Papillary thyroid carcinoma (PTC) is frequently associated with synchronous or cervical lymph node metastasis (CLNM), which caused regional recurrence [
Contrast-enhanced ultrasound (CEUS), which could study the diffuse pattern and alterations of nodal perfusion, has been widely used for differentiating between benign and malignant thyroid nodules [
The aim of the present study was to estimate the performance of conventional US and CEUS in the diagnosis of CLNM and to explain the pathologic basis of CEUS performance.
Informed consent was obtained from all patients and the study was performed in accordance with the ethical guidelines of the Helsinki Declaration and approved by the local ethics committee. From March 2016 to November 2018, medical records of 218 consecutive TC patients after thyroidectomy were involved. Finally, fifty-six patients (16 men and 40 women) with 86 abnormal cervical lymph nodes (ACLNs) were enrolled in the study. The mean age of the examined patients was 52.6 ± 13.5 years (age range, 20–79 years). The median size of the ACLN was 1.2 × 0.7 × 1.0 cm (range, 0.5 × 0.4 × 0.4 cm to 2.5 × 1.5 × 1.8 cm).
The inclusion criteria for CEUS were as follows: (1) PTC patient after thyroidectomy and (2) cervical ACLN detected by conventional US in consecutive follow-up. ACLN was defined as nodes showing at least two following suspicious US features: (1) loss of fatty hilum, (2) presence of calcification or cystic change, (3) hyperechogenicity, and (4) round shape (length/width <2 : 1).
All conventional US scans were performed with a 9–12 MHz transducer (Acuson S2000, Siemens, Germany; Aplio 400, Toshiba, Japan). ACLNs were evaluated for size, distribution (level I to level VI), shape (oval or round), fatty hilum (present or loss) echogenicity (hypo- or hyperecho), cystic change (presence or absence), and microcalcification (presence or absence).
After grayscale US, color Doppler flow imaging (CDFI) was performed. The CDFI distribution of ACLN was classified into four types [
All CEUS examination was performed by two senior clinical ultrasound examiners (J. Z. and X.-H. D.), with more than 8 years of experience in ultrasound thyroid examination. After the conventional US, the largest diameter of the nodule was chosen before the CEUS mode was switched. The focus zone was always placed at the bottom level of the nodule, and CEUS was performed using low mechanical index (MI < 0.10). Contrast agents (SonoVue, Bracco International, Milan, Italy) were injected intravenously as a bolus at a 1.2 mL dose, followed by a 5 mL saline flush. The timer was started during the CEUS process, and the images that lasted at least 2 min were digitally stored as raw data. Due to prior thyroidectomy, ACLNs on CEUS were evaluated individually, not relative to surrounding tissue. The entrance mode on CEUS was classified as centripetal, or noncentripetal; the echo intensity at peak enhancement was classified as hyper- or hypoenhancement; the homogeneity of enhancement was classified as homogeneous or heterogeneous.
US-guided FNA was performed simultaneously on ACLN with suspicious US features in our institution. FNA was performed with a 23-gauge needle attached to a 2 mL disposable plastic syringe and aspirator. Materials obtained from aspiration were smeared onto glass slides. All smears were immediately placed in 95% alcohol for Papanicolaou staining, and the remaining material was rinsed in saline for cell block processing. Cytopathologists were not on-site during the biopsy.
Continuous quantitative data were expressed as mean ± standard deviation (SD).
All statistical tests were performed using commercially available software (Stata version 10.0; Stata Corp, College Station, TX, USA). For all tests, a
There were 54 metastatic (62.8%) and 32 benign (37.2%) lymph nodes at final cytopathology. Fifty-four CLNMs originated from 33 patients; as a result, unilateral modified neck dissection was performed on 27 patients, and 6 patients underwent radioiodine (RAI) therapy. Results of surgical pathology showed that 95 CLNMs of 375 lymph nodes were diagnosed in 27 patients.
Basic characteristics of the PTC patients are shown in Table
Basic characteristics of 56 PTC patients with ACLN after thyroidectomy.
