Utility of quantitative contrast-enhanced ultrasound: a valuable prediction for capsule invasion assessment in papillary thyroid cancer

Introduction

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy (1), for which most patients have a favorable prognosis (2). However, some PTC patients have a risk of poor clinical outcomes, including local recurrence, extracapsular extension (ECE), and cervical lymph node metastases (CLNM) (3). ECE has an important role in determining the tumor stage and surgical management in patients with PTC (4,5). However, sonographers are often not concerned with ECE. Relatively, conventional ultrasound (US) is the first modality for evaluating capsule invasion, as it can demonstrate the nodule and its capsular abutment. Capsule invasion has been shown to be related to ECE and CLNM of PTC in the neck (6,7). Hence, the assessment of capsule invasion is a simplified method for evaluating the invasiveness of PTC.

ECE is a dominant fact of stage 3 and single capsule invasion to be stage 2 by the TNM/AJCC staging system (8th edition), including capsular abutment, contour bulging, vascularity beyond the capsule, as well as loss of the echogenic capsule, which indicate the capsule invasion, and these features should be described in the US report (8). However, conventional US has several shortcomings in detecting ECE or capsule invasion when compared with surgical pathology. Low detection of ECE may be caused by the PTC nodules growing into deep locations and identification of capsule invasion is also difficult to ascertain on conventional US when the capsule is compressed by a tumor. Therefore, more advanced US devices are required for surgical management in patients with PTC and predict ECE and capsule invasion.

Contrast-enhanced ultrasound (CEUS) can clearly display micro-vessel perfusion in tumor tissue and its surroundings. Existing studies show that CEUS could contribute to the diagnosis of ECE in PTC, which could benefit in determining the tumor stage and the surgical management of patients with PTC (9). However, the qualitative assessment of CEUS may be uncertain when the intensity of the nodule is not visibly different from the normal thyroid parenchyma. A quantitative assessment may reduce the objective bias and assist the diagnosis (10).

Therefore, the aims of this study were to evaluate the diagnostic accuracy of qualitative and quantitative CEUS in predicting capsule invasion and to determine the extent of surgery. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2194/rc).

Methods

Patients

Informed consent was provided by all patients. The retrospective study design was approved by the Shanghai General Hospital Ethics Committee (No. 2024SQ241), and the study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

The study was conducted between April 2019 and August 2024. A patient enrollment flow diagram is presented in Figure 1. A total of 204 PTC patients who underwent CEUS before thyroidectomy were involved in this study. The inclusion criteria were as follows: (I) nodules that underwent fine-needle aspiration (FNA), with cytological analysis revealing PTC or suspicious PTC; (II) the nodule showed a capsular abutment in conventional ultrasound; and (III) nodules larger than 0.6 cm. The exclusion criteria were as follows: (I) nodules with inconclusive cytological diagnoses; (II) nodules not undergoing surgical resection; (III) nodules that failed successful imaging with CEUS; and (IV) pathological results confirming benign nodules.

Figure 1 The patient enrollment flow diagram. CEUS, contrast-enhanced ultrasound; PTC, papillary thyroid carcinoma; US, ultrasound.

Conventional US examination

Conventional US examinations were performed using 10–14 MHz high-frequency linear transducers (Apoli 400 and 500; Canon, Irvine, CA, USA). Patients were scanned in the supine position with their necks extended. PTC was confirmed by fine-needle aspiration biopsy (FNAB). Thus, regular sonographic features (e.g., size, position, shape, margin, internal components, taller-than-wide shape, and calcifications) were not the concern. The conventional US features of capsule invasion were classified as follows: the capsular abutment of PTC, bulge in the thyroid contour, capsule echogenic loss, and vascularity extending beyond the nodule.

CEUS examination

After the conventional US examination, the largest view of the nodule was chosen before the CEUS mode was switched. The 10–14 MHz high frequency linear transducer (Apoli 400 and 500, Canon) and a low mechanical index (MI <0.10) were used to perform CEUS examinations. The focus zone was always placed at the bottom level of the nodule. Contrast agent (SonoVue, Bracco International, Milan, Italy) was injected intravenously as a bolus at a 1.2 mL dose, followed by a 5 mL saline flush. The CEUS images were digitally stored within 2 minutes.

The PTC detected on CEUS was evaluated relative to normal thyroid parenchyma. The peak intensity (PI) was classified as hyper-, iso-, or hypo-enhancement; the other CEUS features were not evaluated. The CEUS status of capsule invasion was observed during multi-angle scanning. According to Zhang et al. (10), the features were classified as follows: capsular abutment or not, loss of the echogenic capsule or not, and vascularity extending beyond the capsule or not. The conventional US and CEUS features of capsule invasion images were retrospectively reviewed by two observers independently who were blinded to the other reviewer’s judgment. Discrepancies were adjudicated by discussions with a third reviewer.

