Patients
A prospective study was conducted on a consecutive series of 157 patients (74 males and 83 females; age range, 30–92 years; mean age, 61.4 years) with 160 focal liver lesions examined between 30 March 2010 and 30 March 2011. All subjects gave their informed consent to undergo the imaging procedure.
There were 80 patients with a normal liver, 44 patients with a known primary malignancy and 33 patients with liver cirrhosis. In our radiology department CEUS is used as a second-level technique after detection of focal liver lesions in both the normal and cirrhotic liver according to the 2004 and 2011 EFSUMB guidelines [16, 17]. In fact, the study included all patients who underwent liver CEUS as a second-level investigation for the characterisation of focal lesions detected on other imaging techniques and considered indeterminate by the operator; in more detail, in 74 patients CEUS was carried out after baseline ultrasound, in 77 after CT, in 5 after MR imaging and in 1 after scintigraphy (Indio-111 octreotide).
As for the lesions detected on unenhanced US, these were newly discovered focal lesions in patients with a known primary malignancy in 9 cases, suspicious findings for malignancy in patients with cirrhosis in 22 cases, newly detected findings that could not be characterised on unenhanced US in 11 cases, focal liver lesions discovered incidentally during unenhanced US examinations performed in an emergency setting in 12 cases and focal lesions identified but not characterised at another institution in 20 cases.
As for the indeterminate focal liver lesions detected with CT, 32 were identified during a staging or follow-up examination performed with a single-contrast phase in patients with known malignancy, 10 were suspicious lesions in patients with cirrhotic livers, 7 were incidental findings on CT angiography (n = 4) or CT urography (n = 3), 17 were incidental findings during single- or dual-phase emergency CT, 5 were lesions presenting an atypical dynamic contrast pattern on multiphase CT, and 6 were lesions detected with single- or dual-phase CT at other institutions/hospitals and not characterised.
Of the five cases of CEUS performed after MR imaging, 2 had MR findings compatible with atypical haemangioma in high-risk patients, two required differentiation between well-differentiated hepatocellular carcinoma (HCC) nodules and benign lesions, and one was a request for further contrast-enhanced investigation to confirm a suspicion of single metastasis in a cancer patient (known malignancy).
The single patient who underwent CEUS after positive scintigraphic examination (patient with colon carcinoma and focal uptake in the liver area) underwent CEUS to remove any doubts relating to the finding.
Examination technique
Liver CEUS was conducted with Sequoia S2000 equipment (Acuson-Siemens, Mountan View, CA) in 133 patients and with an Aplio XG system (Toshiba Medical Systems, Tokyo, Japan) in 24 patients. After performing an initial baseline greyscale study and colour and/or power Doppler imaging with multifrequency convex probes in order to identify the lesion and select the best scanning plane, we proceeded to cannulate a forearm vein and carry out the CEUS study. A bolus of sulphur hexafluoride microbubbles (SonoVue ® Bracco Imaging, Milan, Italy) was injected at an average dose of 2.29 ml (mode and median, 2.4 ml) followed by a 10-ml saline bolus chase. The arterial phase was set at 15–35 s from contrast administration, the venous phase at 40–70 s and the late phase up to 300 s. The contrast-specific techniques used were cadence contrast pulse sequencing (CPS) (Acuson-Siemens, Mountan View, CA) and a tissue contrast discriminator (Toshiba Medical Systems, Tokyo, Japan) with a mechanical index of 0.09–0.14, a dynamic range of 65 dB and a temporal resolution between 75 and 100 ms (10–13 frames per second). Signal amplification was adjusted below visibility of noise and the focus immediately below the lesion.
Four-phase CT was conducted using 64-slice equipment (Aquilion, Toshiba Medical Systems, Tokyo) with the following technical parameters: 400-ms rotation time, 64 × 0.5-mm collimation, pitch normalised at 1, 32-mm Z-axis coverage, 0.3-mm reconstruction interval, 120 kV, 180–250-mAs tube current intensity in relation to patient size and 40-cm field of view. The images were reconstructed with a field of view of 25–35 cm in relation to the physical constitution of the patient. We acquired unenhanced, arterial, portal and late phase scans after the intravenous bolus administration of 120 ml of iodinated contrast medium (iopromide) at a concentration of 370 mg/ml at a flow rate of 5 ml/s, followed by a 50-ml saline bolus. The arterial phase was acquired using the bolus tracking technique with a delay of 18 s after a threshold of 140 HU had been reached in a region of interest (ROI) placed over the abdominal aorta. The portal and late phases were acquired with a delay of 70–80 s and 180–210 s, respectively, from the beginning of contrast administration.
