Conventional ultrasound combined with contrast-enhanced ultrasound predicts lateral lymph node metastasis in papillary thyroid carcinoma

Abstract

BACKGROUND:

This study aimed to investigate the correlation between conventional ultrasound and contrast-enhanced ultrasound (CEUS) features and lateral lymph node metastasis (LLNM) in papillary thyroid carcinoma (PTC), establish a predictive model, and provide imaging evidence for clinical diagnosis and treatment.

METHODS:

This study selected 428 patients with postoperative pathologically confirmed PTC, who had undergone cervical lymph node dissection, from September 2020 to August 2021 at the First Affiliated Hospital of Soochow University. According to the postoperative pathological results, the patients were divided into those with LLNM (n = 94) and those without LLNM (n = 334). The clinical characteristics and conventional ultrasound and CEUS characteristics of the two groups were retrospectively analyzed, and the differences between them were compared. Independent risk factors related to LLNM were screened, a prediction model was constructed, and its prediction efficiency and clinical practicality were evaluated.

RESULTS:

The independent risk factors for LLNM were nodules located in the upper thyroid (odds ratio [OR] = 2.640, 95% confidence interval [CI]: 1.488–4.682), maximum tumor diameter≥1.0 cm (OR = 2.027, 95% CI: 1.146–3.586), microcalcification (OR = 2.176, 95% CI: 1.153–4.106), central lymph node metastasis (OR = 3.091, 95% CI: 1.721–5.549), enhanced late hyperenhancement (OR = 2.440, 95% CI: 1.081–5.508), and membrane continuity interruption in early enhancement (OR = 3.988, 95% CI: 2.315–6.871) (P < 0.05 for all). The sensitivity and specificity of the combined index in predicting LLNM in PTC patients were 72.34% and 78.74%, respectively (best cut-off value: 0.511); the area under the curve (AUC) was 0.818 (95% CI: 0.778–0.853). Moreover, the AUC of the combined index in predicting LLNM in PTC patients was greater than that of conventional ultrasound alone. The calibration curve of the nomogram constructed based on the aforementioned six independent risk factors showed that the model could fit the actual probability of LLNM well with high calibration. Decision curve analysis revealed that the model has good clinical applicability.

CONCLUSIONS:

The nomogram model constructed by conventional ultrasound combined with CEUS can effectively predict lateral cervical lymph node metastasis, providing an intuitive guide tool diagnosis and treatment.

Keywords

Papillary thyroid carcinoma lateral lymph node metastasis contrast-enhanced ultrasound nomogram

1 Introduction

Recently, the incidence and mortality rate of thyroid cancer have been on the rise both domestically and internationally [1, 2]. PTC is the most common subtype of thyroid cancer, accounting for approximately 80–90% of cases [3]. PTC is prone to cervical lymph node metastasis, with a metastasis rate of over 50% [4]; lymph node metastasis is a major risk factor for local recurrence and poor prognosis.

Currently, ultrasound is the preferred imaging method for evaluating thyroid nodules and cervical lymph nodes [5, 6]. However, due to the deep location of lymph nodes in the tracheoesophageal groove, ultrasound is difficult to probe, and it is difficult to distinguish metastatic hypoechoic lymph nodes from reactive hyperplasia lymph nodes in conventional ultrasound, resulting in low sensitivity and high missed diagnosis rate of cervical lymph node metastasis in conventional ultrasound diagnosis of PTC [7]. Lymph node metastasis affects the treatment choice [8 –10]. Therefore, methods that are more objective and accurate are required to predict LLNM in patients with PTC to guide the clinicians in developing a reasonable surgical plan, reduce the recurrence rate and reoperation complications, and improve the prognosis.

CEUS is a clean blood pool imaging technique that reflects the blood perfusion within the tumor and surrounding tissues and compensates for the shortcomings of conventional ultrasound through qualitative and quantitative analyses [11 –13]. In this study, we constructed a nomogram prediction model by combining the clinical characteristics and conventional ultrasound and CEUS features to provide a reliable and intuitively visualized guidance tool for clinicians.

