Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series
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 therapeu...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Current Oncology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1718-7729/32/5/255 |
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| Summary: | 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 <i>IDH1/2</i> mutations and <i>FGFR2</i> fusions, a mass-forming growth pattern, and longer PFS. In contrast, large-duct-predominant iCCA exhibited <i>KRAS</i>, <i>TP53</i>, and <i>NF1</i> 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 <i>IDH1/2</i>- and <i>FGFR2</i>-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. |
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| ISSN: | 1198-0052 1718-7729 |