MR of the liver was performed using a superconducting magnet operating at 1.5 T (Achieva, Philips Medical Systems, The Netherlands). Axial acquisitions were obtained during an expiratory breath-hold using a four-channel phased-array surface coil and breathing synchronisation. The following sequences were used: T2-weighted single-shot turbo spin-echo (SS TSE) (TR/TE, 593/80), T2-weighted inversion recovery with fat suppression (SPAIR) (TR/TE, 448/80), in-phase and out-of-phase T1-weighted fast field echo (FFE) (TR/TE, 332/4.6-2.3) and T1-weighted high-resolution isotropic volume examination (THRIVE) with fat suppression (TR/TE, 3.2/1.62) performed before and after the administration of 0.2 mmol/kg gadobenate dimeglumine (Gd-BOPTA) into a vein of the arm at a flow rate of 2 ml/s and followed by 20 ml of saline bolus chase. The arterial phase was acquired using the bolus chase technique with a delay of 5–10 s after visualisation of the contrast medium at the level of the abdominal aorta. The portal and late phases were acquired with a delay of 70–80 and 180–210 s, respectively. Finally, a hepatobiliary phase was acquired at 1.5–2 h after the administration of contrast medium.
Image evaluation
The images were evaluated on a PACS (picture archiving and communications system)-integrated workstation (19-inch TFT display, resolution 2,560 × 1,600 pixels, EBIT AET Health, Genoa, Italy) by the radiologist who performed the examination. In particular, three radiologists with 5, 14 and 15 years of experience in liver imaging reviewed the CEUS images, another three radiologists with 9, 13 and 14 years of experience reviewed the CT images, and two radiologists with 9 and 12 years of experience reviewed the MR images.
Evaluation of the CEUS images was performed in real time, whereas the CT images were reviewed just after the acquisition and reconstruction of the four phases (unenhanced, arterial, portal and late phase); the characterisation of focal liver lesions on MR imaging required waiting until after the acquisition of the hepato-specific phase 60 min after administration of the contrast medium.
We used the reference criteria reported in the literature for CEUS [18] and MR imaging and CT [3] for lesion characterisation or to propose a possible nature diagnosis, benign or malignant, for each focal liver lesion.
Cost analysis
For the purposes of the economic assessment we used a method already applied in previous studies [19] and in industrial settings [20] to compare the relative costs of the three imaging techniques used for the characterisation of liver lesions: CEUS, CT and MR imaging.
For CEUS, data were collected for 157 patients. Given that only a small percentage of these patients required subsequent assessment with multiphase CT (n = 6 ) and/or dynamic MR imaging with hepato-specific contrast material (n = 13), the variable costs and personnel costs for these two modalities were calculated on a sample of 50 patients with focal liver lesions.
For each technique, we calculated and compared the full cost, defined as the sum of the variable costs and fixed costs of capacity (technology and staff costs), which represents the most relevant cost component as it differs among CEUS, CT and MR imaging; the indirect costs of the department were not taken into account as they do not depend on the application of the three techniques.
For each method, the cost of the technology was calculated based on the purchase cost of the equipment, obtained from the official hospital documentation, and depreciation over time considered at a constant annual rate except in cases in which the degradation of the device was available. The useful economic lifespan of the equipment was defined as 10 years, i.e., the maximum time that includes both technological obsolescence and degradation of care efficacy.
For each investigation, we then assessed the variable costs relating to the type and quantity of materials and services related to its use.
Subsequently, we evaluated the personnel costs in terms of physician time (person responsible for the activity, including staff radiologists and trainee radiologists) and radiology technician and nursing staff time, considering the specific activities undertaken by the various professionals for each of the three imaging techniques; this provided a calculation of both fixed and variable costs closely reflecting the current situation at our university hospital.
The costs of fixed asset utilisation (technology and staff costs) were obtained from time measurements of the use of capacity that these production factors offer.
The calculated costs of materials and equipment are inclusive of value added tax at 20 %.
Then we calculated the common costs, which correspond to the internal costs of the production factors of the radiology division and are necessary for providing services common to all diagnostic activities carried out within the division. These include capacity costs related to personnel and support materials, which remain constant, regardless of the total number of examinations performed in a year.
Finally, we considered the external costs to the radiology division for each of the imaging techniques being compared: in particular, the costs arising from determination of serum creatinine levels (performed in all patients undergoing CT or contrast-enhanced MR imaging) and those arising from anti-allergic preparations through the use of corticosteroids associated with anti-H1 and anti-H2 (performed in all patients undergoing CT with a history of moderate and severe reactions to iodinated contrast media or a history of asthma or allergy requiring medical treatment).
The total cost for each investigation, and hence the cost of the diagnostic process, is given by the sum of the full costs, common and external costs.
We computed the actual historical full cost for the three different imaging techniques, CEUS, CT and MR imaging, which corresponds to average costs. We followed an activity-based method [36] consisting of two tasks: producing the images and reporting. In our case the second task closely follows the first one; it is performed in the same cost and responsibility department, and its cost is computed separately (as lead time times cost per hour); therefore, the two tasks are additive.
The economic evaluation method is cost-effectiveness [20], namely the diagnostic effectiveness, as an intermediate time of the whole treatment process. We assumed the provider point of view for the costs. We excluded the costs for the patient, the patient’s family or discounted future effects for the patient.