Quantitative parameters of the time-intensity curve (TIC) were obtained using the quantitative analysis software incorporated in the Aplio 400 or 500 systems. A region of interest (ROI) was placed at the area of thyroid nodule, avoiding the surrounding thyroid parenchyma and large feeding vessels. If a partial PTC was larger than 2 cm, it was difficult to acquire surrounding normal thyroid tissue; thus, quantitative parameters were analyzed only within the PTC nodule. Quantitative parameters were categorized as follows: PI referred to the maximum intensity of the TIC; time to peak (TTP) was the time taken to reach PI from the moment the first microbubble reached the lesion; mean transit time (MTT) was the time the contrast medium circulated inside the lesion; the area under the TIC (AUC) was proportionate to the total volume of blood in the ROI.

Surgery and pathology

Patients with clinically suspicious lymph node metastasis (LNM) or bilateral nodules underwent total thyroidectomy with bilateral and central lymph node dissection. The remaining patients underwent hemithyroidectomy with central lymph node dissection. ECE refers to tumor cells breaching the confines of the thyroid gland’s fibrous capsule or extending beyond the lymph node capsule into surrounding tissues (11). Capsular invasion refers to the histopathological evidence of tumor cells penetrating the fibrous capsule without breaching into surrounding tissues.

Statistical analysis

All statistical analyses were conducted using commercially available software (Stata, version 10.0; Stata Corp, College Station, TX, USA). A P value of <0.05 was considered indicative of statistical significance for all tests.

The Cochran-Mantel-Haensel (CMH) χ² test was employed for the analysis of stratified or matched categorical data. The non-capsule invasion was defined as “1”; Single capsule invasion was defined as “2”; ECE was defined as “3”. The Spearman correlation test was used in PTC patients to correlate capsule invasion with cervical LNM. Multivariate logistic regression analysis was used to identify the independent factors associated with capsular invasion. Receiver operating characteristic (ROC) curves were drawn for parameters found to be significant in multivariate logistic regression analysis. Student’s t-test was used to in the parameters PI and TTP, and the rank-sum test was used to in the parameters MTT and AUC due to their non-normal distribution.

Results

Demographic and clinicopathological data

A total of 107 patients with 109 PTC nodules were included in the study, among whom 34 (31.7%) were men. The mean age was 45.2±14.2 years (range, 16–87 years). The mean maximum nodule diameter was 10.7±6.2 mm (range, 6–35 mm).

A total of 51 of the 109 (46.8%) PTC nodules had capsule invasion (including 19 nodules with ECE), whereas 58 (53.2%) PTC nodules were without capsule invasion. There was no significant difference in age and gender between PTC patients with and without capsule invasion (P>0.05). Nodule size was significantly different between the two groups (P<0.05) (Table 1).

The relationship between capsule invasion and cervical LNM is shown in Figure 2. A significant difference in cervical LNM rate was found in nodules with non-capsule invasion, single capsule invasion, and ECE groups (χ²=11.34, P<0.01). Non-capsule invasion, single capsule invasion, and ECE demonstrated a significant linear trend with cervical LNM (r=0.309, P=0.001) (Figure 3).

Figure 2 Pathological results showing the relationship between capsule invasion and cervical LNM in patients with PTC. ECE, extracapsular extension; LNM, lymph node metastasis; PTC, papillary thyroid carcinoma; US, ultrasound.

Figure 3 The linear trend between capsule state (0 = no ECE, 1 = single capsule invasion, and 2 = ECE) and cervical lymph node metastasis (0 = no CLNM, 1 = CLNM). CLNM, cervical lymph node metastasis; ECE, extracapsular extension.