2 Materials and methods

2.1 Patient population

This study included 428 PTC patients who underwent thyroidectomy, central lymph node dissection, or lateral cervical lymph node dissection at the First Affiliated Hospital of Soochow University from September 2020 to August 2021. When a patient had several lesions at the same time, CEUS was performed for the most suspicious malignant lesion. All patients provided written informed consent before undergoing CEUS. Thus, 428 lesions were included in this study. According to the postoperative pathological results, the patients were divided into the group with LLNM (n = 94) and the group without LLNM (n = 334).

The inclusion criteria were as follows: (1) voluntary cooperation in ultrasound and CEUS examinations; (2) the pathological diagnosis after surgery was PTC; (3) thyroidectomy performed at our hospital, with central or lateral lymph node dissection performed during the operation; (4) no treatment received before ultrasound; (5) no history of head and neck radiation exposure or family history of thyroid cancer; and (6) no history of distant metastasis or other malignancies.

The exclusion criteria were as follows: (1) poor quality of ultrasound images; (2) severe cardiac and pulmonary function impairment, resulting in the inability to undergo CEUS; and (3) incomplete clinical case data.

2.2 Instruments and methods

This study used LOGIQ E20 ultrasonic diagnostic instrument (GE Healthcare, Milwaukee, Wisconsin, USA) with ML6-15 and L2-9VN high-frequency linear array probes (frequencies: 5–13 MHz and 2–10 MHz, respectively; mechanical index: 1.4). The contrast medium used was SonoVue (Braco, Milan, Italy), which was mixed with 5.0 mL of 0.9% sodium chloride solution before use and shaken to form a milky white suspension for later use. The patient was placed in the supine position with full exposure of the target neck area. The routine ultrasound pattern for the thyroid was followed, with multi-section sweeps of the nodules and retention of the dynamic images. The best viewing section of the most suspicious malignant nodule was selected, and we switched to the CEUS mode. The patient was instructed to breathe calmly and avoid coughing or swallowing. First, 1.5 mL of SonoVue suspension was rapidly injected into the median elbow vein, followed by 5 mL of normal saline. Simultaneously, the timer and dynamic storage key of the ultrasound examination instrument were activated and maintained for more than 90 s.

2.3 Image interpretation and analysis

Without any clinical and postoperative information, the images were re-analyzed, interpreted, and recorded by two senior attending physicians in the Ultrasound Department. When the results were inconsistent, re-analysis and discussions were conducted until a consensus was reached.

The main observation indicators for each imaging modality were as follows:

Conventional ultrasound: Location of the nodule (upper, middle, lower, isthmus), maximum tumor diameter, aspect ratio, border, calcification, contact/no contact with the thyroid peritoneum, and central lymph node metastasis

Color Doppler flow imaging (CDFI) [14]: Type I: no blood flow signal in and around the nodule; Type II: limited blood flow signal seen in or around the nodule; Type III: rich blood flow in the nodule

CEUS: Enhanced mode, enhancement intensity, peak uniformity, presence/absence of perfusion defect, enhanced border, expansion/no expansion of the nodule after enhancement, and continuity of the thyroid capsule around the nodules in the early stage of enhancement

2.4 Statistical analysis

SPSS v. 23.0 software (IBM Corp.) and MedCalc 15.8 were used for statistical analyses. In the univariate analysis, the chi-square test or Fisher exact probability method was used; P-values < 0.05 indicated statistically significant differences. In the multivariate analysis, binary stepwise logistic regression analysis was conducted to identify independent risk factors and establish prediction models. Moreover, receiver operating characteristic curves (ROC) were plotted for predictive models, the area under the curve (AUC) was calculated, and the diagnostic performances of the models were evaluated. The “rms” package in R 4.2.0 software was used to build a nomogram for predicting LLNM. Calibration curves were plotted and decision curve analysis (DCA) was performed to evaluate the accuracy and clinical utility of the models.

