This chapter serves as a guide to the use of contrast-enhanced ultrasound (CEUS) in gynecology. It covers applications of CEUS in the diagnosis of various gynecological conditions, ranging from benign uterine anomalies to ovarian malignancies.

As with any other organ system, perfusion studies and study of blood-flow patterns help to characterize gynecological lesions. Conventional techniques (B-mode ultrasound and Doppler ultrasound) have limitations in depicting perfusion at the microvascular level (typically <2 mm diameter), in deep vessels (>10 cm from the skin), and in regions with tissue motion. These limitations are due to the weak reflection of ultrasound waves by blood relative to surrounding tissue.^1,2 This limits their use in gynecology, especially in characterization of ovarian and endometrial malignancies. However, these limitations have been largely overcome by the introduction of CEUS. CEUS utilizes microbubbles, the small size (1-10 microns) of which enables them to mix up with red blood cells. The high intrinsic compressibility of microbubbles with resultant high echogenicity makes CEUS an extremely suitable technique to study blood flow at the microvascular level.³

CEUS is a well-established technique in the characterization of liver masses. The World Federation for Ultrasound in Medicine and Biology (WFUMB) has published guidelines for the use of contrast in liver applications,⁴ and guidelines for the use of contrast in nonliver applications have been published by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB).⁵ However, these guidelines do not include gynecological applications. CEUS has potential in evaluating various gynecological disorders. It can be helpful in distinguishing between fibroids and adenomyomas,^6-8 characterizing endometrial pathologies,^9-13 characterizing adnexal masses,^14-21 confirming adnexal torsion,²² distinguishing between retained products of conception and arteriovenous malformations, testing tubal patency,^23-26 and diagnosing vaginal fistulas.²⁷ These applications along with distinguishing features of corresponding pathologies are tabulated in Appendix 38-1.

Adoption of ultrasound contrast agents (UCAs) in clinical practice was pioneered by Gramiak and Shah in 1968 for use in echocardiography. Since then, UCA have evolved from “unprotected unstable room air bubbles” to a “complex stable system of core-shell structures” with a coating of biodegradable material such as albumin, phospholipids, and polymers containing low diffusivity gases like nitrogen and perfluorocarbons^2,3 (Table 38-1). These advances have facilitated transpulmonary passage of UCA for systemic circulation perfusion studies and increased their stability allowing longer duration studies.^28,29

The limitation of conventional ultrasound modalities in depicting microvascular perfusion can be overcome by introducing UCA into the blood stream. UCA are microbubbles with superior scattering properties compared to blood cells, and as a result, they improve the sensitivity of ultrasound for imaging the microvasculature.³⁰

The list of commercially available UCA is provided in Table 38-1. SonoVue (Figure 38-1) is one of the most widely used UCA for gynecological applications. All the clinical results described in this chapter have been obtained using this agent. Other commonly used UCA in gynecology are Echovist, Levovist, and Definity.

After bolus IV injection, UCA tend to remain in the intravascular compartment. Once the tissue containing them is insonated at clinically used ultrasound frequencies (1-20 MHz), they tend to resonate.^3,31 Depending on the amount of insonation pressure, 3 broad categories of imaging techniques are practiced. In gynecology practice, “low mechanical index (low MI)” techniques are the most widely used.

Low MI techniques utilize moderate insonation pressure (30-70 kilo Pascal or kPa; equivalent to MI <0.1). When UCA are subjected to acoustic pressures in this range, they undergo stable, asymmetric oscillations (“stable cavitation”), generating nonlinear harmonic ultrasound frequencies after reflection of incoming ultrasound waves. For this reason, these techniques are also termed “nonlinear/harmonic CEUS imaging techniques.” Generated “signature signals” contribute to enhancement of signals from UCA and their distinction from the surrounding tissues. Separation of these harmonic overtones from the original frequency in the reflected signal improves contrast-to-tissue signal ratio by eliminating echoes from surrounding tissues (which are “linear reflectors”).^2,28,31,32

Low MI techniques include, among others, “conventional harmonic imaging,” “pulse inversion imaging,” and “power modulation imaging.” Conventional harmonic imaging is based on filtering out fundamental component from backscattered echoes and utilizing second harmonic component. It combines conventional ultrasound modalities like B-mode and Doppler ultrasound with contrast enhancement. Contrast-enhanced power Doppler is particularly useful for detection of certain malignancies like ovarian malignancies due to the “blooming effect” seen with it, which is more pronounced in malignancies as compared to benign lesions, due to excessive neovascularization, and causes faster arrival of contrast in these lesions.^19,20 However, these techniques suffer from incomplete separation of contrast from tissue and narrow transmission bandwidth. Pulse inversion imaging relies on different reflection of two out-of-phase (180 degrees) ultrasound pulses that combine to give signature signals of UCA. Since such pulses reflecting from surrounding tissues tend to cancel each other out, this technique helps to improve signal-to-noise ratio without limiting the bandwidth, and hence gives a better spatial resolution. On the other hand, power modulation imaging exploits differential reflection (linear vs nonlinear) of different amplitude pulses by UCA. A combination of the last two techniques gives better results in some cases.^2,28

The use of CEUS in gynecology is relatively new. There are a lot of gynecological pathologies for which CEUS can be a potential diagnostic tool. These applications can be broadly categorized into vascular and nonvascular applications.

