Major and ancillary features according to LI-RADS in the assessment of combined hepatocellular-cholangiocarcinoma

The institutional review board approved this retrospective study, and the requirement for patient informed consent was waived. We searched the surgical database at our institution from January 2013 to September 2018 and selected 74 patients with pre surgical biopsy and radiological diagnosis of HCC, who underwent hepatic resection. The inclusion criteria for the study population were as follows: (a) patients who had pathologically-proven HCC; (b) patients who had undergone MR imaging and liver MDCT with less than a 1-month interval between imaging modalities; (c) patients who had less than a 1-month interval between imaging and pathologic diagnosis; and (d) availability of diagnostic quality pictures of the cut sections of the resected specimens in patients who underwent surgical resection for matching of imaging and pathology findings. The exclusion criteria were as follows: (a) conflict between the imaging-based diagnosis and the pathologically confirmed diagnosis, (b) no available MR or MDCT images.

In total, 73 patients with HCC confirmed at pathology fulfilled the inclusion criteria during the study period. Among them, 11 patients were excluded for the following reasons: (a) 4 patients no had available MR or MDCT images and (b) 7 patients because the final diagnosis were not HCC. Finally, 62 patients (14 women, 48 men; median age, 63 years; range, 38–80 years), with pre-surgical biopsy and radiological diagnosis of HCC comprised our study population. Characteristics of the 62 patients are summarized in Table 1.

All original pathological samples were reviewed by one experienced hepatic pathologist (F.T.). Lesions were confirmed histopathologically as hepatic tumours comprising unequivocal elements of both HCC and CC according to the tumour classification of the World Health Organization. The CC component was defined as glandular differentiation with mucin production, while the HCC component was defined as trabecular, solid sheet, or pseudoacinar arrangements with interspersed sinusoids. All pathological samples displayed an intimate intermingling of trabecular hepatocellular and true glandular elements (type C). The bidirectional differentiation was further supported by immunohistochemical stain. For each specimen, biliary differentiation was confirmed with mucin positivity or with immunohistochemical stains characteristic of bile duct differentiation (cytokeratin 7, cytokeratin 19), whereas hepatocellular differentiation was confirmed with immunohistochemical stains characteristic of hepatocyte differentiation (Hepatocyte-Paraffin-1).

All patients underwent to MDCT and 23 to MR.

MDCT was performed with a 64-detector row scanner (Optima 660, GE Healthcare, United States). MDCT scanning parameters were 120 kVp, 100–470 mAs (NI 16.36), 2.5 mm slice thickness and table speed 0.984/1 mm/rotation. Scans were carried out including a region encompassing the liver from diaphragm to iliac crests. Liver protocol examinations were composed of quadruple phases, including the unenhanced, arterial, portal venous, and equilibrium phases. CT images were obtained after injection of 120 mL of a nonionic contrast medium (iomeprol, Iomeron 400, Bracco, Milan, Italy) at a rate of 3.0–4.0 mL/sec by using an automatic power injector (Empower CTA, E-Z-EM Inc., New York, United States). Image acquisition in the arterial phase was initiated 19 seconds after attenuation in the descending aorta reached 100 HU, as measured with the bolus tracking method; in the portal venous phase, images were acquired 33 seconds after the arterial phase; in the equilibrium phase, images were acquired 180 seconds after administration of contrast media.

MR imaging was performed by using a 1.5 T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Our routine liver MR imaging protocol consisted of a breath-hold fat-saturated and not fat-saturated T2-weighted turbo spin-echo sequence, an in- and opposed-phase T1-weighted gradient-echo sequence, dynamic imaging with a fat-saturated T1-weighted gradient-echo sequence, and diffusion-weighted imaging. Diffusion weighted imaging (DWI) was obtained with planar echo-pulse sequence (b values 0, 50, 100, 200, 400, 600, and 800 s/mm²). A non-specific agent the Gd-BT-DO3A (Gadovist, Bayer Schering Pharma, Germany) was employed. All patients received 0.1 ml/kg of Gd-BT-DO3A by means of a power injector (Spectris Solaris® EP MR, MEDRAD Inc., Indianola, IA, USA), at an infusion rate of 2 ml/s followed by a 30-mL saline flush. Arterial phase images were acquired 7 seconds after contrast material arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase and equilibrium phase were obtained 60 seconds and 3 minutes after contrast material administration, respectively. Detailed information regarding the MR imaging parameters are summarized in Table 2.

For each patient, MDCT and MR images were independently and blindly evaluated in random order within and between three radiologists (V.G., S.V.S., A.P.; 10, 15, and 20 years of experience in abdominal imaging). A consensus evaluation was performed when there was disagreement between the readers. The readers were blinded to previous radiological examination, pathologic results and history of previous treatment but were aware that the patients had cirrhosis and thus were at higher risk for HCC. To reduce recall bias, all three readers maintained an interval of more than 2 weeks between interpretation sessions of MR and MDCT images.

Each radiologist was asked to identify the presence of lesion, that was considered to be detectable if the nodule had attenuation or signal intensity that differed from that of the surrounding liver parenchyma. Thereafter, they reported the presence of the HCC by using LIRADS v2018 assessing major and ancillary features19; also the radiologists reported any radiological accessory findings if detected.

Readers assessed and recorded the following parameters: greatest nodule diameter, attenuation at unenhanced CT, signal intensity on T1- and T2-weighted images, vascular hyperenhancement pattern during arterial phase (wash-in), wash-out appearance during portal phase, vascular enhancement during equilibrium or late phases.13

Region of interests (ROIs) have been manually drawn by an expert radiologist on T1-w and T2-w images and on DW images at the highest b value (including hyperintense voxels at b value 800 s/ mm²) considering the same slices position. The contours of lesions were validated by another expert radiologist of 25 years of experience.