3 Results

3.1 Demographic information of patients and lymph node metastasis rate

This study included 428 PTC patients of average age 40.43±10.76 years (range: 21–71 years), comprising 136 men (31.8%) and 292 women (68.2%). Cervical lymph node metastasis was confirmed in 232 cases (54.21%), including 211 cases (49.30%) with central lymph node metastasis and 94 cases (21.96%) with LLNM. Among the 94 LLNM cases, 21 (4.91%) showed skip metastasis.

3.2 Univariate analysis of lateral lymph node metastasis

The preoperative ultrasound revealed that 113 nodules (26.4%) were located in the upper part of the thyroid, 163 (38.1%) in the middle part, 121 (28.3%) in the lower part, and 31 (7.2%) in the isthmus.

According to the maximum tumor diameter, the lesions were divided into those measuring < 1.0 cm (n = 220) and those measuring≥1.0 cm (n = 208). The location of the cancer foci and maximum tumor diameter showed statistically significant differences between the groups with and without LLNM (P < 0.05) (Table 1).

Table 1
Univariate analysis of the risk factors for lateral lymph node metastasis

Characteristics Lateral lymph node metastasis Total (n = 428) X² P-value

NO (n = 334) YES (n = 94)

Age, years <55 292 83 375 0.051 0.820

≥55 42 11 53

Sex Male 100 36 136 2.364 0.124

Female 234 58 292

Tumor location Isthmus 27 4 31 11.163 0.011

Upper third 76 37 113

Middle third 131 32 163

Lower third 100 21 121

PTC with HT Yes 66 21 87 0.301 0.583

No 268 73 341

Maximum tumor diameter <1cm 194 26 220 27.181 <0.001

≥1cm 140 68 208

Aspect ratio ≥1 156 29 185 7.515 0.006

<1 178 65 243

Borders Clear/Vague 231 64 295 0.040 0.842

Irregular 103 30 133

Calcification No 98 12 110 13.360 0.001

Coarse calcification 33 6 39

Microcalcification 203 76 279

CDFI None 78 15 93 7.699 0.021

Few 236 66 302

Rich 20 13 33

Contact with the capsule No 95 11 106 11.034 0.001

Yes 239 83 322

CLNM No 196 21 217 38.761 <0.001

Yes 138 73 211

Characteristics	Lateral lymph node metastasis	Total (n = 428)	X²	P-value
Age, years	<55	292	83	375	0.051	0.820
	≥55	42	11	53
Sex	Male	100	36	136	2.364	0.124
	Female	234	58	292
Tumor location	Isthmus	27	4	31	11.163	0.011
	Upper third	76	37	113
	Middle third	131	32	163
	Lower third	100	21	121
PTC with HT	Yes	66	21	87	0.301	0.583
	No	268	73	341
Maximum tumor diameter	<1cm	194	26	220	27.181	<0.001
	≥1cm	140	68	208
Aspect ratio	≥1	156	29	185	7.515	0.006
	<1	178	65	243
Borders	Clear/Vague	231	64	295	0.040	0.842
	Irregular	103	30	133
Calcification	No	98	12	110	13.360	0.001
	Coarse calcification	33	6	39
	Microcalcification	203	76	279
CDFI	None	78	15	93	7.699	0.021
	Few	236	66	302
	Rich	20	13	33
Contact with the capsule	No	95	11	106	11.034	0.001
Yes	239	83	322
CLNM	No	196	21	217	38.761	<0.001
	Yes	138	73	211

(PTC, papillary thyroid carcinoma; HT, hyperthyroidism; CDFI, color Doppler flow imaging; CLNM, central lymph node metastasis).

