# Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series

## TL;DR

This study examines the differences between two types of liver cancer, showing they have distinct genetic and clinical features that require personalized treatment approaches.

## Contribution

The study identifies distinct molecular and pathological profiles of synchronous small- and large-duct intrahepatic cholangiocarcinoma and their clinical implications.

## Key findings

- Small-duct iCCA is linked to IDH1/2 mutations and FGFR2 fusions with better progression-free survival.
- Large-duct iCCA shows KRAS, TP53, and NF1 mutations with aggressive behavior and lower survival rates.
- Some large-duct cases show TMB-H and MSI-H, suggesting potential for immune checkpoint inhibitors.

## Abstract

Background: Synchronous small- and large-duct intrahepatic cholangiocarcinoma (iCCA) represents a rare and heterogeneous entity, posing challenges for diagnosis, prognosis, and treatment selection. The pathological and molecular diversity between these subtypes influences tumor behavior and therapeutic response, necessitating a personalized approach. This study investigates the molecular and pathological heterogeneity of synchronous iCCA and its clinical implications. Methods: This prospective case series included six patients diagnosed with synchronous small- and large-duct iCCA at the Military Medical Academy, Sofia, between January 2023 and January 2025, with a median follow-up of 15 months. Tumor classification was based on histopathological examination, immunohistochemical analysis, and next-generation sequencing (NGS)-based genomic profiling. Radiological and clinical data were analyzed to assess tumor growth patterns, treatment response, and progression-free survival (PFS). Results: Small-duct-predominant iCCA was associated with IDH1/2 mutations and FGFR2 fusions, a mass-forming growth pattern, and longer PFS. In contrast, large-duct-predominant iCCA exhibited KRAS, TP53, and NF1 mutations, an infiltrative periductal growth pattern, and a more aggressive clinical course with shorter PFS. Tumor mutational burden-high (TMB-H) and microsatellite instability-high (MSI-H) were observed in a subset of large-duct iCCA cases, suggesting potential benefit from immune checkpoint inhibitors (ICIs). Conclusions: Synchronous small- and large-duct iCCA demonstrates distinct molecular, histopathological, and clinical features, necessitating individualized treatment strategies. Targeted therapies for IDH1/2- and FGFR2-altered small-duct iCCA have shown efficacy, whereas large-duct iCCA remains more aggressive and treatment-resistant, requiring novel therapeutic approaches. Future research should focus on adaptive treatment strategies that account for tumor heterogeneity and dominant molecular drivers.