Imaging Features of Hepatocellular Carcinoma With Bile Duct Tumor Thrombus: A Multicenter Study

Objectives There are still challenging problems in diagnosis of hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) before operation. This study aimed to analyze the imaging features of HCC with B1–B3 BDTT. Materials and Methods The clinicopathological data and imaging findings of 30 HCC patients with B1–B3 BDTT from three high-volume institutions were retrospectively reviewed. A total of 631 patients without BDTT who were randomly collected from each of the enrolled centers were recorded as the control group to analyze the differences in clinicopathological characteristics and imaging features between the two groups. A total of 453 HCC patients who underwent surgical treatment in the three institutions from January 2020 to December 2020 were collected for a blinded reading test as the validation group. Results HCC patients with B1–B3 BDTT had more advanced tumor stages and adverse clinicopathological features. HCC lesions were detected in all patients, and intrahepatic bile duct dilation was observed in 28 (93.3%) patients with B1–B3 BDTT and 9 (1.43%) patients in HCC without BDTT. The intrahepatic bile duct dilation showed no enhancement at hepatic arterial phase (HAP) and no progressively delayed enhancement at portal venous phase (PVP), but it was more obvious at PVP on CT. In the reports of the 30 HCC patients with B1–B3 BDTT generated for the image when the scan was done, BDTT was observed in all 13 B3 patients and 3 of 12 B2 patients, but none of the 5 B1 patients. Fourteen patients were misdiagnosed before surgery. However, when using intrahepatic bile duct dilation in HCC patients as a potential biomarker for BDTT diagnosis, the sensitivity and specificity for BDTT diagnosis were 93.33% and 98.57%, respectively. The blinded reading test showed that intrahepatic bile duct dilation in CT and MRI scans could be for separating HCC patients with B1–B3 BDTT from HCC patients without BDTT. Conclusions The HCC lesions and intrahepatic bile duct dilation on CT or MRI scans are imaging features of HCC with BDTT, which might facilitate the early diagnosis of B1–B3 BDTT.

Results: HCC patients with B1-B3 BDTT had more advanced tumor stages and adverse clinicopathological features. HCC lesions were detected in all patients, and intrahepatic bile duct dilation was observed in 28 (93.3%) patients with B1-B3 BDTT and 9 (1.43%) patients in HCC without BDTT. The intrahepatic bile duct dilation showed no enhancement at hepatic arterial phase (HAP) and no progressively delayed enhancement at portal venous phase (PVP), but it was more obvious at PVP on CT. In the reports of the 30 HCC patients with B1-B3 BDTT generated for the image when the scan was done, BDTT was observed in all 13 B3 patients and 3 of 12 B2 patients, but none of the 5 B1 patients. Fourteen patients were misdiagnosed before surgery. However, when using intrahepatic bile duct dilation in HCC patients as a potential biomarker for BDTT diagnosis, the sensitivity and specificity for BDTT diagnosis were 93.33% and 98.57%, respectively. The blinded reading test showed that intrahepatic bile duct dilation in CT and MRI scans could be for separating HCC patients with B1-B3 BDTT from HCC patients without BDTT.

INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide (1). HCC often invades the portal vein and forms a tumor thrombus. HCC with bile duct tumor thrombus (BDTT) is uncommon, with an incidence between 0.53% and 12.9% (2)(3)(4)(5).
Previous studies have attempted to explore the clinicopathological characteristics and surgical treatment of HCC with BDTT (6)(7)(8)(9)(10). Hepatectomy is generally considered the preferred treatment for HCC with BDTT. Therefore, accurate diagnosis and surgical treatment are important to improve survival. Both computed tomography (CT) and magnetic resonance imaging (MRI) have diagnostic value for HCC with BDTT. There remain challenges in the diagnosis of HCC with BDTT before operation. According to the classification proposed by the liver cancer study group of Japan, BDTT was classified as B1-B4 (11). Several reports focusing on the CT or MRI features of HCC with B4 BDTT have been described (12)(13)(14)(15)(16)(17).
However, to the best of our knowledge, the imaging features of HCC with B1-B3 BDTT have not been reported in the literature. Thus, the purpose of our study was to analyze the CT or MRI characteristics of HCC with B1-B3 BDTT to have a better understanding and early diagnosis of this disease.

