The application of Contrast-enhanced US in distinguishing adrenal neuroblastoma from adrenal hemorrhage in infants

doi:10.21203/rs.3.rs-5013745/v1

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The application of Contrast-enhanced US in distinguishing adrenal neuroblastoma from adrenal hemorrhage in infants

https://doi.org/10.21203/rs.3.rs-5013745/v1

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Background

Neuroblastoma and hemorrhage are the two most frequently occurred in adrenal region in infants. However, their characterization and differentiation is challenging on baseline ultrasound (BUS). As an increasingly sophisticated tool, contrast-enhanced US(CEUS) is proposed for differentiating such lesions.

Objectives

To investigate the usefulness of CEUS in the differentiation of adrenal neuroblastoma and adrenal hemorrhage (AH) in infants less than 6 months old.

Materials and Methods

The imaging and medical records of 20 infants with adrenal lesions (including 11 neuroblastoma and AH in 9) were retrospectively reviewed. Four readers(two resident and two attending doctors) independently reviewed the images and the diagnostic performances were evaluated by receiver operating characteristic (ROC) analysis. The interobserver agreement was evaluated with κ value.

Results

There had differences between them on BUS and CEUS (all p < 0.05). CEUS yielded a sensitivity of 100% (95% CI 0.571–0.995), specificity of 100% (95% CI 0.402–0.961), higher than BUS (sensitivity 81.8%, specificity 66.9%). The diagnostic performance of one resident and both attending doctors in terms of the area under the ROC curve (0.712 vs 0.995, 0.561 vs 0.884, and 0.621 vs 0.958, respectively), specificity and positive predictive value improved and sensitivity, negative predictive of all readers improved after CEUS (all p < 0.05). Indeterminate lesions reduced significantly (35.0% vs 25.0% in residents doctors, 25.0% vs 10.0% in attending physicians). The interobserver agreement increased from κ = 0.550 to κ = 0.824 after CEUS.

Conclusion

The diagnostic performance of CEUS in the differentiation of adrenal neuroblastoma from AH might be greatly improved compared with BUS.

Infant

Adrenal hemorrhage

Adrenal neuroblastomas

Contrast-enhanced ultrasound

Neuroblastoma and hemorrhage are the two most frequently occurred lesions in adrenal region in infants [1]. Adrenal neuroblastoma in children less than 1 year old is known to show the highest rate of spontaneous regression among malignant tumors, even in those with 4S stage disease [2]. However, a minority of adrenal neuroblastoma might present aggressive growth pattern and finally lead to bad outcomes [3]. Thus, infants with adrenal neuroblastoma need to be continuously followed up in clinical practice. Invasive biopsy to confirm diagnosis, minimal cytotoxic treatment or even surgery are needed for some of them [4]. On the contrary, adrenal hemorrhage is a definitely benign disease with good outcomes [5]. Therefore, the differential diagnosis between them is very important for infants with adrenal lesions.

Ultrasound (US) is the first-line tool to detect and follow-up adrenal lesions in small children because of its convenience, cost-effectiveness and non-radiation [6,7]. However, it is hard for US to completely differentiate adrenal neuroblastoma from adrenal hemorrhage due to the fact that both of them can be heterogeneous solid mass with cystic component on grey-scale US [5]. In contrast to neuroblastoma, hemorrhage is avascular. Therefore, color doppler US might be helpful in the differential diagnosis. However, there might be false positive blood sign on color doppler US because of the movement of small children during examination [8]. Contrast-enhanced US(CEUS) allows precisely evaluating blood perfusion of organs and lesions and has been applied to children with focal liver lesions [9]. Thus, with the application of CEUS, it might be very useful to differentiate adrenal hemorrhage from adrenal neuroblastoma.

The aim of this study is to investigate the usefulness of CEUS in the differentiation of adrenal hemorrhage and adrenal neuroblastoma in children less than 6-month-old by retrospectively analyze 20 infants with adrenal lesions.

Written informed consent was obtained from each infants’ guardian and the study was approved by the institutional ethics committee.