Characteristics | Total PTCs with ACLN ( |
|
|
---|---|---|---|
CLNM group ( |
Benign group ( | ||
Mean age | 50.2 ± 2.7 | 56.1 ± 1.9 | 0.111 |
Range of age | 20–79 | 30–73 | |
Gender | 0.385 | ||
Male | 11 (19.6%) | 5 (8.9%) | |
Female | 22 (39.3%) | 18 (32.2%) | |
Multiple LNs | 0.282 | ||
Yes | 24 (42.9%) | 16 (28.5%) | |
No | 9 (16.1%) | 7 (12.5%) | |
Mean FNAB period after operation (month) | 56.3 ± 16.3 | 37.0 ± 7.4 | 0.352 |
Metastasis in history | 0.007 | ||
Yes | 24 (42.9%) | 8 (14.3%) | |
No | 9 (16.1%) | 15 (26.7%) |
With regard to conventional US and CEUS features, intensity at peak time, homogeneity, CDFI patterns, echogenicity, and cystic change or microcalcification were significantly associated with CLNM, whereas shape, fatty hilum, position, and entrance mode in CEUS were not (Table
Conventional US, CDFI, and CEUS indicators of ACLN (
US feature | Benign | CLNM |
|
---|---|---|---|
( |
( | ||
Median size | 10 × 5 mm | 12 × 6 mm | 1.000 |
Shape | 0.171 | ||
Round | 16 (18.6%) | 36 (41.9%) | |
Oval | 16 (18.6%) | 18 (20.9%) | |
Fatty hilum | 0.101 | ||
Absent | 18 (20.9%) | 40 (46.5%) | |
Present | 14 (16.3%) | 14 (16.3%) | |
Echogenicity | 0.067 | ||
Hyper | 8 (9.3%) | 25 (29.1%) | |
Hypo | 24 (27.9%) | 29 (33.7%) | |
Cystic change or microcalcification | 0.004 | ||
Present | 2 (2.3%) | 19 (22.1%) | |
Absent | 30 (34.9%) | 35 (40.7%) | |
Position | 0.366 | ||
Level II | 3 (3.5%) | 7 (8.1%) | |
Level III | 8 (9.3%) | 11 (12.8%) | |
Level IV | 19 (22.1%) | 29 (33.7%) | |
Level V | 1 (1.2%) | 0 (0%) | |
Level VI | 1 (1.2%) | 7 (8.1%) | |
CDFI patterns | 0.014 | ||
Type I | 20 (23.3%) | 16 (18.6%) | |
Type II | 3 (3.5%) | 7 (8.1%) | |
Type III | 3 (3.5%) | 4 (4.7%) | |
Type IV | 6 (7.0%) | 27 (31.4%) | |
Intensity at peak time | ≤0.001 | ||
Hyperenhancement | 10 (11.6%) | 42 (48.8%) | |
Hypoenhancement | 22 (25.6%) | 12 (14.0%) | |
Entrance mode | 0.142 | ||
Centripetal | 6 (7.0%) | 19 (22.1%) | |
Noncentripetal | 26 (30.2%) | 35 (40.7%) | |
Homogeneity | ≤0.001 | ||
Heterogeneous | 4 (4.6%) | 44 (51.2%) | |
Homogeneous | 28 (32.6%) | 10 (11.6%) |
Multivariate logistic regression analysis showed that homogeneity (OR = 53.9,
Multivariate logistic regression analysis in predicting CLNM.
Overall ( |
B | SE |
|
Odds ratio | 95% CI |
---|---|---|---|---|---|
Cystic change or calcification | 2.78 | 1.17 | 0.018 | 16.1 | 1.62–158.8 |
CDFI patterns | 0.13 | 0.29 | 0.648 | 1.14 | 0.64–2.06 |
Intensity at peak time | 2.43 | 0.93 | 0.009 | 11.4 | 1.82–71.2 |
Homogeneity | 3.65 | 0.85 | 0.000 | 38.6 | 7.25–204.9 |
The overall diagnostic performance of homogeneity (Az: 0.845; 95% CIs: 0.767–0.923) was superior to other predictors such as intensity at peak time (Az: 0.733; 95% CIs: 0.634–0.832), CDFI patterns (Az: 0.689; 95% CIs: 0.582–0.797), and cystic change or calcification (Az: 0.645; 95% CIs: 0.568–0.722) (Table
ROC analyses for the characteristics in prediction of CLNM from patients with PTCs.