In the univariate analysis, LLNM correlated significantly with the aspect ratio, calcification, CDFI findings, contact/no contact with the capsule, contrast enhancement intensity, peak uniformity, expansion/no expansion of the nodule after enhancement, and continuity of the capsule at the early stage of enhancement (P < 0.05 for all) (Tables 1 and 2).

Table 2

Univariate analysis of contrast-enhanced ultrasound features in lateral lymph node metastasis

Characteristics	Lateral lymph node metastasis		Total (n = 428)	X²	P-value
		NO (n = 334)	YES (n = 94)
Enhanced mode	Centripetal	217	63	280	0.136	0.712
	Non-centripetal	117	31	148
Early intensity	Hypoenhancement	179	56	235	12.850	0.002
	Iso-enhancement	122	19	141
	Hyperenhancement	33	19	52
Peak intensity	Hypoenhancement	171	55	226	13.706	0.001
	Iso-enhancement	130	20	150
	Hyperenhancement	33	19	52
Late intensity	Hypoenhancement	164	52	216	15.038	0.001
	Iso-enhancement	146	25	171
	Hyperenhancement	24	17	41
Peak uniformity	Uniformity	110	15	125	10.225	0.001
	Non-uniformity	224	79	303
Perfusion defect	No	322	86	408	—	0.055
	Yes	12	8	20
Nodule enlargement after enhancement	No	292	71	363	8.056	0.005
	Yes	42	23	65
Enhanced border	Well-defined	29	10	39	0.339	0.561
	Ill-defined	305	84	389
Envelope continuity	Continuous	250	34	284	49.160	<0.001
	Interrupted	84	60	144

3.3 Multivariate binary logistic regression analysis

Binary stepwise logistic regression analysis showed that the following were independent risk factors for LLNM: nodules located in the upper thyroid (OR = 2.640, 95% CI: 1.488–4.682; P < 0.001), maximum tumor diameter≥1.0 cm (OR = 2.027, 95% CI: 1.146–3.586; P = 0.015), microcalcification (OR = 2.176, 95% CI: 1.153–4.106; P = 0.016), central lymph node metastasis (OR = 3.091, 95% CI: 1.721–5.549; P < 0.001), enhanced late hyperenhancement (OR = 2.440, 95% CI: 1.081–5.508; P = 0.032), and membrane continuity interruption in early enhancement (OR = 3.988, 95% CI: 2.315–6.871; P < 0.001) (Table 3).

Table 3
Multivariate analysis of risk factors for lateral lymph node metastasis

Characteristics β SE Wald P OR 95% CI

Lower Limit Upper Limit

Location (upper thyroid) 0.971 0.292 11.018 0.001 2.640 1.488 4.682

Maximum tumor diameter (≥1 cm) 0.707 0.291 5.893 0.015 2.027 1.146 3.586

Microcalcification 0.778 0.324 5.763 0.016 2.176 1.153 4.106

Central lymph node metastasis 1.128 0.299 14.279 <0.001 3.091 1.721 5.549

Enhanced late hyperenhancement 0.892 0.415 4.608 0.032 2.440 1.081 5.508

Membrane continuity interruption 1.383 0.278 24.836 <0.001 3.988 2.315 6.871

Constant –3.919

Characteristics	β	SE	Wald	P	OR	95% CI
Location (upper thyroid)	0.971	0.292	11.018	0.001	2.640	1.488	4.682
Maximum tumor diameter (≥1 cm)	0.707	0.291	5.893	0.015	2.027	1.146	3.586
Microcalcification	0.778	0.324	5.763	0.016	2.176	1.153	4.106
Central lymph node metastasis	1.128	0.299	14.279	<0.001	3.091	1.721	5.549
Enhanced late hyperenhancement	0.892	0.415	4.608	0.032	2.440	1.081	5.508
Membrane continuity interruption	1.383	0.278	24.836	<0.001	3.988	2.315	6.871
Constant	–3.919

(SE, standard error; OR, odds ratio; CI, confidence interval).

