FGFR2/3-altered intrahepatic cholangiocarcinoma has a recognisable morphology

Design

Retrospective series with whole-exome and whole-transcriptome sequencing, single institution, 5 years

Population

90 intrahepatic cholangiocarcinomas (25 FGFR2/3-altered, 65 wild-type)

Primary outcome

Clinicopathological and molecular features; survival by FGFR status

Effect

Small-duct type 100% vs 32.3%; unadjusted DSS HR 0.29 (0.09–0.95), not significant after adjustment

A five-year retrospective series profiled 90 intrahepatic cholangiocarcinomas with combined whole-exome and whole-transcriptome sequencing. Twenty-five (28%) carried FGFR2 fusions with a wide range of partners, an FGFR3::TACC3 fusion, or activating FGFR2 mutations.

These tumours looked different. Patients were younger, tumours were larger and far more often well differentiated and non-mucin-producing, and every one was of small-duct type, against about a third of wild-type tumours. BAP1 alterations were more common, while TP53, KRAS and ARID1A alterations were rare. Disease-specific survival was better on unadjusted analysis but not after adjustment, suggesting the advantage comes with the overall phenotype rather than the FGFR alteration alone.

For the reporting pathologist, the practical point is triage. A small-duct, non-mucinous, well-differentiated intrahepatic tumour in a younger patient is the profile most likely to carry an actionable FGFR2 fusion, and the variety of fusion partners argues for an RNA-based or broad fusion assay rather than a narrow DNA panel. All iCCAs still warrant molecular profiling where treatment depends on it; morphology flags priority, not eligibility.

• Record small-duct versus large-duct subtype and mucin production in every intrahepatic cholangiocarcinoma report.
• Flag small-duct, non-mucinous, well-differentiated tumours as most likely to harbour FGFR2 fusions.
• Prefer an RNA-based or partner-agnostic fusion assay; the FGFR2 partners here were numerous and varied.
• Recommend molecular profiling for all advanced iCCAs; morphology helps prioritise but does not exclude.
• Note BAP1 loss as a co-alteration that was more frequent in FGFR-altered tumours.

Why it matters

FGFR inhibitors are an established option in previously treated FGFR2 fusion-positive cholangiocarcinoma, and the fusion has to be found to be used.

Don't overread it

The survival advantage was lost after adjustment, so FGFR status should not be reported as a favourable prognostic marker on its own.

The statistics, in plain English

The unadjusted hazard ratio of 0.29 for disease-specific death became 2.52 with a 95% confidence interval from 0.14 to 45 after adjustment — so wide that the adjusted analysis tells us nothing either way. With 90 patients, few events and many variables, that instability is expected.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.