A Step Closer to Improving Early Detection Rates of Hepatocellular Carcinoma

Liver cancer or liver tumor, Hepatocellular carcinoma (HCC), causes, symptoms, treatments, 3d illustration
Researchers have developed a blood test that uses PCR technology to detect early stage liver cancer. Credit: Getty Images
Researchers have developed a blood test that uses PCR technology to detect early stage liver cancer, possibly paving the way to increase early detection rates.

Hepatocellular carcinoma (HCC) is typically associated with a poor prognosis due to advanced stage of disease at the time of diagnosis.1 While evidence suggests that early detection of HCC is linked to improved outcomes, studies consistently show suboptimal rates of HCC screening despite the guideline recommendation of biannual ultrasonography with or without serum alpha-fetoprotein (AFP).

In a 2022 multicenter cohort study of 629 patients, Parikh et al found that 63.7% of patients received no screening prior to HCC diagnosis, most commonly due to lack of orders by clinicians, nonadherence by patients once screening was ordered, or failure to recognize cirrhosis prior to HCC diagnosis.2 A study published in 2021 demonstrated similar results: Only 24.7% of patients with known cirrhosis received screening at the recommended intervals, and screening underuse was attributed to lack of screening orders in nearly half of patients.3

Hepatocellular Carcinoma Screening Challenges

These results point to a clear need for efforts to improve clinician surveillance and patient adherence to HCC screening. However, experts have noted the ambiguity associated with the effectiveness of ultrasonography for HCC detection, which may contribute to the suboptimal screening rates observed across studies.

The recommended screening approach has a sensitivity of only 69% to 88% for early-stage disease,4 and results have been largely mixed regarding the benefit of adding AFP to ultrasound screening for HCC.5 Additionally, some study results indicate that ultrasound screening may lead to early detection of HCC in only one-third of patients with cirrhosis, and there are conflicting results regarding the link between HCC screening and survival benefit.2,6 In the study by Parikh et al, for example, regular HCC surveillance was not associated with overall survival.2 

Among other HCC screening challenges, ultrasound testing is financially inaccessible to many patients, further contributing to low screening rates. Ultrasound testing may also have lower accuracy in patients with smaller tumors, more advanced liver disease, or higher body weight.7 In a 2020 study of patients with HCC, the sensitivity of ultrasound testing for HCC was 77% in patients with BMI lower than 30 and 21% in those with BMI of at least 30. In patients with BMI greater than or equal to 30 and negative ultrasounds results, computed tomography scans detected HCC in 98% of cases.8

A Promising Alternative

Such findings highlight the critical need for more reliable and accurate HCC screening methods for at-risk patients. In a phase 2 multicenter case-control study published in July 2022 in Hepatology, researchers at Cedars Sinai Medical Center in Los Angeles showed encouraging results with the use of a blood test for detecting early-stage HCC biomarkers on the surface of extracellular vesicles (EVs). “Given their early presence in circulation during tumorigenesis, profiling tumor-derived EVs is regarded as a promising liquid biopsy approach for diagnosis of early-stage cancer,” the study authors wrote.1

Building on their previous research exploring the use of EVs as biomarkers for early HCC detection, Sun et al developed a PCR-based surface protein assay capable of quantifying subpopulations of EVs.4 The assay identified 3 HCC EV surface protein signatures (EpCAM+ CD63+ HCC EVs, CD147+ CD63+ HCC EVs, GPC3+ CD63+ HCC EVs) that were highly associated with HCC and thus used to establish an HCC EV ECG score that was tested in the detection of early-stage HCC in a training cohort and an independent validation cohort.

The HCC EV ECG score distinguished between early-stage HCC patients and cirrhosis patients in the training cohort (n=106) with an area under the receiver operating curve (AUROC) of 0.95. The sensitivity and specificity of the score was 91% and 90%, respectively, at the optimal cutoff of -0.40. The positive predictive value was 87%, and the negative predictive value was 93%.

In an independent validation cohort of 72 patients with early-stage HCC or cirrhosis, the AUROC was 0.93. In subgroups stratified by etiology, the AUROC was 0.95 among patients with viral etiology and 0.94 in those with nonviral etiology. In a subgroup of patients with HCC and cirrhosis, the AUROC was 0.94 with a sensitivity of 91% and specificity of 87%.

Investigators found that scores from patients with early-stage HCC were significantly higher than scores of control patients with several other types of cancer, confirming the specificity of HCC EV ECG score to HCC.

Further analyses revealed no additional benefit in adding the serum AFP level to HCC EV ECG scores.

Next Steps

If validated in future studies, this novel approach could drastically increase rates of early detection and ultimately improve long-term outcomes among patients with HCC, the study authors concluded.4 Sun et al plan to conduct a larger phase 2 biomarker study and a phase 3 study to further validate the HCC EV ECG for use in clinical practice.

“In addition to its excellent performance, this marker has the advantages of being user-friendly, cost efficient, and having a fast turnaround time—within six hours from sample collection to result,” Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, noted in a news release.5 “PCR testing technology has been widely deployed during the COVID-19 era, and once this marker has been validated in subsequent studies, it can be easily adopted by existing PCR facilities.”

Due to its proposed advantages as a more accurate, less expensive test to detect early-stage HCC, the new test could hold particular value for patients and regions with limited access to imaging resources.7


  1. Sun N, Zhang C, Lee Y-T, et al. HCC EV ECG score: an extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma. Published online July 31, 2022. Hepatology. doi:10.1002/hep.32692
  2. Parikh ND, Tayob N, Al-Jarrah T, et al. Barriers to surveillance for hepatocellular carcinoma in a multicenter cohort. JAMA Netw Open. 2022;5(7):e2223504. doi:10.1001/jamanetworkopen.2022.23504
  3. Marquardt P, Liu P-H, Immergluck J, et al. Hepatocellular carcinoma screening process failures in patients with cirrhosis. Hepatol Commun. 2021;5(9):1481-1489. doi:10.1002/hep4.1735
  4. Ahn JC, Lee Y-T, Agopian VG, et al. Hepatocellular carcinoma surveillance: current practice and future directions. Hepatoma Res. 2022;8:10. doi:10.20517/2394-5079.2021.131
  5. Francica G, Borzio M. Status of, and strategies for improving, adherence to HCC screening and surveillance. J Hepatocell Carcinoma. 2019;6:131-141. doi:10.2147/JHC.S159269
  6. Haq MI, Drake TM, Goh TL, et al. Effect of hepatocellular carcinoma surveillance programmes on overall survival in a mixed cirrhotic UK population: A prospective, longitudinal cohort study. J Clin Med. 2021;10(13):2770. doi:10.3390/jcm10132770
  7. Cedars-Sinai team pioneers liver cancer blood test. News release. Cedars-Sinai Cancer. August 20, 2022. Accessed September 28, 2022.
  8. Esfeh JM, Hajifathalian K, Ansari-Gilani K. Sensitivity of ultrasound in detecting hepatocellular carcinoma in obese patients compared to explant pathology as the gold standard. Clin Mol Hepatol. 2020;26(1):54-59. doi:10.3350/cmh.2019.0039