ROC curves of conventional ultrasound alone and combined with CEUS were plotted to predict LLNM in PTC patients (Fig. 3). The results showed that the sensitivity, specificity, and AUC of the combined index to predict LLNM in PTC patients were 72.34%, 78.74% (best cut-off value, 0.511), and 0.818 (95% CI: 0.778–0.853), respectively (Table 4). The predictive efficacy of this model was good. The AUC of LLNM in PTC patients predicted by the combined index was greater than that predicted by conventional ultrasound alone, with a statistically significant difference (Z-value: 2.704; P < 0.05).

Fig. 1

The patient was a 35-year-old female with a maximum tumor diameter of 1.1 cm. Postoperative pathology: thyroid papillary carcinoma(d), no cervical lymph node metastasis (e). Gray-scale ultrasound showed solid hypoechoic nodules with aspect ratio < 1(a). CDFI shows streaks of blood flow in and around the nodules(b). CEUS shows uniform low enhancement of the nodules and continuous thyroid membranes around the nodules.

Fig. 2

The patient was a 38-year-old male with a maximum tumor diameter of 1.3 cm. Postoperative pathology: papillary thyroid carcinoma (d), central and lateral cervical lymph node metastasis (e). Gray-scale ultrasound showed that the nodules were solid hypoechoic, the aspect ratio was < 1, and the nodules touched the thyroid capsule(a). CDFI showed that there was no blood flow signal inside the nodule, but streaky blood flow signal around the nodule(b). CEUS showed uneven low enhancement of the nodules and discontinuity of the peripheral thyroid envelope(c).

Fig. 3

Conventional ultrasound alone and combined with contrast-enhanced ultrasound predicting the receiver operating characteristics curve of lateral lymph node metastasis in papillary thyroid carcinoma patients.

Table 4

Diagnostic efficacy of conventional ultrasound alone and combined with contrast-enhanced ultrasound in predicting lateral lymph node metastasis in papillary thyroid carcinoma patients

Index	Sensitivity (%)	Specificity (%)	AUC (95% CI)
Combined conventional ultrasound and contrast-enhanced ultrasound	72.34	78.74	0.818 (0.778∼0.853)
Conventional ultrasound alone	67.02	72.16	0.777 (0.735∼0.816)

(AUC, area under the curve; CI, confidence interval).

3.4 Establishment and evaluation of the nomogram model

The rms package in R software was used to create a nomogram for predicting LLNM in PTC patients (Fig. 4) to assess the risk of LLNM individually in the patients. The calibration curve highlighted that the predicted calibration curve of the model is close to the standard curve, and the calibration degree was high (Fig. 5). DCA showed that when the domain probability range is approximately 10–90%, the net benefit was higher than all or none, indicating that the model has strong clinical practicality (Fig. 6).

Fig. 4

Nomogram for predicting lateral lymph node metastasis in papillary thyroid carcinoma patients.

Fig. 5

Calibration curves of the nomogram for predicting lateral lymph node metastasis in papillary thyroid carcinoma patients.

Fig. 6

Decision curve analysis of the nomogram for lateral lymph node metastasis in papillary thyroid carcinoma patients.

4 Discussion

PTC has a good prognosis, with a 10-year survival rate of over 90% [15]; however, it is prone to cervical lymph node metastasis [16]. According to the relevant literature, the risk of recurrence in PTC patients with cervical lymph node metastasis is six times higher than that in patients without lymph node metastasis, and the disease-free and overall survival rates are significantly lower in the former than in the latter [17]. Therefore, rational and comprehensive initial surgical treatment can reduce the local recurrence rate and improve the overall survival rate.