Patient Population
Because few patients with BDTT have undergone surgical treatment at a single institution, this retrospective study was conducted at three high-volume institutions [ Medical University) who underwent surgical treatment in the three institutions were collected for a reading test by blinded radiologists when using intrahepatic bile duct dilation in HCC patients as a potential biomarker for BDTT diagnosis. A total of six radiologists who did not know the clinicopathological information of the 453 HCC patients including original reports and pathological information were involved to report the scans. The six radiologists worked in pairs and all scans of the 453 HCC patients were reported by two radiologists who were in consensus. The results were compared with the original imaging diagnostic reports, which referred to the reports generated for the images when the scans were done. The present study was approved by the institutional review board of each institution.

Image Acquisition
A 64-slice multidetector CT scanner (Toshiba, Aquilion, Japan) was used. The imaging study was performed from the diaphragm to the iliac crest. The scanning parameters were as follows: section thickness, 3 mm; tube voltage, 120 kV; tube current, 250 mA; and intersection gap, 5.0 mm. Iopromide (Ultravist 370, Bayer Schering Pharma, Berlin, Germany) was used as a contrast agent at a dose of 1.5 ml/kg, injection flow rate: 3-4.0 ml/s. After injection of contrast agent, HAP and PVP scans were performed at 34-37 s and 60-70 s, respectively.

Imaging Analysis
The imaging findings of HCC with BDTT were retrospectively analyzed as follows: background liver, tumor size, number of tumors, tumor capsule, the location of HCC lesions and BDTT, pre-contrast density and contrast enhancement characteristics of HCC lesions and BDTT, vascular tumor thrombus, intrahepatic metastasis or satellite nodule, and lymph node enlargement. Special attention was given to the presence or absence of intrahepatic biliary dilation. In comparison with background liver, the density of HCC and BDTT was divided as hypoattenuation, isoattenuation, or hyperattenuation in the pre-contrast, HAP, and PVP. All images were retrospectively and blindly reviewed by two senior abdominal radiologists in consensus.

Pathology Analysis
HCC with BDTT was diagnosed based on histopathologic findings and immunohistochemical results. Macroscopically, the location, size, and capsule of HCC, presence of satellite nodules, necrosis or hemorrhage, vascular invasion, and the location and appearance of BDTT were observed. The histological differentiation of HCC with BDTT, microvascular invasion, lymph node metastasis, and liver cirrhosis were microscopically observed. The diagnoses and analyses were made by two experienced pathologists who were in consensus.

Data Analysis
Statistical analyses were performed using SPSS software (version 17.0; SPSS, Inc., Chicago, IL, USA). Categorical variables were expressed as percentages and were compared using the chi-square test or Fisher's exact test. Continuous variables were compared using t-test. p < 0.05 was considered statistically significant.

CT and MRI Findings
In HCC with B1-B3 BDTT, 18 patients underwent CT and 12 patients underwent MRI scans. In HCC without BDTT, 280 patients underwent CT and 351 patients underwent MRI scans ( Figure 2A). HCC lesions were detected in all patients. In HCC with B1-B3 BDTT, intrahepatic bile duct dilation was observed in 28 (93.3%) patients, while intrahepatic bile duct dilation was observed in 9 (1.43%) patients in HCC without BDTT. In the reports of the 30 HCC patients with B1-B3 BDTT, generated for the image when the scan was done, BDTT was observed in all B3 patients and 3 of 12 B2 patients, but it was not observed in B1 patients on CT or MRI.
One B1 (Figure 3), 9 B2, and 8 B3 patients with BDTT underwent CT scans. The HCC lesions and BDTT showed relative hypoattenuation on plain CT scan, hyperattenuation at HAP, and hypoattenuation at PVP in all patients. Intrahepatic bile duct dilation showed no enhancement at the HAP and no progressively delayed enhancement at PVP, but it was more apparent in the PVP. Four B1, three B2 (Figure 4), and five B3 BDTT patients ( Figure 5) underwent MRI scans. The HCC lesions and BDTT showed relatively hyperattenuation on T2WI and relatively hypoattenuation on T1WI. Early enhancement of HCC lesions at HAP with hyperattenuation was observed, but thickened and grossly enhanced bile duct wall was not observed in all patients. At PVP, HCC lesions showed hypoattenuation in nine patients and isoattenuation in three patients, and intrahepatic bile duct dilation showed hypoattenuation in all patients.
The imaging features of HCC with BDTT are summarized in Table 2. Intrahepatic bile duct dilation was observed in nine HCC patients without BDTT. Five patients underwent CT ( Figure 6) and four patients underwent MRI scans. Of these patients, intrahepatic bile duct dilation was observed in S2, S3, and S4 (four patients); S4 (one patient); S6 and S7 (one patient); and S5 and S8 (three patients).