Patients

Between July 2019 to August 2023, over 140 patients with retroperitoneal masses underwent CEUS examination in two tertiary hospitals. Some of were referred for further confirmation of the characterization of lesions after adrenal mass were identified on grey-scale US. All of these patients had been confirmed without contraindications such as severe cardiopulmonary diseases and suspected allergy to the contrast agent SonoVue or Sonazoid and uncontrolled vital signs before CEUS examination. The exclusion criteria for this study include: (1)age > 6 months old; (2)presence of liver metastases on conventional ultrasound; (3)lesions with diameter > 5 cm; (4)surgery confirmed that the mass was located in non-adrenal region; (5)lesions had been treated before; (6)the final diagnosis was adrenocortical carcinomas, metastatic carcinomas and others through postoperative pathology. Finally, 20 infants with adrenal lesions (diagnosed as adrenal neuroblastoma or AH) were included in this study (Fig. 1).

Other clinical data, including prenatal findings, CT/MRI images, the level of urine catecholamine metabolite (vanillylmandelic acid, VMA), specific tumor biomarker (neuron-specific enolase, NSE) and pathological findings were also collected if available.

Ultrasound examination

Ultrasound examinations were performed using an Aplio i900 (Canon Medical Systems, Tokyo, Japan) equipped with a 1.9-6.0 MHz curvilinear transducer and a 10.0–14.0 MHz linear transducer, An Aixplorer scanner (Supersonic Imagine, Paris, France) equipped with a 1.0–6.0 MHz curvilinear transducer and a 2.0–1.0 MHz linear transducer and an LOGIQ E9 (General Electric Healthcare) equipped with a 1.7-6.0 MHz curvilinear transducer and a 9.0–18.0 MHz linear transducer. The mechanical index during the CEUS examination was < 0.1. Two different kinds of contrast agents (0.015ml/kg Sonazoid or 0.03ml/kg SonoVue) were chosen for CEUS examination. Contrast agents were administered through 24-gauge or 21-gauge needles. Apart from those who were suggested to accept a subsequent US-guided biopsy, all patients underwent baseline US (BUS) and CEUS examination without sedation.

BUS were performed before CEUS and the static images and videos of bilateral adrenal glands, lesions’ baseline characteristics (included their size, echogenicity and presence of blood flow), locations prone to have metastasis (such as liver and retroperitoneum) were collected. For CEUS, as the contrast-specific imaging mode start, a bolus injection of contrast agent was administered intravenously followed by 5 ml of 0.9% saline and a timing was started at the injection moment. The adrenal lesions were observed continuously for the first 1 min and then intermittently until it was washed out or lasted for 5 min. Videos of CEUS images were collected for further analysis. All BUS and CEUS examinations were performed by radiologists with experience > 10 years in pediatric abdominal ultrasound and > 5 years in CEUS.

Reference standard

The diagnostic criteria of adrenal neuroblastoma were: 1) pathologic findings from surgery or biopsy; or 2) elevated VMA and NSE level meanwhile with enhancement on images (including CEUS, CT or MRI). The diagnostic criteria adrenal hemorrhage were:1) no enhancement on images; 2) normal VMA and NSE level; 3) lesions were gradually shrunken or disappeared during follow up.

Image analysis

Based on the different pathophysiological features between neuroblastoma and AH, diagnostic criteria were set up before image analysis as follows: lesion without blood flow perfusion inside on either CDFI or CEUS were considered as AH, otherwise, they were considered as neuroblastoma.

First, two investigators (L.Y.B and Z.L.Y) who have 3 years and over 10 years’ experience on CEUS respectively participated in image analysis and harmonize the terminology in images’ description. Three cine loops (including grey-scale US, color doppler US and CEUS) of each case were reviewed in order and the adrenal mass was described for size, echogenicity (solid mass, solid mass with < 50% cystic component, solid mass with > 50% cystic component) on grey-scale US, perfusion pattern (classified as definitely without blood flow, probably without blood flow, probably with blood flow, definitely with blood flow) on color doppler US and whether enhancement displayed or not (definitely had enhancement, probably had enhancement, probably had no enhancement or definitely had no enhancement).