The signal intensity of the lesions in T1-w and T2-w images was categorized subjectively as isointense, hypointense, and hyperintense compared to surrounding liver parenchyma. We assessed the signal on DWI sequences and measured the apparent diffusion coefficient (ADC) of each lesion. The diffusion weighted signal decay was analyzed using the mono-exponential model, according to the equation, the apparent diffusion coefficient ADC = (ln [S0/ Sb])/b, where Sb is the signal intensity with diffusion weighting b and S0 is the non-diffusion-weighted signal intensity. This analysis was ROI-based using median value of single voxel signals for each b value. Median diffusion parameters of ROI were used as representative values for each lesion. No motion correction algorithm was used but ROIs were drawn taking care to exclude areas in which movement artifacts or blurring caused voxel misalignments.

We analysed the enhancement pattern during arterial, portal, equilibrium or late phase and described it as homogeneous, heterogeneous, or progressive. We described the capsule appearance, defined as a peripheral rim of smooth hyperenhancement in the portal or delayed phase, as complete or partial. In addition, we recorded the number and segmental location of the nodule for all detected lesions and the presences of satellite nodules.

Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Fisher’s exact test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.

All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).

After pathological evaluation the final diagnosis was HCC for 51 patients and cHCC-CCA for 11 patients (17.7%).

Twelve patients were classified as G3 (19.4%) and 50 G2 (80.6%) according to the grading system of Edmondson-Steiner.21

Among cHCC-CCA 8 patients were classified as G2 (72.7%) and 3 as G3 (27.3%). In 8 out of 11 (72.7%) cHCC-CCA microvascular infiltration was reported.

In two cHCC-CCA patients were reported nodal metastases.

All lesions were detected and analyzed by readers. The consensus in the assessment of the nodules

was 100%. The median nodule size was 46.0 mm (range 10–190 mm). For cHCC-CCA the median size was 33.5 mm (range 20–80 mm), for true HCC the median size was 47.5 mm (range 10–190 mm).

The consensus between pre-surgical radiological report and second evaluation was 100% for each LIRADS categories: LR-5 for 54 (87.1%) nodules, LR-3 for 1 (1.6%) lesion, and LR-M for 7 (11.3%) nodules.

Thirty-nine nodules (63%) showed hyperenhancement in arterial phase; among them 4 were cHCC-CCA (36.4% of cHCC-CCA) and 35 (68.6%) true HCC.

Twenty nodules (32.2%) showed an inhomogeneous hyperenhancement in arterial phase; 7 of them were cHCC-CCA (63.6% of cHCC-CCA) (Figure 1). We found this feature in 13 (25.5%) true HCC.

Figure 1

Forty-three nodules (69.3%) showed wash-out appearance; 6 cHCC-CCAs (54.5% of cHCC-CCA) and 37 true HCC (72.5%) had this feature.

We found inhomogeneous wash-out in 13 (20.9%) nodules; 4 nodules with inhomogeneous wash-out were cHCC-CCA (35.4% of cHCC-CCA). A one cHCC-CCA (9.1% of cHCC-CCA) patient did not show this feature. Nine true HCC (17.6%) showed inhomogeneous wash-out.

Thirty-three (53.2%) nodules showed capsule appearance, 28 (45.2%) did not show this feature and in one patient we found a peripheral halo sign.

Only two cHCC-CCA patients (18.2% of cHCC-CCA) showed capsule appearance while 9 cHCC-CCAs (81.8% of cHCC-CCA) did not have this feature (Figure 2).

Figure 2

Thirty-one (60.8%) true HCC showed capsule appearance and 19 (37.2%) true HCC did not show this feature.

Only 23 patients underwent MR study, among them 7 out of cHCC-CCA. We found T2 hyperintensity of signal in 20 nodules (86.9%), two lesions (8.6%) were isointense and one (4.3%) hypointense.

Five cHCC-CCA (714 % of cHCC-CCA) showed hyperintensity on T2-W sequences while two (28.6%) showed inhomogeneous signal in T2-W (Figure 3).

Figure 3

Fifteen true HCC (93.7%) had hyperintense signal on T2-W and one true HCC (6.2%) inhomogeneous signal on T2-W.

We found restricted diffusion in 23 (100%) nodules with median ADC of 975.6 x 10^-3mm²/s.

All cHCC-CCA showed restricted diffusion with median ADC of 880.7 x 10^-3 mm²/s.

All true HCC showed restricted diffusion with median ADC of 1210.0 x 10^-3 mm²/s.

Progressive contrast enhancement: nine (14.5%) patients showed a progressive contrast enhancement; among them 7 were cHCC-CCA (63.6% of cHCC-CCA) (Figure 4) and 2 (3.9% of HCC) true HCC.

Figure 4

In ten patients (16.1%) we found satellite nodules (neighboring micrometastases), among them 7 were cHCC-CCA (63.6% of cHCC-CCA) (Figure 5) and 3 (5.9% of HCC) were true HCC.

Figure 5

The hyperenhancement in arterial phase (p value = 0.04), the absence of the pseudocapsule (p value = 0.03), progressive contrast enhancement (p value < 0.001) and satellite nodules (neighboring micrometastases, p value < 0.001) showed percentages statistically different respect to the presence of combined HCC and cholangiocarcinoma at Fisher’s exact test (see Table 2).

A statistically significant difference (p value = 0.03 at Mann Whitney test) was detected between ADC median value of the two groups pure HCC and cHCC-CCA group.