Intrahepatic Bile Duct Dilation in HCC Patients for BDTT Diagnosis
Intrahepatic bile duct dilation in CT and MRI scans was used for separating HCC patients with B1-B3 BDTT from HCC patients without BDTT. As it is shown in Table 3, intrahepatic bile duct dilation in HCC patients gives a better result for BDTT diagnosis. The sensitivity and specificity were 93.33% and 98.57%, respectively ( Table 4). The positive predictive value and negative predictive value were 90.32% and 99.68%, respectively ( Table 4).

Results of Blinding Test
A reading test by blinded radiologists was performed ( Table 5). When using intrahepatic bile duct dilation in HCC patients as a potential biomarker for BDTT diagnosis by blinded radiologists in all 453 HCC patients ( Figure 2B), 14 patients were classified as HCC with BDTT (7 as B1-B3 and 7 as B4, respectively).

DISCUSSION
Some studies found that large lesions, capsule infiltration, poor differentiation, portal vein invasion, and intrahepatic metastasis were more frequently observed in HCC patients with BDTT (5,18,19). These differences suggested that patients with BDTT had  a more infiltrative nature, which accounted for poorer prognosis than those without BDTT, even after curative resection (7-9, 18-21). Since the bile duct and portal vein are encapsulated in the Glissonian sheath, tumors can easily involve both. About 46.7% of patients with BDTT had gross PVTT, and 73.3% were in advanced stages in the present study. In addition, patients with HCC and BDTT who underwent hepatectomy had a higher proportion of poorly differentiated tumors, lymphovascular invasion, and macrovascular invasion through systematic review and meta-analysis (7-9, 18-21). In our data, we also found that HCC patients with B1-B3 BDTT had more advanced tumor stages and adverse clinicopathological features. The two groups differed significantly in age, tumor number, portal vein invasion, lymph node metastasis, and TNM stage. For B4 BDTT, Kim et al. had shown that HCC patients with B4 BDTT had a higher incidence of jaundice, major vascular invasion, and a later AJCC stage (10). We also found that for HCC patients with B4 BDTT, there were significant differences in age, tumor number, portal vein invasion, lymph node metastasis, and TNM stage like B1 to B3 BDTT (data no showed). Surgical treatment for HCC is considered the most effective approach, including those with BDTT. In addition, Kasai et al. had shown that extended hepatectomy for HCC patients with BDTT provided a better prognosis (6). Major liver resection and anatomical liver resection may be more suitable for patients with HCC and BDTT because it can remove HCC lesions, BDTT, and PVTT at the same time, improving R0 resection (10,(22)(23)(24)(25). Luo et al. also showed that radical hepatic resection and removal of BDTT, combined with TACE, are the most effective approach for HCC patients with BDTT (26). These results showed that the choice of the most appropriate treatment is very important for the prognosis of HCC with BDTT. However, misdiagnosis of BDTT may lead to inappropriate therapeutic strategies before surgery, resulting in a poor prognosis. Moreover, Lu et al. had indicated that modification of the BCLC system to include BDTT might further enhance its prognostic ability (27). BDTT was associated with significantly worse long-term surgical outcomes in HCC patients (5,20). Therefore, the early diagnosis of B1-B3 BDTT might help to choose suitable therapeutic strategies for patients and predict prognosis before surgery.
Despite recent remarkable improvements in imaging techniques, the diagnosis of HCC with BDTT remains a challenge. Patients with B1-B3 BDTT usually have no specific clinical manifestations and do not develop obstructive jaundice. In addition, both clinicians and radiologists are mostly satisfied with the diagnosis of HCC and lack sufficient awareness of BDTT. Of 34 patients with HCC and BDTT, all patients with B1-B3 BDTT and half of 24 patients with B4 BDTT were not diagnosed on preoperative CT or MRI scans (2). Ikenaga et al. reported that preoperative diagnosis of BDTT was obtained in 7 of 15 HCC patients with BDTT, but none of the 5 patients with B1, and 3 of 6 patients with B3 BDTT were not diagnosed preoperatively (18). Only 1 of 13 patients with B3 BDTT and none of the patients with B1-B2 BDTT were diagnosed before surgery in our study.