With the continuous development of imaging technology, the advantages of ultrasound in diagnosing thyroid lesions and detecting their invasiveness have become increasingly prominent [18]. Ultrasound is safe, noninvasive, non-radioactive, and reproducible, and it has become the clinically preferred method of imaging examination. This study retrospectively analyzed the clinical features and conventional ultrasound and CEUS findings of 428 PTC patients, summarized the risk factors for LLNM, and visualized complex regression equations to construct a reliable and easy-to-use nomogram model for individualized prediction of LLNM to avoid over- or under-treatment.

PTC located in the upper thyroid region and the presence of central lymph node metastasis are independent risk factors for LLNM, which corroborates the results of Dou et al. [19, 20]. Although lymph node metastasis in PTC occurs first in the central region and then extends to the lateral cervical region, it has the property of skip metastasis [21]. This could be attributed to the special anatomy of the upper thyroid gland, which has a separate lymphatic drainage pathway that bypasses the central region and drains directly into the lateral lymph nodes along the lymphatic vessels of the superior thyroid artery [22]. This lymphatic drainage pathway could cause occult lymph node metastasis; hence, it should be carefully evaluated before surgery.

When the maximum diameter of the tumor was≥ 1.0 cm, the LLNM rate was approximately 32.7% (68/208), and when it was < 1 cm, the LLNM rate was almost 11.8% (26/220). These results show that the larger the tumor diameter, the higher the risk of cervical lymph node metastasis, which corroborated the results of previous studies [23, 24]. Malignant tumors secrete vascular endothelial growth factor, which promotes the continuous development of new blood vessels, increases the tumor diameter, and expands the infiltration range. Moreover, the risk of lymphatic metastasis to surrounding lymph nodes increases.

Microcalcification is a risk factor for LLNM, which is consistent with the findings of Wang et al. [25]. Microcalcification is a calcium salt deposit caused by the hyperplasia of blood vessels and fibers in the tumor tissue, reflecting the rapid growth of the cancer cells, and it is a potential malignant feature commonly detected on ultrasound. Univariate analysis revealed that although nodal contact with the thyroid peritoneum was associated with the development of LLNM in PTC patients, it was not an independent risk factor for LLNM. Xue et al. [26] believed that the larger the contact area between the primary tumor and thyroid capsule, the higher the tendency for cervical lymph node metastasis. This study did not calculate the contact area between the nodule and capsule; hence, the results were slightly different.

High enhancement in the late stage of CEUS and disruption of the thyroid envelope continuity around the early stage of enhanced cancer are risk factors for LLNM in PTC patients [27]. Hyperenhanced nodules often suggest that the tumor is rich in feeding vessels. Factors such as several new blood vessels, weak vessel walls, and high permeability render the richly vascular PTC highly invasive, causing invasion of the surrounding capsule, infiltration of the surrounding tissue, and increased risk of cervical lymph node metastasis. Conventional ultrasound does not reveal capsule invasion effectively; angiography can visually present the discontinuity of the capsule, and its sensitivity is higher than that of conventional ultrasound [28].

A nomogram can intuitively provide a quantitative risk score. The advantage of this model is that it can convert complex regression equations into visual graphs and is easy for clinical application. However, this study has some limitations. First, this was a single-center study without external verification. Second, the factors included in this study are all qualitative indicators; hence, further research on the quantitative parameter analysis of CEUS is warranted to improve the accuracy of the prediction model.

5 Conclusion

By combining the characteristics of conventional ultrasound and CEUS, we established a prediction model showing good discrimination, calibration, and clinical applicability. It provides a reliable and visual guide tool for clinicians to customize surgical methods.

Funding

This study was supported by the Jiangsu University Medical Education Collaborative Innovation Fund project(JDYY2023035); Open topic of The Provincial and Ministerial Joint Construction of State Key Laboratory of Radiation Medicine and Radiation Protection (2022) (GZK1202207); Zhangjiagang Youth Science and Technology Project(ZJGQNKJ202326).

Ethical statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of The First Affiliated Hospital of Soochow University, (NO. 343) and informed consent was taken from all the patients.

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