Afterwards, 2 pediatric resident doctors (T.Z.J and L.Z.Q, with 3-year experience on CEUS) and 2 attending physicians (F.S.M and L.L, with at least 10-year experience on CEUS) were recruited and were told the terminology and the diagnostic criteria as mentioned previously. Then they independently reviewed these cine loops in order and choose the most appropriate description for the lesions with the options mentioned above. All of the readers were not involved in the imaging acquisition and were blinded to clinical histories, histopathological results and other imaging findings.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software v.26.0 (IBM Corp, Armonk, NY, USA). Clinical, laboratory and images’ characteristics of patients were expressed as mean (SD) or as median (IQR) respectively for qualitative and quantitative data. Differences between AH group and adrenal neuroblastoma group were analyzed using the Mann-Whitney U test for continuous variables and Chi square or Fisher’s exact tests for categorical variables. The diagnostic performances of BUS and CEUS in differentiating adrenal neuroblastoma and hemorrhage were expressed as areas under receiver operating characteristic curve (AUC), and the Delong test was used to compare the AUCs. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated concomitantly. The κ statistic was used to assess interobserver agreement. Agreement was graded as poor (κ < 0.20), moderate (κ = 0.20 to < 0.40), fair (κ = 0.40 to < 0.60), good (κ = 0.60 to < 0.80), or almost perfect (κ = 0.80–1.00). A p-value less than 0.05 was judged to be statistically significant.

Patients

Twenty infants, ages ranged from 1 day to 183 days (median age, 18.00 days (IQR 9.25-36.00)) were included in this study. There were 11 patients with adrenal neuroblastoma, of whom 5 were diagnosed by pathologic findings, 6 were diagnosed by elevated VMA and NSE level combined with enhancement on images. The rest 9 patients were diagnosed as AH, of which all were without enhancement on images and gradually shrunken during follow up. The VMA and NSE level of two patients with AH were available and in normal range.

The demographic and baseline characteristics are presented in Table 1. In neuroblastoma group, one patient showed both elevated VMA as 169.24mg/24h and NSE as 115.60ng/ml, while one patients showed elevated as 0.23mg/24h and normal NSE level, and another one infant showed elevated NSE as 50.19ng/ml (his VMA test was not perform). Overall, characteristics of infants with adrenal neuroblastoma did not differ significantly from those with AH. In addition, 4 lesions of neuroblastoma and 2 of AH were found in prenatal ultrasound examination.

Table 1

The comparison of baseline characteristics between neuroblastoma and hemorrhage group
Variable	Neuroblastoma(n = 11)	Hemorrhage(n = 9)	p Value
Gender, n (%)
Male	6 (54.5%)	4 (44.4%)	0.653
Female	5 (45.5%)	5 (55.6%)	0.653
Age, days, median (IQR)	26.00 (9.00, 120.00)	15.00 (11.00, 31.50)	0.543
Prenatal finding, n (%)
Benign lesion	3 (75.0%)	1 (50.0%)	0.540
Malignant lesion	1 (25.0%)	1 (50.0%)	0.540
Laterality, n (%)
Left	5 (41.7%)	3 (37.5%)	0.852
Right	7 (58.3%)	5 (62.5%)	0.852
Reference standard, n(%)
Pathology	5 (45.5%)	0 (0.0%)	0.059
With CT/MRI	2 (18.2%)	2 (22.2%)
Follow-up	4 (36.4%)	7 (77.8%)
Note.—VMA = vanillylmandelic acid, NSE = neuron-specific enolase.

There were no adverse events after CEUS requiring prolonged hospitalization or leading to morbidity or mortality.

Baseline US

On grey-scale US, the numbers of adrenal neuroblastoma that showed solid mass, solid mass with less than 50% cystic component and solid mass with more than 50% cystic component were 9 (81.8%), 2 (18.2%) and 0 (0.0%); for AH, the corresponding numbers were 1 (11.1%), 5 (55.6%) and 3 (33.3%) (p < 0.05) .Only 4 lesions in 20 patients (20.0%) were able to determine if the mass had definitely blood flow. Three of 11(27.3%) patients with neuroblastoma had definite blood flow sign. False positive blood sign occurred in 3 of 9(33.3%) patients with AH. There had differences between adrenal neuroblastoma and AH in terms of blood flow signals on the color Doppler flow imaging (CDFI) (p < 0.05) (Table 2).

