Is Fine Needle Aspiration Cytology (FNAC) sufficient or is a biopsy required for starting chemotherapy in advanced gallbladder cancer?

Is FNAC Sufficient or Is Biopsy Required for Starting Chemotherapy in Advanced Gallbladder Cancer?

Core biopsy should be obtained before starting chemotherapy in advanced gallbladder cancer—FNAC alone is insufficient. 1

Primary Recommendation

The 2023 ESMO guidelines explicitly state that pathological diagnosis should be confirmed via core biopsy before any nonsurgical treatment in biliary tract cancers, including gallbladder cancer. 1 This is not merely a suggestion but a firm requirement for initiating systemic therapy in advanced disease.

Why Core Biopsy Over FNAC?

Tissue Adequacy for Molecular Profiling

• Core biopsy provides sufficient tissue for both diagnostic pathology AND molecular profiling, which is essential in advanced gallbladder cancer. 1
• Molecular analysis using next-generation sequencing (NGS) is recommended in advanced disease suitable for systemic treatment to identify actionable targets including FGFR2 fusions, IDH1 mutations, HER2 amplifications, BRAF mutations, and NTRK fusions. 1
• FNAC typically yields insufficient material for comprehensive NGS testing, which requires adequate formalin-fixed paraffin-embedded tissue. 1

Diagnostic Accuracy

• While FNAC may be "easier and safer" in some contexts 1, it lacks the architectural information and tissue quantity needed for definitive diagnosis and molecular characterization in gallbladder cancer.
• The French hepatology guidelines emphasize that cytoblock techniques should be employed for EUS-FNA samples, acknowledging that standard FNAC is inadequate. 1

Preferred Biopsy Approaches for Gallbladder Cancer

EUS-Guided Core Needle Biopsy

• EUS-guided fine needle biopsy (FNB) or core biopsy is preferred over standard FNA for obtaining adequate tissue from the primary tumor or regional lymph nodes. 1
• EUS provides the dual benefit of staging information while obtaining diagnostic tissue. 1
• The risk of needle tract seeding is very low (between 1:10,000 and 1:40,000), though decisions should be made in a multidisciplinary setting for potentially resectable tumors. 1

Percutaneous Core Biopsy

• Image-guided percutaneous core biopsy can be used for tissue acquisition from the primary tumor or nodal metastases depending on location. 1
• This approach provides adequate tissue for both histological diagnosis and molecular profiling. 1

Critical Exception: When Biopsy May Not Be Required

In potentially resectable gallbladder cancer, biopsy is NOT required before surgical resection. 2, 3 Surgery should proceed based on high-quality imaging alone in good surgical candidates, as the risk of benign disease is acceptable if performed at high-volume centers with low morbidity. 2, 3

However, this exception does NOT apply to your question about advanced (unresectable) disease requiring chemotherapy.

What If Initial Biopsy Is Negative or Inadequate?

• At least one repeat biopsy should be performed if the initial attempt does not confirm malignancy. 1
• EUS-FNB with or without core needle biopsy at a high-volume center is preferred for repeat sampling. 1
• The French guidelines state that "suspicious cytology" (as defined by Papanicolaou guidelines) is sufficient for initiating chemotherapy once validated in a specialized multidisciplinary team. 1
• In rare cases with two consecutive negative biopsies but strong clinical and radiological evidence of cholangiocarcinoma, chemotherapy initiation must be validated in an MDT after excluding IgG4-related disease. 1

Common Pitfalls to Avoid

• Do not start chemotherapy based on FNAC alone without attempting core biopsy—you will lack essential molecular profiling data that could guide targeted therapy. 1
• Do not delay chemotherapy indefinitely pursuing multiple biopsy attempts if clinical suspicion is very high and initial sampling shows at least "suspicious" cytology validated by MDT. 1
• Do not perform transperitoneal biopsy in potentially resectable disease without multidisciplinary discussion due to seeding risk. 1
• Do not forget to test for MSI status and PD-L1 expression, as these may guide immunotherapy options in refractory disease. 1, 4

Practical Algorithm for Advanced Gallbladder Cancer

1. Confirm advanced/unresectable status with high-quality cross-sectional imaging (CT/MRI). 2
2. Obtain core biopsy via EUS-FNB or percutaneous approach for both diagnosis and molecular profiling. 1
3. Send tissue for NGS panel including FGFR2, IDH1, HER2, BRAF, NTRK, and MSI testing. 1
4. If initial biopsy inadequate, repeat with EUS-FNB at experienced center. 1
5. If two attempts fail but suspicion high, discuss in MDT whether "suspicious" cytology plus imaging is sufficient to proceed. 1
6. Initiate gemcitabine plus cisplatin as standard first-line therapy once pathological confirmation obtained. 2, 5