Abstract
OBJECTIVE:
To investigate the diagnostic value of CEUS in atypical-enhanced PTC.
METHODS:
The clinical data, qualitative and quantitative parameters of CEUS in 177 Iso/hyper-enhanced thyroid nodules with definite pathological results were retrospectively analyzed in the Lanzhou University Second Hospital from June 2019 to January 2021. And the clinical value of CEUS in the diagnosis of atypical-enhanced PTC was assessed using univariate and multivariate analysis.
RESULTS:
Among the 177 thyroid nodules, 59 were benign and 118 were PTC. There were significant differences in age, enhancement border, ring enhancement, speed of wash in, speed of wash out, enhancement pattern, capsule interruption, time to peak, time to wash out, RT, TPH, and TTP (P < 0.05). Multivariate analysis showed unclear enhancement border and concentric enhancement were independent risk factors for the diagnosis of atypical-enhanced PTC by CEUS. The sensitivity, specificity, PPV, NPV, and accuracy of the model in diagnosing atypical-enhanced PTC were 88.1%, 71.2%, 86.0%, 75.0%, and 82.5%, respectively. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.910.
CONCLUSION:
The diagnosis of atypical-enhanced PTC can be better performed by enhancement characteristics and time intensity curve (TIC) of CEUS, which have a good clinical application value.
Introduction
According to global cancer statistics [1], approximately 586,000 people worldwide were diagnosed with thyroid cancer in 2020, accounting for 3.0% of all malignancies. Its incidence rate ranks the fifth in female malignancies, following breast, colorectal, lung, and cervical cancers. Ultrasonography is the preferred imaging method for thyroid [2–5]. CEUS has been shown in previous studies to have good diagnostic value for papillary thyroid carcinoma (PTC) [6–13]. Among the CEUS enhancement features, hypo-enhancement is considered a typical characteristic of PTC [6, 14]. However, with the increasing application of CEUS in the differential diagnosis of thyroid nodules, the emergence of atypically enhanced PTC has introduced some limitations to its use in distinguishing thyroid nodules. This phenomenon has gradually attracted attention among researchers. However, there is limited research available on the diagnosis of such nodules by CEUS.
Based on this, this study aims to screen the risk factors associated with CEUS iso/hyper-enhanced thyroid nodules and improve the diagnostic accuracy of CEUS for atypical-enhanced PTC by comparing the qualitative characteristics and quantitative parameters of CEUS in iso/high-enhanced benign and malignant thyroid nodules.
Materials and methods
Patients
This retrospective study was approved by the Ethics Committee of Lanzhou University Second Hospital. The number of the ethical approvement is 2020A-161. Written informed consent from each patient was waived. Patients who underwent CEUS examinations for thyroid nodules at Lanzhou University Second Hospital between June 2019 and January 2021 were retrospectively analyzed.
The inclusion criteria were as follows: (1) patients aged ≥18 years; (2) patients with complete clinical data, US and CEUS images; (3) solid or predominantly solid nodules; (4) iso/hyper-enhancing nodules in CEUS; and (5) nodules with accurate pathology obtained by FNAB cytology or postoperative histology. The exclusion criteria were as follows: (1) patients who are allergic to SonoVue contrast agent (Bracco); (2) patients with severe cardiopulmonary insufficiency who are unable to undergo CEUS; (3) nodules too large to have normal thyroid tissue as a control in CEUS; and (4) thyroid cancers other than papillary carcinoma. Ultimately, a total of 177 nodules from 153 patients (42 males and 111 females) were included, with a range of maximum nodule diameters from 0.4 to 3.3 cm, with a mean of (1.26 ± 0.68) cm.
