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After a lapse of seven years, the European Society for Medical Oncology (ESMO) Guidelines Committee has updated the "Biliary Malignancies (BTC): Clinical Practice Guidelines for the Diagnosis, Treatment and Follow-up of ESMO" [1], which was published in Annals of Oncology. The guidelines are based on available evidence and multidisciplinary expert opinion and cover clinical and pathologic diagnosis, staging and risk assessment, treatment and follow-up. This article will focus on the clinical, pathological, and molecular biology diagnosis of BTC for the benefit of readers.
1. Clinical diagnosis
Because each subtype of BTC has specific clinical and molecular features that require individualized testing and evaluation for complications, including biliary obstruction, it is important to determine the anatomical location of BTC [intrahepatic cholangiocarcinoma (iCCA), biliary tract cancer (pCCA), intrahepatic (dCCA), or distal cholangiocarcinoma (GBC)]. Biliary tract tumors should be classified according to ICD11 criteria. The following table has detailed the recommended tests at the first visit for reference.
Table 1 Recommended tests for the diagnosis and staging of BTC
ERCP, endoscopic retrograde cholangiopancreatography, PTC, percutaneous liver puncture cholangiogram, NGS, next-generation sequencing, EUS, endoscopic ultrasound, pCCA, hilar biliary tract cancer, dCCA, distal cholangiocarcinoma, GBC, gallbladder cancer, MRCP, magnetic resonance cholangiopancreatography, MRI, magnetic resonance imaging, CT, computed tomography, PET, positron emission tomography.
Blood tests should be performed to assess liver function and assess for risk factors associated with underlying liver or biliary inflammation or injury, including HBV and HCV infection, nonalcoholic liver disease (nonalcoholic fatty liver disease or nonalcoholic steatohepatitis), or autoimmune diseases such as inflammatory bowel disease, PSC, or primary biliary cholangitis. For all BTC, cross-sectional imaging of the chest, abdomen, and pelvis, as well as multiphase imaging of the liver, is required to assess the extent and metastasis of the primary disease.
2. Pathological diagnosis
Pathologic diagnosis should be performed by needle biopsy prior to any non-surgical treatment. For patients with localized tumors who can undergo radical surgery, a pathologic diagnosis can be obtained by surgery. Nonneoplastic liver tissue should also be evaluated for underlying liver disease. In patients with biliary obstruction due to p/dCCA without extraductal metastases, PTC or ERCP-guided biopsy is preferred over biliary cell brushing and should be performed whenever possible to ensure adequate tissue for pathologic diagnosis and molecular analysis. EUS-guided fine-needle aspiration or biopsy (FNA or FNB) can be used to obtain biopsies of regional lymph nodes (eg, enlargement) or primary tumor, depending on their location, and EUS-guided fine-needle aspiration or biopsy may be considered if PTC or ERCP-guided biopsy results are negative or inconclusive. Cases of tumor spread along the FNA needle tract have been reported, but the exact level of risk is not well established (although it appears to be low). Therefore, for patients with potentially resectable tumors, primary tumor biopsy by any transabdominal route, including EUS, should be advanced after a multidisciplinary team decision.
III. Molecular Biology
CCA, especially iCCA with small ductal histology, is recommended for molecular characterization of patients with advanced disease who are candidates for systemic therapy due to the large number of treatable targets. Next-generation sequencing (NGS) is superior to parallel sequencing of multiple genes compared to single-gene testing. NGS can be performed on formalin-fixed and paraffin-embedded tumor tissues and is suitable for tissue biopsies. If sufficient tumor tissue is not available for NGS, liquid biopsy using cell-free circulating DNA may also be considered.
Currently, genetic panels should include isocitrate dehydrogenase 1 (IDH1), human epidermal growth factor receptor 2 (HER2/ERBB2), and BRAF's respective coding DNA regions (targets) to detect hotspot mutations, but the rapid development of drug targets and predictive biomarkers may require a more comprehensive genetic panel. In tissue-based assays, gene fusions involving fibroblast growth factor receptor 2 (FGFR2) and neurotrophic tyrosine receptor kinase (NTRK) genes are best detected at the RNA level. Ideally, this method should be combined with parallel DNA detection to identify breakpoints that primarily involve exons 17 and 18 of FGFR2. Both DNA and RNA-based NGS assays are best performed using hybridization-capture or anchor-based multiplex PCR.
Microsatellite instability (MSI) status can be inferred by immunohistochemistry (IHC) detection to assess the expression of DNA mismatch repair proteins MutL homolog 1 (MLH1), MutS homolog (MSH) 2, MSH6, and PMS1 homolog 2 (PMS2) in tumor tissues. In addition, DNA-based assays can be used to analyze the composition and length of microsatellites. The preferred technique (e.g., NGS, RNA sequencing, IHC) depends on the target and available assay samples (e.g., tissue or circulating tumor DNA). Discussion with a molecular pathologist or molecular tumor board is highly recommended.
Serum carbohydrate antigen (CA) 19-9 is a nonspecific marker that can be elevated in patients with BTC and other gastrointestinal malignancies, as well as in nonmalignant settings such as biliary obstruction. Although BTC is not diagnostic, marker elevation of CA19-9 levels is associated with a worse prognosis, and the marker can also be used to assess treatment response. It is important to note that 10% of the general population are Lewis antigen-negative (a-, b-) and cannot produce CA19-9, and CA19-9 cannot be used for follow-up in such patients.
4. Recommendations
- BTC should be classified according to the ICD11 standard. [III，A]
- Prior to any non-surgical treatment, a needle biopsy should be performed for pathologic diagnosis and molecular profiling. [III，A]
- For patients with d/pCCA without extraductal metastases, PTC or ERCP-guided biopsy should be performed to obtain sufficient tissue for pathologic diagnosis and molecular characterization. [III，A]
- Depending on the site, EUS-guided FNA or FNB may be used to obtain enlarged regional lymph node biopsy, or if ERCP-guided biopsy is negative or inconclusive, tumor biopsy may be obtained. [II，B]
- Molecular analysis is recommended in patients with advanced tumors who are candidates for systemic therapy. [I，A]
- Elevated CA19-9 is associated with a worse prognosis and can be used to assess response to treatment. [III，C]
Bibliography:
[1] Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34(2):127-140. doi:10.1016/j.annonc.2022.10.506
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