Malignancies after liver transplantation: Value of contrast-enhanced ultrasound (CEUS)

1 Introduction

Contrast-enhanced ultrasound (CEUS) has already been established as an imaging technique equivalent to contrast enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) in the evaluation of unclear liver masses [2–4, 12].

With CEUS an imaging modality has been introduced into daily praxis, which can rapidly generate additional image information by evaluating the vascularisation patterns of unclear liver masses allowing a fast diagnosis [5–7]. In patients with suspicious liver masses mostly additional imaging modalities such as magnetic resonance imaging (MRI) or contrast enhanced computed tomography (CE-CT) is recommended to confirm native B-mode ultrasound findings [3, 10]. Disadvantages of these methods are the use of x-rays and/or of nephrotoxic contrast media. CEUS offers a fast and cost-effective making it a possible alternative to CE-CT and MRI. Ultrasound contrast agents can be used in patients with chronic renal failure or in patients with intolerance to iodine contrast media because of their autonomy from thyroid and renal blood parameters. Allergic reactions to ultrasound contrast agents are described in the literature to occur only in 1 of 10.000 cases [8, 11].

This retrospective analysis study was performed to evaluate the sensitivity and specificity of CEUS in the evaluation of liver masses in liver transplant patients compared to CT being the goldstandard.

2 Materials and methods

Between September 2005 and September 2015 a total of 23 liver transplant patients with unclear suspicious liver masses received imaging series at our institution and the outcome of these imaging studies were analysed retrospectively. The performance of CEUS in the evaluation of these liver masses was matched with the CT findings. CT imaging series from all patients were available from our institution. All study data were collected in compliance with the principles of the Helsinki/Edinburgh Declaration of 2002. The local ethics committee approved this study and the authors followed the ethical guidelines for publication in Clinical Hemorheology and Microcirculation [1]. Oral and written informed consent of all patients was obtained prior to each CEUS and CT examination.

The CE-CT imaging studies consisted of imaging series completed on the basis of scanning protocols and with scanners used at the time of the examination.

The 23 patients had their liver transplantation between 1993 and 2014. Mean age at the time of the CEUS examination was 53 years (Min. 18; Max 72; SD±13.1 years).

Mean time between initial liver transplantation and CEUS examination were 27,8 months (SD±56.7 months).

Mean time between CT and CEUS examination were 12,8 weeks (SD±13.2 weeks).

The CEUS examinations were completed with high-end ultrasound systems with up-to-date CEUS specific examination protocols available at the time of the examination (Siemens Acuson Sequoia and Siemens S2000, EPIQ 7, Philips Ultrasound). The Siemens ultrasound system was used with C4-1 and C6-1 HD probes and the Philips ultrasound system was used with the C9-2 probe. Each CEUS examination was performed and interpreted by a single experienced physician with more than 5000 examinations each year performed during the last 15 years of practice. To avoid early microbubble-destruction a low mechanical index (always <0.2) was configured at each ultrasoundsystem.

In all examinations, a second-generation blood pool contrast agent (SonoVue^®, Bracco, Milan, Italy) was administered through a 20–22G needle in an antecubital vein as a bolus injection followed by a flush-injection of 5 to 10 ml of 0.9% NaCl. After contrast agent injection cine loops of the CEUS examination were acquired and archived in the picture archiving and communication system of our institution. Mean examination time ranged between 3–5 minutes for the completeexamination.

From each patients record files we retrospectively obtained the results of the CEUS and CT examinations.

Out of the 23 patients, 9 patients showed suspicious liver masses in CT including arterial hypervascularized tumours suspicious of hepatocellular carcinoma. In 7 out 9 of cases the suspicious liver mass could also be depicted using CEUS (Figs. 1, 2 and 3). In one patient we had additional MRI imaging to clarify diagnosis using CEUS (See Figs. 4–7). For statistical analysis diagnostic accuracy of CEUS was tested using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) compared to CT being the gold standard.

3 Results

CEUS could be successfully performed in all 23 patients. CT imaging could also be successfully performed in all patients. In one patient we had additionally MRI imaging, which was not used in the statistical analysis of this study, but was later on used in the clinical clarification of the diagnosis of the patient using CEUS and MRI image fusion technique (see Fig. 6). No examination had to be excluded because of poor image quality, all examinations showed a diagnostic image quality.

We experienced no adverse reaction in any of the examined patients using SonoVue^®. In most cases 1.4 to 2.0 ml of contrast agent was given as the usual dose with a maximum of 4.8 ml and minimum of 1.0 ml. Mostly, a single dose of contrast agent was sufficient. Contrast media injection was repeated up to three injections if additional imaging was necessary.

The underlying diseases for the liver transplantation and for the now suspected malignancy were alcohol use disorder (n = 14; 60.9%), infection with hepatitis (n = 3; 13.0%) and immunological disorders of the liver (n = 6; 26.1%).

CEUS showed a sensitivity of 77.8%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 87,5% compared to CT being the gold standard. Out of the 23 patients in 9 patients suspicious liver masses could be depicted in CT, which could also be depicted in 7 out 9 of cases using CEUS. In 2 cases CT revealed a suspicious liver mass that was not reported on the CEUS examination. Concordant, CEUS and CT excluded a malignancy in 14 patients.

4 Discussion

This study is in line with several other studies seeing CEUS as a feasible alternative to CE-CET imaging showing comparable specificity and PPV to CE-CT without using x-rays or nephrotoxic contrast agents (1–3, 9, 12). CEUS is already established as a standard of care for patients with suspicious liver masses and should also be used in liver transplant patients. However, CEUS still cannot overcome some limitations in several patient groups, such as patients suffering from obesity or with bowel gas in the abdomen. Additionally, CEUS examinations are dependant on the skills and experience of the sonographer.

Nonethlesse, for patients with chronic renal failure, history of hyperthyroidism or iodine contrast agent intolerance, CEUS is a possible technique for the assessment of liver masses in liver transplant patients. The excellent PPV and NPV of CEUS could decrease the amount of needed CT scans and the related exposure to x-rays and decrease the usage of nephrotoxic contrast media.

This study was limited by several factors caused by the study design. This study was retrospectively analysed using a mono-center approach with only one physician evaluating the liver masses using CEUS. Several inconsistent ultrasound and CT systems and scanning protocols were used and administered CEUS contrast agent doses varied among patients.

5 Conclusion

This study is in line with several other studies regarding this topic. CEUS shows a very good specificity and PPV in the detection of liver masses and can be used to reduce the number of CT examinations in liver transplant patients. In difficult cases, CT still hast some advantages over CEUS.