Table 2

Adrenal Mass Characteristics on baseline US and CEUS
Variable	Neuroblastoma	Hemorrhage	p Value
BUS, n(%)
Solid mass	9 (81.8%)	1 (11.1%)	0.002
With less than 50% cystic component	2 (18.2%)	5 (55.6%)
With more than 50% cystic component	0 (0.0%)	3 (33.3%)
CDFI, n(%)
Definitely without blood sign	0 (0.0%)	1 (11.1%)	0.025
Probably without blood sign	2 (18.2%)	5 (55.6%)
Probably with blood sign	6 (54.5%)	3 (33.3%)
Definitely With blood sign	3 (27.3%)	0 (0.0%)
CEUS, n(%)
No enhancement	0 (0.0%)	7 (77.8%)	< 0.001
Probably no enhancement	0 (0.0%)	2 (22.2%)
Probably enhancement	1 (9.1%)	0 (0.0%)
Enhancement	10 (90.9%)	0 (0.0%)
Note.—BUS = baseline US, CDFI = color Doppler flow imaging, CEUS = contrast-enhanced US.

CEUS characteristics

The CEUS characteristics of 20 enrolled adrenal lesions are listed in Table 2. In adrenal neuroblastoma group, the number of patients(11/11) showed enhancement were significantly more than that in adrenal AH group(0/9) (p < 0.05). Adrenal neuroblastoma was correctly detected and characterized by CEUS in 10 patients. Two of all nine patients with hemorrhage showed peripheral ringlike enhancement (Fig. 2), which was considered as enhancement of surrounding normal adrenal gland. These two patients showed normal VMA and their lesions had disappeared after 3 months and 16 months of US follow-up, respectively.

Diagnostic performance of CDFI and CEUS

Taking probably enhancement or enhancement as diagnostic criteria, CEUS yielded a sensitivity of 100% (11 of 11; 95% confidence interval [CI] 0.571–0.995), specificity of 100% (9 of 9; 95% CI 0.402–0.961), higher than BUS(taking probably with blood sign or definitely with blood sign as diagnostic criteria) (sensitivity 81.8% [9/11], specificity 66.9% [6/9] respectively) (p < 0.05).

The diagnostic performances of BUS and CEUS for diagnoses of adrenal neuroblastoma and adrenal hemorrhage in 2 pediatric resident doctors and 2 attending physicians were summarized in Table 3. The numbers of lesions assigned by 2 pediatric resident doctors at baseline US were definitely adrenal neuroblastoma in 1 (5.0%), probably adrenal neuroblastoma in 3 (15.0%), indeterminate in 7 (35.0%), probably AH in 9 (45.0%) and definitely AH in 0 (0.0%), respectively. According to the images of CEUS, the numbers were respectively changed to 3 (15.0%), 4 (20.0%), 5 (25.0%), 4 (20.0%) and 4 (20.0%). For 2 attending physicians, the numbers were 0 (0.0%), 4 (20.0%), 5 (25.0%), 11 (55.0%) and 0 (0.0%) at baseline US, and 3 (15.0%), 6 (30.0%), 2 (10.0%), 5 (25.0%) and 4 (20.0%) at CEUS. The number of definite lesions increased significantly (10.0% vs 45.0%, 0% vs 35.0%) and indeterminate lesions decreased (20.0% vs 15.0%, 25.0% vs 10.0%) after CEUS for 4 doctors. The interobserver agreement improved from κ = 0.550 (95%CI 0.232–0.867) at baseline US to κ = 0.824 (95%CI 0.721–0.927) after CEUS. The diagnostic performance of these 4 doctors in specificity, positive predictive value and the area under the curve (AUC) of resident doctor A and both attending physicians, the sensitivity, negative predictive of four readers improved significantly after CEUS (p < 0.05)(Table 5).

