PURPOSE: To evaluate the diagnostic performance of the combination of tumor 
markers [alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9)] and 
imaging features in differentiating combined hepatocellular-cholangiocarcinoma 
(CHC) from hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC).
METHODS: Forty consecutive patients with pathologically proven CHC were 
retrospectively evaluated with contrast-enhanced ultrasound (CEUS). 
Additionally, 40 HCC and 40 CC patients who were randomly selected from the same 
period served as a control group. Images were classified as HCC-like or CC-like 
pattern according to CEUS guidelines recommended by World and European 
Federation for Ultrasound in Medicine and Biology (WFUMB-EFSUMB). The diagnostic 
criteria of CHC were defined as follows: (1) both AFP and CA19-9 are 
simultaneously elevated (AFP > 20 ng/ml and CA19-9 > 100 units/ml); or (2) 
elevated AFP with a CC-like pattern on CEUS and without elevated CA19-9 level; 
or (3) elevated CA19-9 with an HCC-like pattern on CEUS and without elevated AFP 
level. The diagnostic tests were performed with calculation of the sensitivity, 
specificity, accuracy, positive predictive value (PPV), negative predictive 
value (NPV), and area under the receiver operating characteristic curve (AUC).
RESULTS: For the 40 CHC patients, the rates of elevated AFP and CA19-9 serology 
were 55.0 and 30.0%, respectively. Twenty-three (57.5%) patients exhibited an 
HCC-like pattern, and 15 (37.5%) showed a CC-like pattern. After applying the 
above diagnostic criteria of CHC in the 120 patients, the sensitivity, 
specificity, PPV, NPV, accuracy, and AUC were 32.5, 93.8, 72.2, 73.5, 73.3, and 
0.631%, respectively. When the actual prevalence rate (0.4-14.3%) was taken into 
account, the PPV and NPV were modified from 2.1 to 46.7% and 89.3 to 99.7%, 
respectively.
CONCLUSION: The combination of enhancement patterns on CEUS and serum tumor 
markers (AFP and CA19-9) may be a potentially specific diagnostic method to 
differentiate CHC from HCC and CC.