US and CEUS examinations
The grey – scale US and CEUS examinations were performed using iU22 scanner (Phillips Medical Systems, Eindhoven, The Netherlands) equipped with a 5–12 MHz and 3–9 MHz linear probe. The patient was placed in supine position with full exposure of the neck, calm breathing, avoiding swallowing and talking. The L12-5 probe is used to perform grey – scale US examination. Static or dynamic grey – scale US images that could reflect characteristics of nodules in the longitudinal and transverse section were stored for analysis. Then the best section showing the target nodule was selected for CEUS examination, and the machine was switched to CEUS dual-amplitude mode, using the L9-3 probe (mechanical index 0.06). 1.6–2.0 ml contrast agent was injected quickly into the elbow vein, followed by 5 ml saline flush immediately. And at the same time, the time was timed, and the dynamic video was observed and stored for about 150 s for image analysis. All ultrasound images were marked with body markers. All of the above operations were performed by the same experienced radiologists.
Images analysis
Images were analyzed by two radiologists experienced in CEUS without knowledge of the pathology results. (1) CEUS qualitative parameters: Enhancement intensity, enhancement uniformity, enhancement boundary, Rim-like enhancement, entry velocity, fading velocity, enhancement pattern, and periplasmic continuity. (2) CEUS quantitative parameters: The two radiologists played back the CEUS dynamic image and observed the time of onset, peak, and regression of the target nodule. When the nodule was optimally displayed, the region of interest (ROI) of the nodule (ROI1) and the surrounding normal thyroid tissue (ROI2) were outlined using the QLAB software and Freeform Spline mode, and the time intensity curve (TIC) was plotted to obtain the quantitative parameters: Rise time (RT), Peak intensity (PI), Mean transit time (MTT), Rise time (RT), Peak intensity (PI), Mean transit time (MTT), Time from peak to one half (TPH), Wash in slope (WIS), Time to peak (TTP).
Statistical analysis
All statistical analyses were performed with SPSS 23.0. Count data were expressed by n (%), and comparisons between groups were made using the χ2 test or Fisher’s test. When the quantitative data obeyed normal distribution, it was expressed by mean ± SD, and comparisons between groups were made using the t-test. When the quantitative data obeyed non-normal distribution, it was expressed by M(QR), and comparisons between groups were made using the nonparametric Mann– Whitney test. The cut-off values of the quantitative data were calculated using the Jordon index method. Binary logistic regression was used for multifactorial analysis to screen the independent risk factors for diagnosis of atypical enhancing PTC by CEUS, and the ROC curve was plotted using the pathological findings as the gold standard. P < 0.05 was taken as statistically significant difference.
Results
Clinical data for diagnosis of atypical-enhanced PTCs
A total of 177 iso/hyper-enhanced thyroid nodules were included, including 59 benign nodules and 118 PTCs. Comparative analysis of the clinical data of the two groups showed that the difference in the age was statistically significant (P < 0.05), and the differences in gender of the patients and the location of nodules were not statistically significant (P > 0.05) (Table 1).
Clinical data for diagnosis of atypical-enhanced PTCs
Clinical data for diagnosis of atypical-enhanced PTCs
Comparative analysis of CEUS enhancement patterns between the two groups showed that the differences in enhancement boundary, Rim-like enhancement, entry velocity, fading velocity, enhancement pattern, and periplasmic continuity were all statistically significant (p < 0.05). The differences in enhancement intensity and enhancement uniformity were not statistically significant (p≥0.05). The diagnosis of PTC is more likely when the iso/hyper-enhanced nodule exhibits unclear enhancement borders, no ring enhancement or irregular ring enhancement, lately progression, early regression, centripetal enhancement, and disruption of periosteal continuity (Table 2).
CEUS enhancement pattern with diagnosis for atypical-enhanced PTCs [n (%)]
CEUS enhancement pattern with diagnosis for atypical-enhanced PTCs [n (%)]
Comparative analysis of CEUS quantitative parameters between the two groups showed that the differences in time to peak, time to regression, RT, TPH, and TTP were statistically significant (P < 0.05), and the differences in time to onset, PI, MTT, and WIS were not statistically significant (P > 0.05). The diagnosis of PTC was more likely when iso/hyper-enhanced nodules showed shorter time to peak, shorter time to regression, smaller RT, TPH, and TTP (Table 3 and Fig. 1).