Table 3

Diagnostic performances of baseline ultrasound and contrast-enhanced ultrasound for diagnoses of adrenal neuroblastoma and adrenal hemorrhage
	Sensitivity, %	Specificity, %	PPV, %	NPV, %	AUC	*p Value
Resident doctor A
BUS	72.7% (8/11)	66.7% (6/9)	72.7% (8/11)	66.7% (6/9)	0.712(0.480–0.945)	0.032
CEUS	90.9% (10/11)	88.9% (8/9)	90.9% (10/11)	88.9% (8/9)	0.995(0.975-1.000)	0.032
Resident doctor B
BUS	45.5% (5/11)	100.0% (9/9)	100.0% (5/5)	60.0% (9/15)	0.758(0.546–0.969)	0.162
CEUS	63.6% (7/11)	100.0% (9/9)	100.0% (7/7)	69.2% (9/13)	0.949(0.858-1.000)	0.162
Attending physician A
BUS	45.5% (5/11)	66.7% (6/9)	62.5% (5/8)	50.0% (6/12)	0.561(0.303–0.819)	0.029
CEUS	81.8% (9/11)	88.9% (8/9)	90.0% (9/10)	80.0% (8/10)	0.884(0.727-1.000)	0.029
Attending physician B
BUS	36.4% (4/11)	88.9% (8/9)	80.0% (4/5)	53.3% (8/15)	0.621(0.372–0.871)	< 0.001
CEUS	90.9% (10/11)	100.0% (9/9)	100.0% (10/10)	90.0% (9/10)	0.958 (0.863-1.000)	< 0.001
Note.—Data in parentheses are numerator/denominator.
BUS = baseline US, CEUS = contrast-enhanced US, AUC = area under the curve, PPV = positive predictive value, NPV = negative predictive value.
*Diagnostic performance for BUS and CEUS in different radiologists was compared using the DeLong tests.

Compared with grey-scale US and CDFI, the error rate was significantly reduced in CEUS. One patient was diagnosed as adrenal neuroblastoma after CEUS but it was uncertain in grey-scale US as it presented as solid mass with cystic component (Fig. 3). And another one patient was regarded as confirmed enhancement after CEUS while it was regarded as probably without blood sign in CDFI (Fig. 4). Three patients in AH group were suspected of neuroblastoma as they presented as mass with solid component in grey-scale US or probably with blood sign in CDFI (Fig. 5). However, misdiagnosis occurred in one resident doctor and one physician as they mistakenly considered the enhancement of the adrenal gland around AH as solid part of neuroblastoma (Fig. 2).

Follow-up

Of the 11 patients with adrenal neuroblastoma, five underwent surgical treatment after US and CEUS examination, of whom one had multiply muscle metastases after the adrenal lesion had been removed (Fig. 5). One resolved in 12 weeks and four resolved between 5 to 8 months. Still another one patient was still being followed up, and US shows that her lesion is gradually decreasing.

Of the 9 patients with AH, five resolved in 6 months, two after 10 months and one after 16 months since the mass was occurred. One patient is being followed up and the widest diameter of her lesion decreased significantly from 4.8cm to 1.1cm.

Several studies have revealed that the percentage of regressing neuroblastoma in infants varied between 47% and 92%^{[2, 10–14]}. However, Woods WG et al^[3] and Gao RN et al^[15] also reported deaths due to the substantial residual tumors after some degree of regression were observed beyond the second year of life and showed clinical signs of maturation as well as metastatic progression. Thus, the detected adrenal lesions still need to be noted seriously while it is suspected to be neuroblasoma, although they might have a high possibility of regression. Based on SIOPEN (International Society of Paediatric Oncology European Neuroblastoma)^[4], US examination should be repeated and abdominal MRI scan should be performed in 2 months if necessary and urine VMA, lactate dehydrogenase, free cortisol and MIBG (iodine-123 meta-iodobenzylguanidine), specific tumor biomarker such as nNSE are suggested to be measured. Furthermore, confirm diagnosis via invasive biopsy, minimal cytotoxic treatment or even surgery are needed for some of them. Conversely, AH is a definitely benign disease, these infants are referred for sequential US examination instead of CT/MRI scans, laboratory tests or invasive procedures.

US is the first-line tool to detect and follow-up adrenal lesions in small children because of its convenience, cost-effectiveness and non-radiation. The present study summarized the US characteristics of adrenal neuroblastoma and AH by analyzing 20 untreated pediatric adrenal lesions. Our results demonstrate that for BUS characteristics, 81.8% lesions in adrenal neuroblastoma group presented as solid mass, significantly more than lesions in AH group. But as in our cases, only 33.3% AH were recognized as cystic mass (lesions with more than 50% cystic component), consistent with the previous studies.^[7] In this respect, it is still hard to discriminate AH from adrenal neuroblastoma by grey-scale US. Eventually, it resolves completely and becomes anechoic, according to some literature, which can take most commonly within 3 months^{[7, 16, 17]}. However, in our series, one lesion of adrenal neuroblastoma resolved within 12 weeks while five AH resolved in 6 months, two after 10 months and one after 16 months, consistent with some previous cases studies^{[18, 19, 20]}. Therefore, it is hard to completely differentiate adrenal neuroblastoma from AH by grey-scale US alone either on initial examination or follow-up.

