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Cholangiocarcinoma Understanding the details

Understanding the
cholangiocarcinoma patient journey

The diagnostic pathway
in cholangiocarcinomaCCA

  • Cholangiocarcinoma frequently presents late, with subtle or non-specific signs.1 The diagnostic pathway can be complex, and effective tumour sampling is essential for both accurate histology and multi-biomarker NGS1–4
  • Clear communication between radiology, endoscopy, surgery, pathology and oncology helps ensure appropriate biopsy and maximises the likelihood of obtaining tissue suitable for molecular profiling5,6

When to consider cholangiocarcinoma

Cholestatic liver tests
without an obvious benign
explanation2

Unexplained weight loss,
fatigue or abdominal
discomfort1

Biliary dilatation or
stricture on imaging1,2

Atypical liver mass in a
non-cirrhotic liver1,7

History of primary
sclerosing cholangitis or
other recognised risk
factors1,2

Key steps from first suspicion to molecular profiling

  1. Initial suspicion

    Repeated cholestatic liver tests, unexplained weight loss or atypical liver lesions on imaging may prompt evaluation for cholangiocarcinoma.1

  2. Imaging

    Contrast-enhanced CT and/or MRI/MRCP help define tumour location, biliary involvement and potential resectability.1,2

  3. Multidisciplinary team review

    Radiology, hepatobiliary surgery, gastroenterology, oncology and pathology align on the diagnostic plan and identify the best site and method for biopsy.2

  4. Biopsy or cytology

    Approach is tailored to anatomy: percutaneous core biopsy, ERCP-based sampling or EUS-guided tissue acquisition.5,8

  5. Histopathology

    The diagnosis is established. Pathology assesses tumour cellularity and selects material most suitable for NGS.4,8

  6. Molecular profiling

    NGS evaluates clinically relevant molecular alterations in cholangiocarcinoma.4,9

  7. Multidisciplinary team interpretation

    Results are integrated with clinical and radiological findings to guide systemic treatment options and consider potential clinical trials.3,6

Choosing the most appropriate biopsy approach

Choosing the right biopsy method matters. The goal is to safely obtain high-quality material that supports both diagnosis and molecular profiling. The most effective approach varies with tumour location and biliary anatomy.5,6

Intrahepatic mass lesion5,6

  • Preferred sampling: ultrasound- or CT-guided core needle biopsy
  • Practical considerations:
    • Aim for more than one core where safe
    • Target viable tumour, avoiding clearly necrotic areas
    • Let pathology know NGS is planned so cores can be triaged appropriately

Perihilar biliary stricture2,4

  • Preferred sampling: ERCP with brush cytology ± intraductal biopsy
  • Practical considerations:
    • Multiple passes can increase cellular yield
    • Request preparation of a cell block where possible, to support ancillary testing
    • Make the intention for potential molecular profiling explicit on the request form

Distal bile duct10

  • Preferred sampling: EUS-guided FNB or FNA
  • Practical considerations:
    • FNB may be preferred where available to obtain core tissue
    • Multiple passes support diagnostic accuracy and molecular adequacy
    • Minimising sample contamination can help optimise nucleic acid quality

Suspicious lymph node or metastatic lesion5

  • Preferred sampling: EUS-guided or image-guided core biopsy (depending on location)
  • Practical considerations:
    • Prioritise a site that is both accessible and likely to contain tumour
    • Ensure sufficient material is reserved for both histology and NGS

Surgical specimen/laparoscopic biopsy5

  • Preferred sampling: resection or intraoperative targeted biopsy
  • Practical considerations:
    • Pre-operative or intraoperative discussion with pathology helps ensure optimal tissue triage
    • Identify blocks or regions that preserve nucleic acid integrity for molecular profiling

Optimising biopsy samples for molecular profiling success

Before the procedure4,5

  • Confirm that molecular profiling is planned
  • Select the safest, most representative biopsy target
  • Notify pathology so they can prepare for tumour assessment and block selection
  • Check local assay requirements (e.g. tumour percentage and sample type)

During the procedure4,5

  • Obtain multiple cores/passes where safe
  • Target viable, non-necrotic tumour regions
  • For cytology, ensure material is available for a cell block
  • Clearly label samples that may be used for molecular profiling

After the procedure5,6

  • Confirm appropriate fixation and handling; avoid unnecessary decalcification
  • Request an estimate of tumour cellularity and any limitations for NGS
  • If tumour content is low or NGS fails, discuss re-biopsy or alternative strategies with the multidisciplinary team

Why biopsy samples may be unsuitable for molecular profiling

  • Low tumour content6
    Approach: where possible, target regions with radiologically higher tumour density and request macrodissection by pathology if feasible.
  • Insufficient tissue volume6
    Approach: aim to obtain more than one core for histology and NGS, within safety limits.
  • Cytology without a usable cell block6
    Approach: request cell block preparation when sending brushings or aspirates likely to be used for molecular profiling.
  • Haemorrhagic or heavily necrotic samples5,6
    Approach: adjust needle position or target to reduce blood contamination and avoid overtly necrotic areas.
  • Suboptimal fixation or processing5
    Approach: work with pathology to follow local protocols for fixation time and conditions, and to avoid processing steps that may compromise nucleic acid quality where alternatives exist.

What to do when tissue is insufficient for NGS

Repeat biopsy4

A further biopsy may be considered when initial material is non-diagnostic or below tumour thresholds for NGS, balancing clinical benefit against procedural risk.

Plasma ctDNA11,12

ctDNA testing may provide actionable information when tissue sampling is not feasible or has failed, although sensitivity varies with disease burden, assay and target.

Bile-derived cfDNA13,14

Bile-derived cfDNA is being explored as an additional source of tumour DNA during biliary procedures. Its use is currently limited to centres with specific expertise and should be regarded as an evolving, rather than routine, approach.

CCA, cholangiocarcinoma; cfDNA, cell-free deoxyribonucleic acid; CT, computed tomography; ctDNA, circulating tumour deoxyribonucleic acid; DNA, deoxyribonucleic acid; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; FNB, fine-needle biopsy; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; NGS, next-generation sequencing.

References: 1. Banales JM, et al. Nat Rev Gastroenterol Hepatol. 2020;17(9):557–588; 2. Vogel A, et al. Ann Oncol. 2023;34(2):127–140; 3. Vogel A, Ducreux M. ESMO Open. 2025;10(1):104003; 4. Stenzinger A, et al. Cancer Treat Rev. 2024;122:102649; 5. Kendall T, et al. JHEP Rep. 2024;6(6):101067; 6. Madoff DC, et al. Oncologist. 2022;27(10):884–891; 7. Fung BM, et al. World J Gastroenterol. 2019;25(6):659–671; 8. de Scordilli M, et al. ESMO Open. 2025;10(5):105079; 9. Barsch M, et al. J Gastrointest Cancer. 2026;57(1):15; 10. Orzan RI, et al. Diagnostics (Basel). 2023;13(6):1023; 11. Fassan M, et al. Crit Rev Oncol Hematol. 2024;194:104224; 12. Wang Y, et al. Front Cell Dev Biol. 2025;13:1616064; 13. Arechederra M, et al. Gut. 2022;71(6):1141–1151; 14. Driescher C, et al. Cancers (Basel). 2020;13(1):39.