Contrast-enhanced ultrasound (CEUS) and gallbladder diseases - A retrospective mono-center analysis of imaging findings with histopathological correlation

1 Introduction

The detection and differentiation of gallbladder alterations is crucial for the patient as a tumor confrontation in early-stage can improve an initially poor prognosis. In order to avoid patients with advanced disease, radiologic imaging of the gallbladder plays a crucial role in the daily routine. Ultrasound and cross-sectional imaging modalities are able to display differential diagnosis such as inflammation of the gallbladder, xanthogranulomatous cholecystitis, adenomyomatosis, hepatobiliary malignancies and metastatic disease.

Ultrasound (US) is the first imaging modality used to demonstrate the gallbladder by patients with symptoms such as jaundice or non-specific gastrointestinal complaints. Despite its excellent temporal and spatial resolution as well as the ability of real-time imaging, the B-mode technique can be sometimes insufficient in elucidating suspicious US findings.

Contrast-enhanced ultrasound (CEUS) is an imaging modality established for the evaluation of suspicious renal and hepatic masses [1, 2] that overcomes the limitations of US and color Doppler. CEUS has been introduced into the daily praxis because it is cost-effective, easy to perform, can rapidly generate additional image and has no radiation. Moreover, it is a safe tool because the contrast media applied has no cardiac or renal toxicity and can be used in patients with chronic renal failure and thyroid dysfunction [3]. Furthermore, allergic reactions to ultrasound contrast media are very rare: 1 in 10.000 cases [4, 5].

Although its performance in the assessment of unclear kidney and liver lesions has been proved to be equivalent to contrast enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) [1, 6], its use to evaluate gallbladder alterations is still not widely broaden.

CEUS has been used as an additional imaging tool in gallbladder disease due to its ability to demonstrate microvessels flow [7]. This advantage allows the depiction of a vascularization pattern during at least 2 phases: arterial (10–20 seconds postinjection) and late phase (31–180 seconds after contrast agent injection) [7–10].

The vascularity enhancement of the gallbladder on CEUS imaging allows the depiction of normal variants, the differentiation of suspicious masses from sludge or polyp and gallstones. Moreover, CEUS is able to distinguish benign from malignant lesions and infection [10].

The purpose of this retrospective mono-center analysis study is to evaluate the sensitivity and specificity of CEUS in the assessment of gallbladder alterations comparing the imaging results to histopathological findings.

2 Materials and methods

The local institutional ethical committee of the institutional review board approved this study and the ethical guidelines for publication in Clinical Hemorheology and Microcirculation were followed by all authors [11]. All patients provided and signed oral and written informed consent prior to each CEUS examination. All study data was carried out in accordance with the ethical principles expressed in the Declaration of Helsinki 2002. Histologic analysis of a specimen was performed according to the valid techniques, protocols and classifications at the time of the examination.

Due to the high-quality image acquired, all CEUS examinations were included in this study. This study included 17 patients between 2009 and 2017 with pathologic gallbladder alterations who had a CEUS examination and respectively pathologic results. A total of 58.8 % were male and 41.2% were female. Mean age of the patients was 61 years old (SD±13.17 years old), ranging in age from 40 to 89 years.

Several High-end ultrasound system (Siemens Acuson Sequoia and Siemens S2000, EPIQ 7, Philips Ultrasound) with up-to-date CEUS specific protocols were used in this study. C4-1 and C6-1 HD probes for the Siemens ultrasound system were used and the C9-2 probe for Philips ultrasound system was used. To avoid early microbubble-destruction, each system was configured with a low mechanical index (always < 0.2).

For a better view of the gallbladder, all patients underwent fasting at least 6 h prior to each examination. First of all, each patient underwent a baseline greyscale US examination of the gallbladder and the adjacent liver. After the conventional evaluation of the gallbladder, a second-generation blood pool agent (SonoVue^®, Bracco, Milan, Italy) was administered. This contrast agent consists of phospholipid-stabilized shell microbubbles filled with sulfur hexafluoride gas. An individual dose of 1.5 to 2.4 mL SonoVue^® was applied as a bolus injection by using a 20 or 22-gauge cannula placed in the antecubital vein, followed by a flush-injection of 5 to 10 ml of 0.9% NaCl. In the majority of cases, a single dosis of contrast agent was sufficient.