For color doppler US, our results demonstrated that it was difficult to confirm whether the lesion has definitely blood flow as the rate of probably with or without blood sign up to 80.0% (8 in neuroblastoma and 8 in AH), although statistical analysis suggesting that there had differences between adrenal neuroblastoma and AH in terms of blood flow signals (p = 0.025). Firstly, because of the uncontrolled movement of infants during examination, artifacts can occur and false positive blood sign might be detected in AH lesions. Secondly, for neuroblastoma with copious cystic component, micro blood flow in septa might be ignored. All these factors lead to the number of lesions with indeterminate blood flow was more than 50% in our study.

By contrast, CEUS has the potential to qualitatively discern benign lesions from adrenal neuroblastoma as it can significantly improve the accuracy of whether the lesion has blood supply (rate of determined cases improved from 20.0–85.0% after CEUS). CEUS provides valuable assistance for the differential diagnosis as it is highly sensitive to depicting contrast signals even within the smallest vessels^[16]. Furthermore, it performed a better interobserver agreement (κfrom 0.550 to 0.824, graded from fair to very good), which revealed increased reproducibility of the diagnostic performance. Additionally, the current study confirms that the application of CEUS in children is safe as no patient suffering from mild adverse event, this in line with previous reports^{[21, 22]}.

Apart from US, contrast enhanced CT and MRI are another two imaging examination to distinguish AH and adrenal neuroblastoma^[23]. However, it has higher requirements for the cooperation of infants, so sedation is needed. Small adrenal lesions may be difficult to detect for MRI due to the fact that relatively low spatial resolution of MRI may limit the assessment of mass even in dynamic contrast-enhanced sequences. In addition, they are expensive examinations compared with ultrasound. In addition, contrast enhanced CT is associated with significant radiation exposure as well ^{[16, 24, 25]}. Overall, CEUS may be a better choice for infants to initially evaluate adrenal lesions. Nevertheless, CEUS might still lead to misdiagnosis as the enhancement of the adrenal gland around AH may be mistakenly regarded as solid part of neuroblastoma by radiologists without much experience.

Our study had several limitations. First, this was a two-center retrospective study and there might be selection bias. Secondly, different contrast agents were administered (0.015ml/kg Sonazoid or 0.03ml/kg SonoVue)which may potentially influence the enhancement pattern. Thirdly, the diagnoses of all patients with AH and some patients with neuroblastoma were confirmed by clinical information or follow up. This might cause misdiagnosis since both of these two entities can regress during follow up. However, it is ethically unreasonable to recommend patients with unenhanced adrenal lesions to undergo further test such as CT or MRI scan or invasive biopsy. On the other hand, the SIOPEN recommends a continuously observation includes US follow-up until 12-month-old for infants with suspected neuroblastoma. Finally, neonatal AH and adrenal neuroblastoma are relatively so uncommon condition that the sample size of this study was small. Thus, our findings need to be further validated in other centers.

In conclusion, the diagnostic performance of CEUS in the differentiation of adrenal neuroblastoma from AH might be greatly improved compared with BUS.

Author Contribution

Author contributions Guarantors of integrity of entire study, L.Y.B, Z.L.Y; data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, L.Y.B, Z.L.Y; approval of final version of submitted manuscript, all authors; literature research, L.Y.B, Z.L.Y; statistical analysis, L.Y.B, Z.L.Y; and manuscript editing, L.Y.B, Z.L.Y.

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No competing interests reported.

supportingvideoforFigure2.mp4
Supporting video for Figure 2 Adrenal hematoma in a 14-day-old girl. Normal adrenal gland around the mass showed homogeneous hyperenhancement 13 s after contrast agent injection.

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The application of Contrast-enhanced US in distinguishing adrenal neuroblastoma from adrenal hemorrhage in infants

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Abstract

Background

Objectives

Materials and Methods

Results

Conclusion

Figures

Introduction

Materials and Methods

Patients

Ultrasound examination

Image analysis

Statistical analysis

Results

Patients

Baseline US

CEUS characteristics

Diagnostic performance of CDFI and CEUS

Follow-up

Discussion

Declarations

Author Contribution

References

Additional Declarations

Supplementary Files

Status:

Version 1