Current and Emerging Tools for Hepatocellular Carcinoma Surveillance

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6 months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low-dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha-fetoprotein [AFP], AFP lens culinaris agglutinin-reactive fraction, and des-gamma-carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell-free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC. (Hepatology Communications 2021;5:1972-1986).L iver cancer is the sixth most common cancer worldwide and is now the third-leading cause of cancer-related death, behind lung cancer and colorectal cancer. (1) In 2020, more than 900,000 cases of liver cancer were diagnosed globally, with more than 830,000 liver cancer-related deaths, underscoring the high mortality index of this cancer. (1) Hepatocellular carcinoma (HCC) accounts for 75%-85% of primary liver cancers. The global incidence of HCC has increased by more than 75% in the last 30 years, especially in Western countries, (2)(3)(4) and is expected to continue to grow in the near future. Unfortunately, survival rates for patients with HCC in the United States remain dismally low and essentially unchanged over the past 30 years, (5) with only 3%-34% of patients with HCC surviving 5 years after diagnosis. (6) The high HCC mortality rates can be attributed to several factors, with delayed diagnosis of cancer at more advanced stages of disease being an important reason. (2,7,8) HCC typically arises in the background of the cirrhotic liver, where chronic inflammation and fibrosis induce genomic alterations that render the hepatocytes vulnerable to malignant transformation. (9)(10)(11) The presence of cirrhosis is the strongest risk factor for HCC, with 90% of HCCs arising in cirrhotic livers. The

ASAP Score versus GALAD Score for detection of hepatitis C-related hepatocellular carcinoma: A multicenter case-control analysis

“…However, at the most frequently used cut-off value (10%), AFP-L3% has a specificity of 99.4% with a low sensitivity of 18.8%, indicating a poor ability to diagnose HCC as sensitivity takes priority over specificity in surveillance ( 36 , 37 ). For the diagnosis of early-stage HCC, AFP-L3% is not recommended because of the need for an elevated AFP level, which limits its effectiveness; while AFP-L3% may serve as a supplementary for AFP, highly sensitive AFP-L3% measurements are region-restricted and costly ( 38 , 39 ). As such, we constructed the ASAP score excluding AFP-L3% because the measurement of this marker is complex, time-consuming, expensive, and requires up to a 400-μL volume of serum sample; in addition, the contribution of AFP-L3% to risk prediction of HCC was low.…”

Early Detection and Disease Monitoring of Hepatocellular Carcinoma Using Circulating Telomere DNA

“…Current international guidelines recommend HCC screening among high-risk individuals, including patients with chronic HBV infection or cirrhosis 21,22 . However, the effectiveness of HCC screening is hampered by the lack of highly sensitive, specific, and efficient tools 11,23 .…”

Hepatocellular Carcinoma Detection in Hepatitis C Virus-Related Cirrhosis by Glypican-3

“…HCC may be diagnosed with non-invasive methods such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and serum biomarkers while invasive methods such as biopsy not recommended for all lesions for fear of increasing the risk of tumor seeding and bleeding, and false-negative result due to obtain tissue from an inappropriate site, AASLD recommends biopsy only in lesions not typical for HCC on contrast-enhanced imaging (4) .…”

“…Advanced imaging studies or Biopsy are not reliable methods for screening and surveillance of HCC due to their costeffectiveness, time consumption, not being available at every center and intraoperative error, so serum tumor markers such as AFP are the most common method used in the surveillance and early detection of HCC in cirrhotic patients (4) .…”