After the administration of contrast agent, cine loops of the study obtained were archived in the picture archiving and communication system (PACS) of our institution. Mean examination time ranged between 3–5 minutes. No adverse reactions were observed during these examinations.

All baseline B-mode US and CEUS studies were performed and interpreted by a single experienced radiologist with more than fifteen years’ experience in conventional sonography and with CEUS experience since 2003, achieving more than 5000 examinations annually.

For this study, archived images and record files of all patients were retrieved from the PACS of our institution. CEUS and respectively histopathological results from each patient were retrospectively analysed for diagnostic accuracy on CEUS by testing sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).

3 Results

Out of the 17 patients, CEUS imaging depicted 2 cases with a suspicious malignant mass in the gallbladder, which were confirmed in the histopathological results as adenocarcinoma of the gallbladder. In one case of 17, CEUS demonstrated a suspicious malignant alteration of the gallbladder and it was clarified in the pathologic results as an infiltration of a malignant liver tumour. Moreover, CEUS depicted a gallbladder polyp in 2 cases which were also confirmed in the pathologic results. In 5 patients CEUS displayed a cholecystitis pattern of the gallbladder which was acknowledged in the pathology (Figs. 1–5). In one patient, CEUS displayed an adenomyomatosis pattern and it was pathologically validated.

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Fig.1

Coronal CT-reconstruction in a patient with a thickened gallbladder wall (yellow arrows).

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Fig.2

Same patient as in Fig. 1. Axial reconstruction shows a thickened wall of the gallbladder suggestive of cholecystitis.

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Fig.3

B-mode ultrasound of the same patient as in Fig. 1, 2. Native B-mode ultrasound shows a thickened three-layered wall of the gall bladder (yellow arrows) and also reveals a gallbladder stone (red arrow) most likely the cause of the cholecystitis.

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Fig.4

Same patient as in Fig. 1– 3. Power Doppler shows marginal hypervascularization inside the thickened gallbladder wall as a reactive sign of inflammation (yellow arrows).

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Fig.5

Same patient as in Fig. 1– 4. CEUS reveals a vascularization pattern in line with inflammatory changes due to the cholecystits (yellow arrows). There is no sign of abnormal vascularization due to tumorous tissue and malignancy can safely be ruled out using this imaging modality. The patient underwent cholecystectomy and the diagnosis was histopathologically confirmed after surgery.

CEUS results when compared to the histopathological findings presented a sensitivity of 100%, a specificity of 100%, a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 100%.

In recent years, CEUS has been established as an equivalent method to conventional ultrasound and to other cross-sectional modalities in the evaluation of suspicious lesions in organs such as liver [1, 8], kidney [2, 6] pancreas [12]. Moreover, it has also showed its value in the imaging of endoleaks after endovascular aneurysm repair [13, 14]. Although this relatively new method has been standard for suspicious liver and kidney masses, its use for the evaluation of gallbladder pathologic alterations is still unclear and, in some literature, even controversial [15–18].

However, CEUS has been recently increasingly recognized as a useful alternative tool to ultrasound and to other cross-sectional modalities in the evaluation of gallbladder disease because of the applied contrast media in real-time imaging.

The crucial advantage of CEUS is that the additional application of contrast agent displays the macro and microcirculation of a target lesion showing an enhancement in different phases (arterial and parenchymal), overcoming the US limitations and consecutively increasing the diagnostic confidence.

Greyscale US usually allows the differentiation between a normal gallbladder or a suspicious gallbladder appearance such as wall thickened, focal or diffuse mass. However, it is insufficient to differentiate a focal mass as a tumour, sludge or polyp. In addition, native sonography has its limitations in demonstrating features such as gallbladder wall destruction or infiltration suggesting malignancy [7, 17]. As power Doppler and color Doppler are insensitive to depict vessel slow flow as well as to demonstrate deeply located vessels, its additional use in conventional sonography is not always helpful.

