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Using Ultrasound to Analyze Malignant and Benign Orbital Space-Occupying Lesions

Using Ultrasound to Analyze Malignant and Benign Orbital Space-Occupying Lesions

Most orbital space-occupying lesions come from tissues in the orbital space or metastasize from other system tumors. The bulk of clinical manifestations of these lesions such as diplopia, protrusion, and loss of vision are often nonspecific, so imaging technology is crucial in diagnosis. 

Ultrasound is the most preferred diagnostic tool in orbital space-occupying lesions because they are 1)noninvasive, 2)affordable 3)real-time, and 4)convenient. Furthermore, high-frequency ultrasound can be used to conceive the shape, border, location, and surrounding tissues of orbital space-occupying lesions. Color doppler imaging can even show the blood flow in the lesions. However, the analysis using ultrasound cannot be used to differentiate malignant from benign space-occupying lesions because they mostly possess the same morphologies, internal blood flow, and echogenicity.

An ultrasound-guided needle biopsy can be an effective tool for differential diagnosis but it’s difficult to apply in orbital lesions because of safety issues and invasiveness. This is the primary reason that differential diagnosis for malignant and benign orbital space-occupying lesions has been a challenge for medical professionals. 

CEUS (Contrast-enhanced Ultrasound) 

Contrast-enhanced ultrasound (CEUS) is a new ultrasound technology that can provide in-depth information about the microvasculature of lesions. It also has the potential to characterize tumors.

Most CEUS can detect very low-velocity blood flow in blood vessels. CEUS can also display real-time perfusion of lesions which has a significant advantage for differential diagnosis when comparing space-occupying lesions. 

Past studies have also claimed that CEUS does improve the sensitivity of ultrasound diagnoses in various lesions found in the heart, abdomen, and other organs. However, its use in orbital space-occupying lesions is limited and quantitative analysis is rare. 

Study Objectives

  1. To measure the value of time-intensity curve (TIC) analysis of contrast-enhanced ultrasound (CEUS) signal to emphasize difference on malignant and benign orbital space-occupying lesions. 
  2. To explore the perfusion of patterns in both malignant and benign orbital space-occupying lesions.
  3. To compare quantitative CEUS parameters and determine an appropriate threshold for differential diagnosis of malignant and benign orbital space-occupying lesions. 

Study Methods

CEUS signals of 111 patients with orbital space-occupying lesions were analyzed using SonoLiver software. TIC-related parameters were compared between the two groups (malignant and benign). Receiver operating characteristics (ROC) curve analysis was used to measure the cutoff values of the parameters for differential diagnosis. 


From July 2014 to November 2020, 111 patients who underwent CEUS due to unilateral orbital space-occupying lesions were analyzed. They were grouped based on their pathology results. 59 out of 111 patients with benign space-occupying lesions and 52 out of 111 for the malignant space-occupying lesions. The study was approved by the Ethics Committee Board of Renmin Hospital, Wuhan University. All patients also signed informed consent before the CEUS examination. 

Inclusion Criteria 

Conventional ultrasound was unable to identify the lesions so CEUS examinations were done. 

  • Patients without contraindications for ultrasound contrast agents. 
  • A fitting degree of contrast image analysis of more than 80
  • A resected orbital lesion with pathologic diagnosis.   


The machine used was an Esaote Mylab ultrasound with an L522 probe, 9-3 MHz, linear probe. The contrast agent used was SonoVue. Analyses were performed by two doctors with 7-10 years of experience. Grayscale ultrasound and color doppler imaging were performed to analyze the size, shape, location, echogenicity, internal blood flow, and relationship with surrounding tissues. CEUS was only done if the doctor couldn’t identify with the conventional US if the lesion is malignant or benign. 

Before the test, patients were asked to breathe steadily. They selected the view with the richest blood flow while the position of the probe was kept stable. Frequency is set at 9 MHz with a mechanical index of 0.08. They used 1.2ml of contrast agent injected via elbow vein followed by injection of 10ml normal saline. 

The timing when the instrument began was observed and stored on the machine’s hard disk. A real-time agent which lasted around 180 seconds after the injection was studied. The doctors then gave the diagnosis if it was benign or malignant. 