Vascular Applications

These applications primarily rely on the differential perfusion between pathological lesions and healthy tissues. They require intravenous injection of UCA followed by examination, as described in the following section.

Technique

The procedure for performing CEUS for studying perfusion and its interpretation are discussed in this section. It is common for all the vascular applications of CEUS reviewed here.

To begin with, the target lesion or area of interest (AOI) is identified with B-mode and color Doppler ultrasound. Then, the ultrasound transducer is held still, the ultrasound beam is focused on the AOI, and “low MI contrast-specific” mode is turned on. A split-screen showing B-mode and contrast images side by side helps to maintain the AOI within the field of view, although it may affect B-mode image quality adversely.³³ It should be noted that both transabdominal (TAU) and transvaginal (TVU) ultrasound are used for this purpose. TAU allows for use of lower ultrasound frequencies (2-5 MHz), which gives better visualization of contrast medium. This is particularly useful for contrast studies of larger masses as TAU has a larger field of view.

Next, a bolus dose of the contrast agent is injected intravenously in a large peripheral vein (generally antecubital vein) using a large bore IV cannula (20 G or larger), followed by a 10 mL saline flush (Figure 38-2). Simultaneously, a cineloop recording is started to study the enhancement in real time.³³ The imaging time varies with the UCA and is mentioned in Table 38-1. The standard dose of Sono­Vue® for CEUS of liver is 2.4 ml.⁵ Though there is no similar standardized dose for gynecological applications, 1.2 to 2.0 mL of SonoVue® is commonly used with reliable results.

The recorded clip can be interpreted qualitatively and quantitatively. Qualitative analysis is based on description of enhancement with respect to its degree, timing, and distribution in the AOI. Quantitative analysis involves time-intensity curves. Both of these are discussed here.

Qualitative Analysis

Perfusion of the AOI can be described in terms of observed enhancement, considering factors such as timing, degree, and spatial distribution of the enhancement.

1. 
   

   Timing of enhancement is divided into an “arterial phase” and a “venous/late phase.” The arterial phase starts with the arrival of UCA in the AOI which usually takes 10 to 20 seconds after contrast injection. The degree of enhancement increases steadily during this phase (hence termed as the “wash-in phase”). The venous phase, starting about 30 to 45 seconds after contrast injection, constitutes plateauing of enhancement followed by its steady decline (the “wash-out phase”) until the UCA signal reaches background noise level.^5,33

   
   
2. 
   

   Assessment of degree of enhancement requires visual comparison of enhancement of target lesion with either surrounding normal parenchyma or a normal paired organ. In such cases, AOI is reported as either hyperenhancing, isoenhancing, hypoenhancing, or nonenhancing with respect to the reference. In the absence any reference tissue, one may report presence or absence of enhancement along with its distribution. It is important to describe the degree of enhancement separately for the arterial and venous phases.⁵

   
   
3. 
   

   When describing contrast distribution in a particular organ, one needs to consider recommendations based on the anatomy and normal perfusion pattern of that organ or a pathology. Thus, it can be homogeneous or nonhomogeneous, centripetal or peripheral, etc. Any nonperfused regions should be noted.⁵

Quantitative Analysis: Time-Intensity Curve (TIC)

Time-intensity curve (TIC) is a graphical representation of UCA uptake by tissues versus time. It helps to distinguish between normal and abnormal perfusion patterns. It assists in quantitative evaluation of degree, speed, and duration of UCA uptake.

Various software packages available with standard ultrasound machines process the saved DICOM clips to plot TIC. Ideally, TIC for a target lesion should be generated along with a reference TIC from the surrounding normal tissue by selecting two user-defined regions of interests (ROIs) as shown in Figure 38-3. In the absence of a reference tissue, it is difficult to interpret TIC due to lack of standardized parameters.