Therefore, distinctive imaging features of HCC with BDTT seem especially important to recognize. HCC lesions and soft tissue masses in the biliary ducts are two typical features, which is the key for diagnosing HCC with B4 BDTT (15,17). In our data, although B1-B2 BDTT was not observed on CT or MRI scans, intrahepatic bile duct dilation was present in 93.3% of patients and indirectly reflected the presence of BDTT in the study. The tumor invades the bile duct of the subsegment, and bile duct dilation may not be detected on imaging. For example, if the tumor is located in S8 and the tumor thrombus extends to the dorsal bile duct, it does not invade the confluence of the dorsal and ventral bile ducts, and the bile duct dilation of the ventral segment may not be observed on CT or MRI scans. When the tumor thrombus invades the confluence of the dorsal and ventral bile ducts, bile duct dilation of the ventral subsegment is observed. As the tumor thrombus further extends to the confluence of S5 and S8, bile duct dilation of S5 can be seen. The tumor thrombus further extends to the right hepatic duct, and bile duct dilation of the right posterior lobe can also be seen. In HCC patients without BDTT, only 1.43% patients had intrahepatic bile duct dilation in CT or MRI scans. Of the patients, intrahepatic bile duct dilation was caused by the oppression of tumor. Therefore, intrahepatic bile duct dilation in HCC patients without BDTT was always closed to tumor.
Our results confirmed that HCC lesions and the localized bile duct dilation may be imaging features of patients with B1-B3 BDTT. Both CT and MRI have diagnostic value for HCC with BDTT, but MRI displays more detailed information for the diagnosis.  Intrahepatic bile duct dilation can be seen in each phase of MRI, but it is more obvious in PVP on CT scans. When intrahepatic bile duct dilation in CT and MRI scans was used for separating HCC patients with B1-B3 BDTT from HCC patients without BDTT, the accuracy rate of diagnosis is 100% in the blinded reading test. Therefore, a deeper understanding imaging features of different BDTT is key to further improving the diagnosis preoperatively. HCC with BDTT should be differentially diagnosed with intrahepatic cholangiocarcinoma (intraductal type). Both HCC with BDTT and intrahepatic cholangiocarcinoma have similar image features, such as intraductal neoplasm and upstream bile duct dilation (17,28). Most BDTT show early enhancement at HAP and rapid washout of contrast agent with hypointense signal at PVP (14,29). Intrahepatic cholangiocarcinoma usually manifests as a narrowed bile duct with irregular wall thickening and progressively delayed enhancement of the PVP (17). Hepatic parenchymal mass and the T1W hyperintense signal on the distal segment are valuable for distinguishing BDTT from intraductal growing cholangiocarcinoma (28). The presence of liver cirrhosis, serum CA19-9, and AFP levels are also supportive of the differential diagnosis. Another relatively rare disease, but also to be distinguished from BDTT, is the HCC compressing the intrahepatic bile duct. The latter can cause intrahepatic bile ducts to dilate, and the location of bile duct dilation is where the HCC compresses the bile duct. However, bile duct dilation in HCC patients with BDTT is caused by tumor thrombus, not the tumor itself. The tumor and the dilated bile duct have a certain distance, rather than close to the dilated bile duct.
Several limitations of our study need to be acknowledged. First, our study had a relatively small sample size due to the rare incidence of these tumors. Despite this, our population is the largest among the published studies. Second, because there was no jaundice, none of the patients with BDTT received MRCP before the operation. Thus, to some extent, our explanations for the imaging findings of B1-B3 BDTT might be considered speculative before operation.

CONCLUSION
In summary, HCC lesions and intrahepatic bile duct dilation on CT or MRI scans were commonly seen in HCC patients with B1-B3 BDTT. These imaging features facilitate the early diagnosis of B1-B3 BDTT, which might help to choose suitable therapeutic strategies for patients before surgery.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Fujian Provincial Hospital (Fuzhou, China), West China Hospital of Sichuan University (Chengdu, China), and the First Affiliated Hospital of Fujian Medical University (Fuzhou, China). The patients/participants provided their written informed consent for participation in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.     (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.