Conventional US and capsule invasion

The PTC features of conventional US with and without capsule invasion are shown in Table 2. Fifty-one of the 109 PTC cases were larger than 9 mm during the US examination, of which 58.8% (30/51) had capsule invasion. Among the 30 nodules, 19 nodules showed ECE. A total of 36 of the 109 PTC images demonstrated bulging in the normal thyroid contour in conventional US examination. The pathological results showed that 72.2% (26/36) of nodules had capsule invasion. Among the 26 nodules, 10 showed ECE. A total of 21 PTC cases showed vascularity extending beyond the nodule (pathology: 38.1% nodules with ECE, 8/21; 23.8% nodules with single capsule invasion, 5/21). A total of 19 PTC cases displayed a loss in the echogenic capsule (pathology: 31.6% nodules with ECE, 6/19; 26.3% nodules with single capsule invasion, 5/19). There was a significant difference in bulge in the normal thyroid contour and nodule size between the capsular invasion and non-capsular invasion groups. Bulging in the normal thyroid contour showed the best diagnostic performance in conventional US. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were 50.9%, 82.8%, 72.2%, 65.8%, and 67.8%, respectively, when bulge in the normal thyroid contour in conventional US was regarded as capsule invasion, AUC [0.66, 95% confidence interval (CI): 0.58–0.75].

Qualitative CEUS and capsule invasion

Some 31 of the 109 PTC images demonstrated capsular abutment (indicated by nodular enhancement) on CEUS. The pathological results showed that 12.9% of nodules had no capsule invasion (4/31). Among the remaining 27 nodules, 35.4% nodules had ECE, 11/31. Enhancement extending beyond the capsule was present in six nodules (pathology: 66.7% nodules with ECE, 4/6; 16.6% nodules with capsule invasion, 1/6; 16.6% nodules with no capsule invasion, 1/6). Discontinuous capsular enhancement was found in 23 nodules (pathology: 30.4% nodules with ECE, 7/23, and 56.5% nodules with capsule invasion, 13/23). There was a significant difference in two CEUS characteristics (capsular abutment on CEUS and discontinuous capsular enhancement) between the capsular invasion and no capsular invasion groups (Table 2).

ROC analysis demonstrated that qualitative CEUS images with capsular abutment had the highest AUC (0.73, 95% CI: 0.65–0.80) to detect capsular invasion. The diagnostic sensitivity, specificity, PPV, NPV, and accuracy were 52.9%, 93.1%, 87.1%, 69.2%, and 74.3%, respectively.

CEUS characteristics of PTC and capsule invasion

The CEUS characteristics of PTC with and without capsule invasion are shown in Table 3. There were significant differences in the enhancement characteristics (hypo-, iso, and hyper-enhancement) between the capsule invasion group and non-capsule invasion groups (χ²=24.71, P<0.001), but no significant difference was found between the ECE and capsular invasion groups (χ²=5.23, P=0.07).

For PTCs with hypo-, iso-, and hyper-enhancement characteristics, the single invasion rates were 20.3% (12/59), 40.0% (14/35), and 40.0% (6/15), respectively, whereas those of ECE were 13.5% (8/59), 8.6% (3/35), and 53.3% (8/15), respectively. Among the nodules with capsular abutment in CEUS, 15 demonstrated hyper-enhancement (48.3% 15/31), of which 35.3% (11/31) were iso-enhancement and 16.1% (5/31) were hypo-enhancement. The enhancement characteristics demonstrated an AUC of 0.680 for predicting capsule invasion using the optimum cutoff value of hyper- and iso-enhancement. The sensitivity, specificity, PPV, NPV, and accuracy of the model were 52.9%, 93.1%, 87.1%, 69.2%, and 74.3%, respectively.

Quantitative CEUS parameters of PTC and capsule invasion

The findings displayed in Table 4 revealed a significant difference in PI, MTT, AUC, wash in, and wash out between the non-capsule invasion group and the single capsule invasion group (ECE group) (P<0.05). However, no significant differences were observed in these parameters between the single capsule invasion groups and ECE groups (P>0.05), nor were there significant differences in TTP and slope among all three groups (P>0.05).

The parameters demonstrated AUCs of 0.749, 0.702, 0.718, 0.714, and 0.715 for predicting capsule invasion (PI, MTT, AUC, wash in, and wash out). Using the optimum cutoff value of PI >13 in the validation cohort, the sensitivity, specificity, PPV, NPV, and accuracy of the model were 68.6%, 67.2%, 64.8%, 82.5%, and 67.9%, respectively.

According to multivariable analysis, prediction models were constructed with variables of superior predictive performance including nodule size, bulge in the normal thyroid contour, discontinuous capsular enhancement in CEUS, discontinuous capsular enhancement in CEUS, and quantitative CEUS parameter PI. An equation was derived for multivariate logistic regression with the five most significant predictive factors:

P=11+exp(−(−2.72+2.9x1+1.8x2+8.9x3+3.5x4+9.4x5))[1]

Where x₁ is bulge in the normal thyroid contour, x₂ is nodule size >9 mm, x₃ is capsular abutment in CEUS, x₄ is discontinuous capsular enhancement in CEUS, and x₅ is PI >13.