CEUS quantitative parameters with diagnosis for atypical-enhanced PTCs [
*The data obeyed non-normal distribution, which was expressed by M(QR), and the non-parametric rank-sum test was used for comparison between groups, and the results were expressed as z-value and P-value.
A 51-year-old male. Two-dimensional ultrasound showed a hypoechoic nodule with irregular margins in the left lobe of the thyroid (shown by arrows in Fig. A); The CEUS reveals peak enhancement at 16 s after contrast agent injection, showing heterogeneous and slightly hyperenhancement (shown by arrows in Fig. B) with localized areas of hypoenhancement (shown by asterisks in Fig. B). The enhancement border is indistinct, and there is interruption of the posterior thyroid capsule (shown by triangles in Fig. B). At 28 seconds after contrast agent injection, the contrast agent within the nodule starts to wash out, showing low enhancement (shown by arrow in Fig. C). The TIC showed RT of 2.91 s, TPH of 32.89 s, and TTP of 11.36 s (shown in Fig. D). The pathologic finding confirms PTC.
The optimal cutoff values for diagnosing atypical-enhanced PTCs were determined as follows: peak time (17.5 s), fading time (48.5 s), RT (6.85 s), TPH (75.76 s), and TTP (11.36 s), obtained by using the Jordon’s index method. These cutoff values were employed to convert quantitative data into categorical data. Indicators with statistically significant differences in the univariate analysis were included in the binary logistic regression analysis, which showed that ill-defined enhancement borders and centripetal enhancement were independent risk factors for diagnosing atypical enhancement PTCs. While regular annular enhancement and simultaneous washout were its protective factors. The risk of diagnosing PTC in iso/hyperenhanced nodules with unclear enhancement borders was 3.770 times higher than those with clear borders, and the centripetal enhancement was 9.764 times higher than those without centripetal enhancement. The sensitivity, specificity, PPV, NPV, and accuracy of the model for diagnosing atypical enhancing PTCs were 88.1%, 71.2%, 86.0%, 75.0%, and 82.5%, respectively, (Table 4). The area under the ROC curve was 0.910. (Fig. 2).
Binary logistic regression analysis of CEUS diagnosis of atypical-enhanced PTCs
Binary logistic regression analysis of CEUS diagnosis of atypical-enhanced PTCs
ROC for the diagnosis of atypical-enhanced PTCs by multifactor analytic model.
With the sharp increase in the incidence of thyroid cancer, achieving an accurate diagnosis has become a necessary condition for standardized and individualized diagnosis and treatment. The application of CEUS in thyroid nodules has improved the diagnostic accuracy of thyroid nodules [8, 9]. The uneven low enhancement in CEUS is identified as the most accurate malignant enhancement feature for thyroid nodules. However, with the increasing clinical application of CEUS, a large number of nodules with atypical enhancement have emerged with diverse contrast manifestations. Previous study [15] has shown that CEUS enhancement characteristics of thyroid cancer were correlated with nodule size. Larger nodules tend to exhibit hyper-enhancement. Which may be related to the fact that the smaller the nodule is, the more it lacks a substantial blood supply system within it. Studies [16, 17] have shown that cervical lymph node metastasis is more likely to occur when PTC presents iso/hyperenhancement. Therefore, accurate diagnosis becomes both crucial and challenging when the suspicious nodules lack typical enhancement features.
