Early Detection and Screening for CCA

December 2022, Vol 3, No 4

Pictured left to right: Gregory J. Gores, MD, large screen; seated, left to right: Eugene Koay, MD, PhD; Steven Lin, MD, PhD; Yujin Hoshida, MD, PhD

Early detection and diagnosis of cancer is imperative to prevent cancer-related deaths; however, early detection of cholangiocarcinoma (CCA) is challenging because patients with early-stage CCA are often asymptomatic, and it can be difficult to determine which patients are at high risk. Primary sclerosing cholangitis (PSC) is a well-known risk factor for CCA and represents a patient population that may benefit from surveillance. Magnetic resonance cholangiopancreatography (MRCP) and ultrasound imaging methods used for screening patients with PSC are highly specific yet lack necessary sensitivity for early detection.

Liquid biopsies using circulating tumor DNA may be suitable for screening and diagnosis due to their noninvasive nature; however, these methods also lack sensitivity for early-stage disease due to the lack of tumor-specific DNA in the blood. Improvement in the sensitivity of current methods is needed for them to function as reliable cancer diagnosis tools.

Eugene Koay, MD, PhD

Eugene Koay, MD, PhD, of MD Anderson Cancer Center, described an innovative method of liquid biopsy that can detect viable cancer using tumor exosomes. Exosomes are actively secreted by living cancer cells and can reflect the true heterogeneity of the disease. Unlike DNA, they do not require amplification and have low background noise because normal tissues have low exosome secretion. Dr. Koay and his team have been developing iCITE technology, which amplifies the signal of the exosome and allows a pathologist, from 1 drop of blood, to examine the specimen under a normal microscope for the presence of exosomes and determine their molecular characterization. Preclinical and in-human studies utilizing this technology have demonstrated that the detection of exosomes in blood correlates with tumor growth compared with controls. With further investigation and validation, this method may be used in collaboration with imaging-based technologies for early screening for CCA.

Screening Programs for PSC as a Risk Factor for CCA

PSC is an important risk factor for CCA, and patients with PSC have a lifetime risk of 10% to 15% for developing CCA. American Association for the Study of Liver Diseases (AASLD) guidelines recommend annual surveillance in patients with PSC using MRI/MRCP imaging with or without testing serum CA 19-9 levels, based on data that suggest patients with PSC have improved outcomes with annual imaging compared with those without annual imaging. Elevated CA 19-9 suggests malignancy in patients with PSC, which can trigger more invasive tests with endoscopy. Fluorescence in situ hybridization (FISH) is a more sensitive method than routine cytology to identify chromosomal abnormalities; patients with polysomy detected by FISH and an elevated CA 19-9 are likely to have CCA.

Gregory J. Gores, MD, of the Mayo Clinic, described the AASLD PSC-CCA guideline recommendations in which MRI/MRCP imaging in PSC patients with high-grade strictures without a mass but with sufficient concern on imaging studies, followed by endoscopic retrograde cholangiopancreatography (ERCP) with biliary biopsy and brushings (cytology and FISH). If biopsy, cytology, and FISH are all negative, the guidelines recommend MRI/MRCP imaging in 6 to 12 months. If cytology is suspicious and FISH is negative, guidelines recommend repeat ERCP. However, if cytology is negative or suspicious and FISH continues to detect polysomy after repeat ERCP, patients are likely to have CCA. If the biopsy and/or cytology are positive, patients are also likely to have CCA. Overall, annual imaging may improve survival of patients with PSC, and FISH results should be interpreted individually in the context of polysomy, suspicious cytology, and elevated CA 19-9.

Cancer Risk–Predictive Molecular Biomarkers in BTC

Patients with increased cancer risk should participate in regular screening for early detection to increase the chance of curative treatment and ultimately improved survival. Determination of high-risk biomarkers and clinical risk factors contributes to cancer risk prediction; however, clinical and molecular heterogeneity in biliary tract cancers (BTCs) can pose challenges in determining target populations. Screening the general population is an unrealistic approach in terms of feasibility and roughly half of patients with BTC do not have clinically recognizable risk conditions. The diversity of clinical risk conditions also brings into question whether different biomarkers need to be considered for individual risk conditions.

An important consideration in recognizing risk biomarkers is the strategy in which they are identified. Yujin Hoshida, MD, PhD, from UT Southwestern Medical Center, described several approaches to identify risk biomarkers in BTC, including case-control studies, cohort studies with longitudinal follow-up, and population-based registry studies. Alpha1-antitrypsin (A1AT) has been recognized in 2 case studies that determined a heterozygous single nucleotide polymorphism (SNP; Z allele) and serum oxidized A1AT as risk biomarkers.1 In addition, germline variants in known cancer-predisposing genes (11% of patients) have been reported in the literature, including BRCA1/2, RAD51D, MSH2/6, MLH1, and TP53.2 Studies also suggest that SNPs in inflammatory cytokines may play a role in driving BTC development. The biliary microbiome may also be considered a risk factor as studies have shown that bile fusobacteria correlate with the presence of CCA and duration of PSC.3

Overall, molecular heterogeneity poses a challenge in identifying BTC risk biomarkers and remains an unmet need that is often understudied. Small case-control studies have identified candidates; however, these studies need further validation


  1. Jamnongkan W, Techasen A, Thanan R, et al. Oxidized alpha-1 antitrypsin as a predictive risk marker of opisthorchiasis-associated cholangiocarcinoma. Tumour Biol. 2013;34(2):695-704.
  2. Wardell CP, Fujita M, Yamada T, et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 2018;68(5):959-969.
  3. Miyabe K, Chandrasekhara V, Wongjarupong N, et al. Potential role of inflammation-promoting biliary microbiome in primary sclerosing cholangitis and cholangiocarcinoma. Cancers (Basel). 2022;14(9):2120.

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