This equation displayed a better diagnostic performance compared with other models alone (P<0.05 for all) (Figure 4, Table 5).

Figure 4 Comparison of AUCs among models for predicting capsule invasion. US model: bulge in the normal thyroid contour; CEUS model; capsular abutment on CEUS; PI model: quantitative PI >13. AUCs, areas under the ROC curve; CEUS, contrast-enhanced ultrasound; PI, peak intensity; ROC, receiver operating characteristic; US, ultrasound.

Discussion

The ECE status is important in pathological and clinical staging of PTC and also in determining the following surgical strategies (11). On pathological sections, single capsule invasion represents an early stage of ECE (6). However, it is difficult for conventional US to distinguish the status of single capsule invasion from ECE. In fact, capsular invasion without ECE has also been shown to be a poor predictor of PTC (12). Therefore, this study focused on the sonographic features for predicting capsular invasion.

Tumor size is relative to invasion, and a larger tumor has a greater possibility of invading the thyroid capsule (13). In the present study, the mean nodule size of the capsular invasion group (12.5±1.1 mm) was larger than that of the non-capsular invasion group (9.4±0.6 mm), and this difference was significant (P=0.0083). According to previous studies, the tumor size cutoff values differentiating between ECE and non-extrathyroidal extension (ETE) groups were 9 mm (14). In the present study, PTC with capsular abutment detected on conventional US caused more thyroid microcarcinomas to be confirmed with capsular invasion (Figure 5).

Figure 5 PTC with capsule invasion. (A) A hypoechoic nodule with an unclear margin and taller-than-wide shape was found in the left lobe of the thyroid gland by a conventional ultrasound (5 mm × 7 mm in size). A slight bulge in the normal thyroid contour and capsule capsular abutment are displayed in the sonogram. (B) Hypo-enhancement in the nodule is revealed by CEUS (arrows). The capsular abutment is detected in the anterior margin of capsule. (C) Quantitative CEUS features of PTC: the nodule shows heterogeneous hypo-enhancement at peak time (purple circle “T”) compared to normal thyroid parenchyma (cyan circle “1”), which was also higher than PI threshold (15.9>13). (D) The surgical pathology indicates thyroid papillary carcinoma with capsule invasion (H&E staining, ×40). CEUS, contrast-enhanced ultrasound; H&E, hematoxylin and eosin; PI, peak intensity; PTC, papillary thyroid carcinoma.

Several studies have explored ECE detection using conventional ultrasound: the presence of capsular abutment, bulge in the normal thyroid contour, capsule echogenic loss, and vascularity extending beyond nodule are considered characteristics of ECE (15); however, features of capsule invasion remain unknown. In fact, these conventional US features substantially correspond to the CEUS imaging characteristics: capsular abutment on CEUS occurred in 24.7% (31/109) of all PTCs with a sensitivity of 87.1% (27/31), and capsular abutment on CEUS was more conspicuous, which reduced the false-positive rate for detecting capsule invasion (Figure 6).

Figure 6 PTC without capsule invasion. (A) A hypoechoic nodule with a clear margin and oval shape was found in the left lobe of the thyroid gland by a conventional ultrasound (10 mm × 11 mm in size). An obvious bulge in the normal thyroid contour and capsule capsular abutment are displayed in the sonogram. (B) Qualitative CEUS features of PTC: the nodule shows heterogeneous hypo-enhancement at peak time; the capsular abutment is not detected in the anterior margin. (C) Quantitative CEUS features of PTC: the nodule shows heterogeneous hypo-enhancement at peak time, which was lower than PI threshold (12.6<13). (D) The surgical pathology indicates PTC without capsule invasion (H&E staining, ×40). CEUS, contrast-enhanced ultrasound; H&E, hematoxylin and eosin; PI, peak intensity; PTC, papillary thyroid carcinoma.

In this study, 19 nodules demonstrated capsular echogenic loss in conventional US, whereas 23 nodules showed discontinuous capsular enhancement in CEUS: in the case of similar detection rates, the accuracy has been improved (11/19 vs. 20/23, P<0.05). Loss of capsular echogenicity in the posterior capsule was not assured in conventional US yet discontinuous capsular enhancement in CEUS was more prominent. Continuous fibrous capsules do not always surround the thyroid and thyroid capsule—these are sometimes defined as pseudo-capsules composed of fibro-adipose tissue (6). This unique characteristic may influence the conventional US appearance of the thyroid capsule, making it difficult to evaluate thyroid capsular continuity. Meanwhile, CEUS is sensitive in detecting capsule invasion when discontinuous capsular enhancement is the diagnostic criteria.