In the univariate analysis of the qualitative data in this study, it was observed that individuals aged 55 or younger, those with unclear enhancement borders, the absence of annular enhancement or irregular annular enhancement, late wash in, early wash out, centripetal enhancement, and interrupted thyroid capsule were more likely to be diagnosed with PTC. The younger the age of patient, the higher likelihood of PTC, and increasing age served as a protective factor for PTC [18]. Cancerous tissue harbors a large number of immature and structurally disorganized neovascularization characterized by the formation of microthrombi emboli and numerous arteriovenous shunts [19]. Consequently, PTC exhibits late wash in and early wash out in CEUS, compared to normal thyroid tissue. In addition, the blood flow pattern was reconfigured in cancer nodules compared with normal thyroid tissue. The periphery area was more richly vascularized than the central area of nodules, and this vascular difference may be the main reason for centripetal enhancement. The indistinct enhancement border and interrupted capsule continuity are both related to the biological characteristics and its invasiveness of PTC. Cancerous tissues infiltrate into the surrounding normal thyroid tissues without clear boundaries. And when the nodule is adjacent to the capsule, the capsule of the thyroid is easy to be invaded, which is manifested by the appearance of a non-enhancing in the hyperechoic thyroid capsule. In benign nodules, CEUS may show a homogeneous ring of hyperenhancement around the nodule, due to perinodal vascular bypass or compression of surrounding normal thyroid tissue. The atypical-enhanced PTCs in this study may exhibit irregular ring-like enhancement, which is consistent with the findings of Zhang et al [20]. This may be related to the irregular invasive growth of PTC triggers peritumor immune response, leading to the enhancement of neovascularization following injection of contrast.
The TIC quantitatively responded to the changes in tissue microcirculatory perfusion over time. To further investigate, this study further evaluated the diagnostic performance of atypical-enhanced PTCs by CEUS using TIC and quantitative analysis of onset time, peak time, and wash out time obtained through observational methods. The results showed that the atypical-enhanced PTCs group exhibited shorter time to peak, wash out time, RT, TPH, and TTP values, compared to the benign group. Time to peak, RT, and TTP are all perfusion parameters [21–23]. Time to peak through observational methods refers to the time from the injection of the contrast agent to the degree of enhancement of the nodule is at its maximum. TTP is the time it takes for the TIC to reach peak intensity from the starting point. RT is the time at which the TIC goes from the starting point to the 50% of the peak intensity. These parameters to some extent both reflect the rate of microbubble perfusion within the nodule. The wash out time and TPH are clearance parameters [21–23], wash out time is the time from the injection of contrast agent into the nodule until the contrast agent starts to wash out from the nodule obtained by the observational method, and TPH is the time it takes for the enhancement level on the TIC to decrease from the peak value to 50%. These parameters to some extent both reflect the rate of microbubble clearance within the nodule. The shorter wash out time and TPH indicate a faster clearance rate compared to the benign groups in atypical-enhanced PTCs. These differences may be due to the regular distribution and well-functioning of microvasculature in benign nodules, whereas malignant nodules exhibit a significant presence of immature and structurally disorganized neovascularization. Which allows the contrast agent to diffuse and peak rapidly upon arrival at the nodule, followed by rapidly clearance.
There were several limitations in this study. First, the study was retrospective. And CEUS was only conducted on suspicious nodules identified in grayscale ultrasound. Therefore, there exists a potential bias in case selection. Second, this study is a single-center study, and future research will be multi-center studies with larger sample sizes specifically targeting atypical-enhanced PTCs.
Conclusion
In summary, suspicious thyroid nodules with CEUS manifesting iso/hyperenhancement can be further analyzed for additional CEUS features and TIC for assistance. Particularly, when the nodule exhibits centripetal enhancement and unclear enhancement borders, it is highly suspicious for PTC.
Conflict of interest
The authors have no conflicts of interest to declare.
Funding
This study was supported by The Gansu Province Youth Science and Technology Plan Project (22JR11RA078) and The Lanzhou University Second Hospital Outstanding Doctoral Fund Project (CY2022-YB-B02).
Author contributions
Conception and design: Guojuan Wang, Ci Yin, Yanfang Wang, Fang Nie. Acquisition of data: Yanfang Wang, Qi Li, Dan Yang. Analysis and interpretation of data: Guojuan Wang, Ci Yin, Peihua Wang.