations found between LLNM and various established risk factors, such as age, size, sex, multifocality, HT, or ACR TI-RADS score (Tables 4 and 5).

Table 4.

Univariate analyses for LNM in PTCs <10 mm with TR5.

Parameter	CLNM + (n = 109, 49.5%)	CLNM – (n = 111, 50.5%)	P value	LLNM + (n = 50, 22.7%)	LLNM – (n = 170, 77.3%)	P value
Age (years)	42.0 (35.5–52.5)	48.0 (40.0–55.0)	0.010*	42.5 (38.0–53.0)	48.0 (37.0–54.0)	0.350*
>48	35 (32.1)	55 (49.5)	0.009	15 (30.0)	75 (44.1)	0.074
≤48	74 (67.9)	56 (50.5)		35 (70.0)	95 (55.9)
Size (mm)	6.4 (5.0–8.0)	6.5 (5.1–8.0)	0.623*	6.7 (5.2–8.2)	6.5 (5.0–8.0)	0.415*
≤8	92 (84.4)	87 (78.4)	0.251	38 (76.0)	141 (82.9)	0.268
>8	17 (15.6)	24 (21.6)		12 (24.0)	29 (17.1)
Sex
Male	30 (27.5)	26 (23.4)	0.485	18 (36.0)	38 (22.4)	0.051
Female	79 (72.5)	85 (76.6)		32 (64.0)	132 (77.6)
Multifocality
Negative	65 (59.6)	94 (84.7)	<0.001	34 (68.0)	125 (73.5)	0.443
Positive	44 (40.4)	17 (15.3)		16 (32.0)	45 (26.5)
Hashimoto's thyroiditis
Negative	84 (77.1)	71 (64.0)	0.033	38 (76.0)	117 (68.8)	0.328
Positive	25 (22.9)	40 (36.0)		12 (24.0)	53 (31.2)
ACR TI-RADS score
7–8	37 (34.0)	41 (37.0)	0.721	17 (34.0)	61 (35.9)	0.944
9–10	53 (48.6)	48 (43.2)		24 (48.0)	77 (45.3)
≥11	19 (17.4)	22 (19.8)		9 (18.0)	32 (18.8)

Values are given as n (%) or median (IQR).

*P values were calculated using the Mann–Whitney U-test.

CLNM, central lymph node metastasis; IQR, interquartile range; LLNM, lateral lymph node metastasis; PTC, papillary thyroid carcinoma.

Table 5.

Multivariate analyses for LNM in PTCs <10 mm with TR5.

	CLNM		LLNM
	OR (95% CI)	P value	OR (95% CI)	P value
Age (years)
>48	1 (reference)		1 (reference)
≤48	2.294 (1.277–4.121)	0.005	1.806 (0.912–3.578)	0.090
Size (mm)
≤8	–	–	–	–
>8	–		–
Sex
Male	–	–	1 (reference)
Female	–		0.516 (0.259–1.027)	0.059
Multifocality
Negative	1 (reference)		–	–
Positive	3.853 (1.981–7.494)	<0.001	–
Hashimoto's thyroiditis
Negative	1 (reference)		–	–
Positive	0.542 (0.288–1.019)	0.057	–
ACR TI-RADS score		0.689		0.929
7–8	1 (reference)		1 (reference)
9–10	1.212 (0.638–2.302)	0.557	1.105 (0.538–2.271)	0.786
≥11	0.885 (0.396–1.977)	0.766	0.944 (0.373–2.392)	0.904

CI, confidence interval; CLNM, central lymph node metastasis; LLNM, lateral lymph node metastasis; OR, odds ratio; PTC, papillary thyroid carcinoma.