This retrospective mono-center study investigated the diagnostic performance of CEUS in gallbladder diseases compared to respectively histopathological findings in 17 patients.

Greyscale US imaging demonstrated a mass and a thickened gallbladder wall in two patients. After the application of contrast agent, CEUS displayed a suspicious malignant mass in the gallbladder and features of malignancy such as an asymmetrical, tortuous arterial enhancement, also presented in other studies [18–21]. However, arterial enhancement of a tumour followed by its early washout has been showed not to be a specific criterion for malignancy [18, 21]. Other features such as tortuous-type vascularity, disrupted wall and patient age have also to be cogitated [18, 21]. The histopathological results confirmed the imaging by reporting the mass as adenocarcinoma of the gallbladder. The recognition of a malignant mass is essential for the prognosis as carcinoma of the gallbladder has a low overall prevalence [22].

In one case, CEUS demonstrated a suspicious malignant alteration of the gallbladder by displaying a tortuous-type vascularity, disrupted wall and arterial enhancement and clarified in pathologic results confirmed tis alteration as an infiltration of a malignant liver tumour.

Other alteration such as gallbladder polyp was also depicted by CEUS in two cases and verified in the histopathological results. Gallbladder polyps are common alterations that are incidentally found at US [22, 23]. Benign or malignant pseudotumors may manifest as gallbladder polyps, however, most of them are benign. Imaging findings and various clinical factors are important to recognize gallbladder cancer at an early stage and determine the recommended management [23]. According to radiologic findings, gallbladder polyp’s management can be divided into three groups: no further follow-up, follow-up and resectable (cholecystectomy). Gallbladder polyps are depicted as sessile projections of the gallbladder wall into the lumen [23].

However, sludge or adherent gallstones when immobile can imitate true gallbladder polyps. Gallbladder sludge is normally seen as mobile intraluminal, hyperechoic, nonshadowing and nonvascular alteration [24, 25].

Cholecystitis was another gallbladder alteration depicted by CEUS in 5 patients and verified in the pathology. Grayscale US demonstrated a gallbladder wall thickening and edema. Additional CEUS displayed in the arterial phase a homogeneous, fast, and intense enhancement of the thickened gallbladder wall suggesting an inflammation of the gallbladder. This inflammation when not treated can lead to an abscess of the adjacent liver. In case of a liver abscess, CEUS shows an enhancement of the abscess wall without intraluminal enhancement.

Adenomyomatosis is also an alteration of the gallbladder and CEUS can display this pattern as a focal, segmental, or diffuse benign hyperplasia of the gallbladder wall. In one patient, CEUS showed in the arterial phase a “moth-eaten” enhancement of the gallbladder wall, simultaneously to the hepatic enhancement. The gallbladder wall may occasionally enhance homogeneously with a “hourglass” appearance [26, 27]. Adenomyomatosis was also pathologically validated.

Finally, the excellent results achieved in this study (sensitivity (100%), specificity (100%), and PPV (100%) verified that CEUS is a feasible tool that can be used to depict and differentiate gallbladder pathologic alterations. Patients with contraindications to other cross-sectional modalities benefit from this safe technique as it does not use radiation and the contrast agent applied has no renal, thyroid or cardiac toxicity [3, 5].

5 Conclusion

Ultrasound imaging plays an essential role in the evaluation of gallbladder alterations. The additional use of contrast media has been used as a complementary method in order to depict gallbladder malignancy.

This study demonstrated the feasibility and diagnostic accuracy of CEUS in gallbladder diseases. CEUS results showed a high diagnostic specificity and PPV compared to histopathological findings by being able to detect and differentiate not only malignancy features in the gallbladder imaging but also other alterations in the gallbladder such as inflammation, sludge, polyps or anatomic perfusion variations. With these excellent results, this cost-effective and safe technique proved to be a valuable additional tool to the established cross-sectional modalities.