UCA kinetics can be studied from various parameters and indices calculated from TIC, such as arrival time (AT), peak intensity/enhancement (PI), time to peak enhancement (TTP), wash-in and wash-out rates, area under curve (AUC), mean transit time, flow velocity, etc. This quantitative information can be valuable in diagnosis and prognosis of many pathological conditions.^34,35

After a bolus injection, most gynecological malignancies tend to show a faster uptake, a sustained retention (longer plateau phase), and a faster washout rate of UCA as compared to benign lesions. This translates into a greater AUC for malignant lesions. Figure 38-4 illustrates the use of TIC to distinguish between benign and malignant lesions of endometrium.^3,35

It should be kept in mind that this quantitative technique has limitations due to variations in obtaining TIC (can be in the same patient, in the same ROI, or even during the same scan), due to factors such as scanner settings, position of the probe, physiological interaction of patient’s body with UCA, and manner of UCA handling.³⁵

Specific Applications

Distinguishing Between Fibroids and Focal Adenomyosis

Abnormal uterine bleeding (AUB) is a common symptom among women of all age groups. Fibroids and adenomyosis are both common causes of AUB and chronic pelvic pain. They coexist in 10% to 20% of patients and may have overlapping symptomatology as well as imaging features. Unlike fibroids, adenomyosis is a commonly overlooked pathology. Focal adenomyomas are sometimes misdiagnosed as fibroids. It is therapeutically important to differentiate between the two, since well-established and definitive modalities of treatment for fibroids like myomectomy and uterine artery embolization may not be effective for adenomyomas. Surgical intervention in unexpected cases of adenomyosis may be difficult due to poorly defined anatomical planes with the myometrium, unlike those encountered in fibroids.^36,37

On B-mode ultrasound, fibroids generally tend to be hypoechoic in relation to the myometrium, though few may be iso- or hyperechoic. They are well delineated from the surrounding myometrium due to the presence of a pseudocapsule (Figure 38-5). There may be presence of areas of degeneration and calcification. On color Doppler ultrasound, fibroids show peripheral, draping-type vascularity, and an outer feeder may be visualized (Figure 38-6).

Adenomyosis, on the other hand, tends to have ill-defined margins. Various B-mode criteria such as globular enlargement of uterus or asymmetric myometrial thickening, heterogeneous myometrial echotexture, subendometrial myometrial cysts, hyperechoic islands, subendometrial echogenic linear striations, fan-shaped shadowing (sun-ray appearance), poorly defined or interrupted junctional area have been described (Figure 38-7).^36,38 On color Doppler ultrasound, adenomyosis shows penetrating, randomly scattered intralesional vessels (see Figure 38-6).

Despite such well-defined differentiating criteria, the reported sensitivity and specificity of TVS for diagnosing adenomyosis varies widely from 53% to 89% and 67% to 98%, respectively,^38-43 which makes it difficult at times to differentiate between the two.

CEUS can be used to better demonstrate differences in the flow patterns between fibroids and adenomyosis than Doppler ultrasound, especially during the early phase of enhancement. Fibroids typically show peripheral capsular enhancement with gradual centripetal filling (also known as “basket pattern”) in the early phase and a diffuse enhancement in the late phase (see Figure 38-5). Very often a feeding capsular vessel is seen at the periphery (Figure 38-8). Adenomyosis shows relatively faster, diffuse, and heterogeneous enhancement in both early and late phases with “moth-eaten filling defects” (see Figure 38-7).^6-8 The differences are easily appreciable on a real-time cineloop.

Additionally, CEUS is helpful in guiding fibroid devasularization procedures like uterine artery embolization and high intensity focused ultrasound (HIFU), and to check adequacy of the procedure once it is done.^44-47 It is a cost-effective, safe, and noninvasive alternative to MRI or angiography traditionally used for the purpose.

CEUS can also be useful in differentiating broad ligament and pedunculated fibroids from other adnexal masses because of the characteristic uptake pattern of fibroids. It has a potential to differentiate degenerative changes in a fibroid from sarcomatous changes.⁴⁸

Characterization of Endometrial Pathologies

Endometrial pathologies are important causes of postmenopausal bleeding. It is important to accurately differentiate a hyperplastic endometrium from endometrial malignancy, which are the two causes to be considered in a case of postmenopausal bleeding with thickened endometrium on B-mode ultrasound. Endometrial carcinoma is the most common gynecological malignancy in developed countries, and its incidence is increasing.^49,50 Early diagnosis and assessment of myometrial invasion in case of endometrial malignancy can significantly alter its prognosis and treatment modality. Depth of myometrial invasion is a predictor of lymph node metastases and hence determines the need for retroperitoneal lymph node dissection.⁹ Apart from these, endometrial polyps occasionally present as postmenopausal bleeding and can be tricky to diagnose at times. They are a commonly suspected gynecological pathology on transvaginal ultrasound, both incidentally as well as in symptomatic patients.