Discussion

In the present study, we used univariate and multivariate analyses to assess the risk factors for cervical LNM in PTCs. We found that a higher ACR TI-RADS score was independently associated with LNM in both PTCs with TR4 and PTCs ≥ 10 mm with TR5. In addition, our results suggested that younger age and multifocality were risk factors for CLNM in PTCs with TR5. For LLNM, younger age, larger tumor size, and HT were statistically significant factors in PTCs ≥ 10 mm with TR5.

Some studies have tried to reveal the relationship between US features and LNM in PTCs. A study found that suspicious US features such as calcification, taller-than-wide shape, and poor margins were significantly associated with CLNM in PTCs (11). In one study, a number of suspicious US features based on TI-RADS (12) were independently related to LLNM in PTCs >10 mm (9). In addition, a previous study found that the high suspicion US pattern of the 2015 ATA guidelines could be a predicting marker of LNM in PTCs (8). The 2017 ACR TI-RADS guidelines provided not only the classification (TR1–TR5), but also a specific score of each nodule, which was different from previous guidelines. In our study, we divided all nodules into two groups according to TR4 and TR5. In PTCs with TR4, we found that ACR TI-RADS scores 5–6 were risk factors for predicting LNM (odds ratio [OR] = 2.888; P = 0.041). Moreover, we further divided TR5 nodules into two groups (tumor size ≥10 mm and <10 mm) according to the fine-needle aspiration size threshold of the 2017 ACR TI-RADS guidelines (7). In PTCs ≥10 mm with TR5, the ACR TI-RADS score was significantly associated with LLNM but not with CLNM. In addition, ACR TI-RADS scores 9–10 and ≥11 conferred risks for LLNM with the ORs 2.085 and 3.463, respectively. However, in PTCs <10 mm with TR5, the ACR TI-RADS score was not significantly related to either CLNM or LLNM. Our findings indicated that in patients with PTC with TR5 (tumor size ≥10 mm) or TR4, as the ACR TI-RADS score increases, we need to pay more attention to cervical lymph nodes, which may be important for the identification of patients with increased risk of LNM and surgeons would be encouraged to perform a more meticulous evaluation preoperatively.

Age is known to be an important risk factor for CLNM in PTCs. Many studies have shown that younger age could be an independent predictor of CLNM (13,14). Our results suggested that younger age was significantly related not only to CLNM in PTCs with TR5, but also to LLNM in PTCs ≥10 mm with TR5.As for size, larger tumor size has been regarded as a predictor for poor outcome in PTCs (15 –17). Many studies have reported that larger tumor size was more likely to have LLNM in PTCs (18,19). We found that larger tumor size(>15 mm) was only significantly associated with LLNM in PTCs ≥10 mm.

Multifocality was considered an independent risk factor for CLNM in PTCs (20,21). In our study, multifocality was independently correlated with CLNM in PTCs with TR5.The relationship between LNM and HT in PTCs remains controversial. Some studies reported HT as an independent predictor for LNM in PTCs (21,22), while another study found no association between LNM and HT (23). In addition, some studies suggested that HT was negatively associated with LNM in PTCs (24,25). Our results indicated that HT was independently correlated with LLNM in PTCs ≥10 mm with TR5. For PTCs with TR4, LNM were not significantly related to age, sex, tumor size, or HT. The specific underlying mechanisms responsible for this difference in results are unclear and further research is needed to clarify the reasons.

The present study has some limitations. First, this was a retrospective study with an inevitable selection bias. Second, the sample size was small, and all the data were collected from a single center; thus further multicenter researches and larger sample size are required to confirm our findings. Third, we did not have clinical follow-up data for approximately 27% of patients; therefore, this study may have false negatives of late nodal metastases. Finally, we used a single observer for scoring with no inter-observer agreement.

In conclusion, a higher ACR TI-RADS score is a risk factor for cervical LNM in PTCs with TR4 and PTCs ≥10 mm with TR5. Assessing the ACR TI-RADS score preoperatively could help to identify patients with high risk of cervical LNM and aid surgeons in performing more exhaustive assessments.

Footnotes

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ronger Shangguan

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