Overall ( |
Az | 95% CI | Sen (%) | Spe (%) | PPV (%) | NPV (%) | Accuracy (%) |
---|---|---|---|---|---|---|---|
Cystic change or calcification | 0.645 | 0.568–0.722 | 35.2 | 93.8 | 90.5 | 46.2 | 57.0 |
CDFI patterns | 0.689 | 0.582–0.797 | 70.4 | 62.5 | 76.0 | 55.6 | 67.4 |
Intensity at peak time | 0.733 | 0.634–0.832 | 77.8 | 68.8 | 80.8 | 64.7 | 74.4 |
Homogeneity | 0.845 | 0.767–0.923 | 81.5 | 87.5 | 91.6 | 73.7 | 83.7 |
US | 0.746 | 0.647–0.848 | 83.3 | 56.2 | 74.1 | 56.2 | 67.4 |
CEUS | 0.895 | 0.838–0.952 | 64.8 | 100.0 | 100 | 62.7 | 77.9 |
Predictive equation | 0.936 | 0.885–0.986 | 87.0 | 87.5 | 92.2 | 80.0 | 87.2 |
A multivariate logistic regression equation was established with the following significant predictive factors:
Although controversy still exists that CLNM has no major impact on PTC specific survival after thyroidectomy, surgical excision of locoregional disease was recommended in combination with RAI therapy for patients with stable or slowly progressive asymptomatic disease. Conventional US is recommended as a primary screening tool for PTC patients, while FNA is further recommended for ACLN in guidelines [
Fifty-one-year-old PTC woman had received left thyroidectomy two years ago. ACLNs were detected on the right neck, located in level IV. (a) Loss of fatty hilum, hyperechogenicity, and oval in conventional US (17 × 10 mm). A peripheral (Type IV) vascular pattern was shown in CDFI. Compared with previously conventional sonographic figures, aberrant vessels were clearly shown in chronological order in CEUS figures. (b) Microbubbles rose at the nodal capsule (red arrows) in the beginning (11 s after SonoVue injection). (c) Then aberrant vessels developed from the nodal capsule to hilum (red arrows, 13 s after SonoVue injection). (d) LN showed hyperenhancement 18 s after SonoVue injection. And this ACLN was proved to be metastatic PTC by FNA.
Color Doppler flow pattern is a good tool to distinguish benign and malignant nodes. Histopathological studies indicate that arteries and veins enter the node at the hilum and spread in benign nodes. By comparison, most CLNMs have aberrant vessels with a curved course entering from the nodal capsule to hilum (Figure
Twenty-eight-year-old PTC woman had received left thyroidectomy two years ago. ACLNs were detected on the left neck twice by conventional US in consecutive follow-up. (a) ACLN located in level IV: loss of fatty hilum and round shape (6 × 5 mm) in conventional US. None CDFI was shown (Type I). (b) Hypoenhancement on CEUS (13 s after SonoVue injection). (c) Needle was inserted in ACLN. (d) FNA revealed scattered normal lymph cell in a blood cell background. (e) Another ACLN located in level II: loss of fatty hilum and round shape (4 × 4 mm) in conventional US. A normal hilar (type II) pattern is shown in CDFI. (f) Hyperenhancement on CEUS (15 s after SonoVue injection). (g) Needle was inserted in ACLN. (h) FNA diagnosis was metastatic PTC.
CEUS has the capability to clearly display microvascular blood flow in tumors and can accurately evaluate the sequence and intensity of tumor perfusion and vascularity [
Different from previous literature which pointed that lymph node metastasis showed hyperenhancement [
Forty-one-year-old man had received left thyroidectomy four years ago. ACLNs were detected on the left neck one year ago. (a) ACLN located in level IV: loss of fatty hilum, microcalcification, and hyperechogenicity in conventional US (15 × 7 mm). A normal hilar (Type II) pattern is shown. Notice: right lower edge of LN showed hypoechogenicity. (b) Heterogeneous hyperenhancement on CEUS (19 s after SonoVue injection). Notice: right lower edge of LN showed hypoenhancement.) (c) Needle was inserted in ACLN, and FNA diagnosis was metastatic PTC. (d) This CLNM was filled with cancerous thyroid tissue under optical microscopy, and normal lymph tissues still exist in the edge of LN.
Several clinical phenomena had recently aroused the interest of examiners. Firstly, in most CLNM group patients (24/33) was found metastasis on the first thyroidectomy which implied that preoperative CLNM patients have greater possibility of having second metastasis even if they received RAI therapy after operation. Secondly, we reviewed primary PTC lesions on stored video and found that most PTCs preoperatively showed hypoenhancement on CEUS (Figure
Fifty-five-year-old woman had undergone right thyroidectomy three years ago. ACLNs were detected on the left neck one year ago. (a) ACLN located in level I: loss of fatty hilum and hyperechogenicity in conventional US (23 × 13 mm). A peripheral (Type IV) vascular pattern with evidence of abundant atypical peripheral flow is shown in CDFI. (b) Heterogeneous hyperenhancement on CEUS (13 s after SonoVue injection). (c) A hypoechoic, solid, and calcified thyroid nodule in the right lobe (TI-RADS category 4b) three years ago before the first thyroidectomy. (d) It showed hyperenhancement in CEUS (18 s after SonoVue injection) on stored video.
Previous studies [
In a word, conventional US is the primary tool for cervical evaluation of PTC patients postoperatively. CEUS will be further recommended once ACLNs are found. Heterogeneous enhancement and hyperenhancement are useful criteria to distinguish malignant LNs from benign ones.
All data generated or analyzed during this study are included in this article.
The authors declare that they have no conflicts of interest.
Xue-Hong Diao contributed equally to this work and should be considered co-first authors.
This work was supported by Grant 14411970400 from the Medical Guide Project of the Shanghai Science and Technology Commission.