Vascularity extending beyond the nodule can suggest abundant blood supply, which is associated with the tumor’s aggressiveness (16). Color Doppler flow imaging is convenient for the visualization of new blood vessels, which can supplement the diagnosis of capsule invasion. Nevertheless, color Doppler is greatly influenced by operator judgement and blood overflow of machines. Consequently, there is an urgent need to accurately assess the vascularity of nodules. Enhancement extending beyond the capsule corresponds to vascularity extending beyond the nodule; in CEUS mode, this feature is more sensitive (5/6 83.3%) than it is in color Doppler flow imaging (13/21 61.9%). The false-negative rate was considerably higher, which also can be attributable to the detection of capsule invasion in this population.

Bulge in the normal thyroid contour was considered the further stage of the capsular abutment (17). The infiltrating growth of PTC squeezes normal tissue, which bulges the thyroid contour. In this study, 72.2% (26/36) of nodule bulges in the normal thyroid contour had capsule invasion, whereas 38.5% (10/26) were cases of ECE. Significant differences (P<0.001) were observed in capsule invasion between the bulge in the normal thyroid contour group (26/36) and the group without bulge (25/73). It should be noted that bulge in the normal thyroid contour is the only conventional US feature without a corresponding CEUS imaging characteristic.

Hyper-enhanced nodules had the highest incidence of capsule invasion (93.3%) in different enhancement degrees, and hypo-enhanced nodules had a higher incidence of no capsule invasion, which suggests that the blood supply within a tumor may lead to progression (18,19). However, it was difficult to distinguish between iso- and hyper-enhanced nodules using CEUS, whereas hypo-enhanced nodules were confirmed owing to the good contrast. Meanwhile, the judgement of “hypo-enhancement” was compared with the surrounding tissue, and it does not indicate “real” poor blood supply (Figure 7). Moreover, capsular abutment in CEUS had the highest diagnostic efficiency in all qualitative CEUS parameters, yet it was still not satisfactory (AUC =0.73). Hence, using observer-independent quantitative assessments is necessary. Quantitative PI in PTC with capsule invasion was found to be higher than it was in those without capsule invasion. However, it was not sensitive in predicting capsule invasion with a single parameter. Following the addition of the PI >13 to the equation, the model’s diagnostic performance improved. With this parameter, we could reliably detect capsule invasion in PTC.

Figure 7 PTC with ECE and LNM. (A) A hypoechoic nodule with a clear margin and oval shape was found in the right lobe of the thyroid gland by a conventional ultrasound (20 mm × 26 mm in size). An obvious bulge in the normal thyroid contour and capsule capsular abutment is displayed in the sonogram. (B) Qualitative CEUS features of PTC: the nodule shows heterogeneous hyper-enhancement area in the nodule (arrows). Capsule abutment is displayed in both the anterior and posterior capsules. (C) Quantitative CEUS features of PTC: the nodule shows heterogeneous hyper-enhancement at peak time (PI =20.9); normal thyroid tissue around the mass was difficult to acquire. (D) An abnormal cervical lymph node (arrows) was observed on the ipsilateral upper neck (14 mm × 5 mm). The surgical pathology was PTC with ECE and LNM. CEUS, contrast-enhanced ultrasound; ECE, extracapsular extension; LNM, lymph node metastasis; PI, peak intensity; PTC, papillary thyroid carcinoma.

Our study has several limitations. Firstly, we only included cases with PTC; the capsule invasion risk of PTC in our patients may have been higher than that in the general population, potentially leading to selection bias. Secondly, the diagnostic performance of conventional US and qualitative CEUS may be contingent on the experience level of the radiologists, and the reproducibility of the conventional US feature and qualitative CEUS features was not discussed in the present study. Thirdly, the quantitative CEUS assessment of surrounding normal thyroid tissue was not available, so valuable information may have been lost. Finally, this was a single-center study with small sample size (especially for the cases with ECE), which may have caused a random error. Moreover, participants were retrospectively included in the trial, potentially leading to selection bias. A prospectively designed study may demonstrate convincing results in the future.

Conclusions

The application of a TIC-assisted quantitative CEUS approach can enhance the prediction of capsule invasion of PTC. The CEUS method presents significant potential for improving the clinician’s ability to determine the optimal management of PTC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2194/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2194/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2194/coif). The authors have no conflicts of interest to declare.

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. Informed consent was obtained from all patients. The retrospective study design was approved by the Shanghai General Hospital Ethics Committee (No. 2024SQ241), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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