Case Control Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 14, 2020; 26(46): 7325-7337
Published online Dec 14, 2020. doi: 10.3748/wjg.v26.i46.7325
Contrast-enhanced ultrasound in association with serum biomarkers for differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and intrahepatic cholangiocarcinoma
Jie Yang, Ya-han Zhang, Jia-Wu Li, Ying-Yu Shi, Jia-Yan Huang, Yan Luo, Ji-Bin Liu, Qiang Lu
Jie Yang, Jia-Wu Li, Ying-Yu Shi, Jia-Yan Huang, Yan Luo, Qiang Lu, Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
Ya-han Zhang, Department of Pathology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
Ji-Bin Liu, Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, United States
Author contributions: Yang J and Lu Q designed the research; Yang J, Li JW, Shi YY, Luo Y and Lu Q performed the research; Zhang YH contributed to pathologic analysis studies; Yang J, Li JW, Shi YY, Huang JY and Lu Q collected the data. Yang J and Lu Q drafted the manuscript and reviewed the literature; Luo Y and Liu JB revised the manuscript; All authors approve the final version of the submitted manuscript and agree to ensure that any questions related to the work are appropriately resolved.
Supported by National Natural Science Foundation of China, No. 81571697; and The Science and Technology Department of Sichuan Province, No. 2017SZ0003 and No. 2018FZ0044.
Institutional review board statement: This study was reviewed and approved by the review board of West China Hospital of Sichuan University.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors have no financial relationships to disclose.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Qiang Lu, MD, Professor, Department of Medical Ultrasound, West China Hospital of Sichuan University, No. 37 Guoxue Xiang, Chengdu 610041, Sichuan Province, China. luqiang@scu.edu.cn
Received: August 6, 2020
Peer-review started: August 6, 2020
First decision: October 18, 2020
Revised: October 31, 2020
Accepted: November 9, 2020
Article in press: November 9, 2020
Published online: December 14, 2020
Processing time: 129 Days and 18.9 Hours
Abstract
BACKGROUND

Combined hepatocellular-cholangiocarcinoma (CHC) is a rare type of primary liver cancer. Due to its complex histopathological characteristics, the imaging features of CHC can overlap with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).

AIM

To investigate the possibility and efficacy of differentiating CHC from HCC and ICC by using contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) and tumor biomarkers.

METHODS

Between January 2016 and December 2019, patients with histologically confirmed CHC, ICC and HCC with chronic liver disease were enrolled. The diagnostic formula for CHC was as follows: (1) LR-5 or LR-M with elevated alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9); (2) LR-M with elevated AFP and normal CA19-9; or (3) LR-5 with elevated CA19-9 and normal AFP. The sensitivity, specificity, accuracy and area under the receiver operating characteristic curve were calculated to determine the diagnostic value of the criteria.

RESULTS

After propensity score matching, 134 patients (mean age of 51.4 ± 9.4 years, 108 men) were enrolled, including 35 CHC, 29 ICC and 70 HCC patients. Based on CEUS LI-RADS classification, 74.3% (26/35) and 25.7% (9/35) of CHC lesions were assessed as LR-M and LR-5, respectively. The rates of elevated AFP and CA19-9 in CHC patients were 51.4% and 11.4%, respectively, and simultaneous elevations of AFP and CA19-9 were found in 8.6% (3/35) of CHC patients. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the receiver operating characteristic curve of the aforementioned diagnostic criteria for discriminating CHC from HCC and ICC were 40.0%, 89.9%, 58.3%, 80.9%, 76.9% and 0.649, respectively. When considering the reported prevalence of CHC (0.4%-14.2%), the positive predictive value and NPV were revised to 1.6%-39.6% and 90.1%-99.7%, respectively.

CONCLUSION

CHCs are more likely to be classified as LR-M than LR-5 by CEUS LI-RADS. The combination of the CEUS LI-RADS classification with serum tumor markers shows high specificity but low sensitivity for the diagnosis of CHC. Moreover, CHC could be confidently excluded with high NPV.

Keywords: Combined hepatocellular-cholangiocarcinoma; Contrast-enhanced ultrasound; Liver imaging reporting and data system; Sensitivity; Diagnosis; Liver neoplasms

Core Tip: The imaging features of combined hepatocellular-cholangiocarcinoma (CHC) are complicated due to its complex histopathological characteristics. In addition, biopsy may misguide the correct diagnosis of CHC due to sampling error or tissue insufficiency. This study investigated the diagnostic value of the contrast-enhanced ultrasound Liver Imaging Reporting and Data System classification in association with serological tumor markers in differentiating CHC from hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The results showed that the combined diagnostic criteria had high specificity and negative predictive value but low sensitivity for the diagnosis of CHC. These findings could help radiologists and clinical investigators confidently exclude CHC lesions in the clinical setting.