A total of 59 males and 52 males participated in the study. Their mean age was 51 with a range of 18-83 years. The main clinical manifestations were ocular motility disorder, vision decline, and exophthalmos. 

Results showed 50 benign space-occupying lesions with 32 cavernous hemangiomas, 15 inflammatory pseudotumors, 5 pleomorphic adenomas of the lacrimal gland, 4 meningiomas, 2 solitary fibrous tumors, and 1 lymphangioma. The most common benign space-occupying lesion in the study was hemangiomas and inflammatory pseudotumors. 

In the other group, they found 52 cases of malignant tumors which include 33 lymphoma, 12 metastatic carcinomas, 4 malignant epithelial tumors of the lacrimal gland, and 3 melanomas. The most common malignant space-occupying lesion was lymphoma. 

TIC patterns were grouped by fast increase and fast decrease in signal intensity in the malignant group and fast increase slow decrease in the signal intensity in the benign group. 

The differences in various parameters were recorded. ROC curve analysis showed that IMAX = 472.29, DS = 34.72, and mTT – 33.55 were the perfect cut-off values for differential diagnosis of the two groups. The accuracy rate of CEUS visual evaluation for differential diagnosis was 66.67% while TIC quantitative analysis could improve accuracy to 89.19%. 

Using the conventional ultrasound, the benign space-occupying lesions looked like hypoechoic masses with clear boundaries and internal echoes. There’s also an abundant blood flow signal shown at color doppler imaging. For malignant tumors, there’s usually a solid echogenic mass with unclear boundaries. They also found irregular morphology and uneven internal echoes with rich blood flow signals. 


The study used SonoLiver software to analyze CEUS features of orbital space-occupying lesions. The study also showed that TIC-based quantitative analysis significantly improved the accuracy of CEUS from 66.67% by visual evaluation to 89% via quantitative analysis. The TIC-based quantitative parameters could also identify malignant vs benign lesions.   

Because orbital space-occupying lesions are rare ophthalmic diseases, differentiating the benign from the malignant by simply using conventional ultrasound is extremely hard. It’s the reason why contrast-enhanced MRI is very important for a good differential diagnosis. However, enhanced MRI is very expensive and it may also result in many contraindications for some patients with renal insufficiency or metallic implants.

CEUS can adequately measure the microcirculation perfusion of space-occupying lesions in detail. It solves the problems that the conventional ultrasound can’t do for a better differential diagnosis of orbital space-occupying lesions. 

Also, compared with enhanced MRI, CEUS has many advantages. First of all, it has no nephrotoxicity. It’s also non-allergic, not radioactive, very easy to perform, and offers real-time observation. In the study, the researchers found that most TIC-based qualitative parameters were different from the two groups except for the AT.IMAX in which the malignant group was significantly higher than the benign group. The rest, the malignant group were all lower than the benign group.

Overall,  malignant tumors were “fast wash-in” and “fast wash-out” contrast patterns while the “fast wash-in” and “slow washout” were dominant in benign tumors.  The explanations in these results are focused on the variation in blood vessels within each tumor. 

Since malignant tumors grow rapidly, more blood vessels are formed which results in increased vascular density in the tumor.  The increment of neovascularization also denotes higher blood perfusion and higher intensity of contrast agent within the tumor. Therefore, malignant tumors are present with a high IMAx and fast enhancement. 

Since the structure of new blood vessels is often disordered, there are many arteriovenous fistulas in the tumor. Furthermore, the basal membrane of the vascular wall is discontinuous and hyperpermeable which often leads to contrast leakage in the surrounding tissue. All these reasons result in the increase in the elimination of a contrast agent. 

More ROC curve analysis indicates that TIC-based qualitative parameters such as the IMAX, mTT, and DS could effectively identify malignant benign with cut-off values of IMAX=427.20, DS = 34.72, and mTT = 33.55. A DS higher than 34.72 is the highest diagnostic value. 


TIC analysis significantly made improvements in CEUS efficiency in differentiating malignant from benign orbital space-occupying lesions. 

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