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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MDPI AG
2025-04-01
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| Series: | Current Oncology |
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| author | Savelina Popovska Vladislav Nankov Boriana Ilcheva George Dimitrov |
| author_facet | Savelina Popovska Vladislav Nankov Boriana Ilcheva George Dimitrov |
| author_sort | Savelina Popovska |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bf15d377a50849588c2b4b0aed490487 |
| institution | DOAJ |
| issn | 1198-0052 1718-7729 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Oncology |
| spelling | doaj-art-bf15d377a50849588c2b4b0aed4904872025-08-20T03:14:39ZengMDPI AGCurrent Oncology1198-00521718-77292025-04-0132525510.3390/curroncol32050255Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case SeriesSavelina Popovska0Vladislav Nankov1Boriana Ilcheva2George Dimitrov3Department of Clinical Pathology, Medical University of Pleven, 5800 Pleven, BulgariaCentre of Competence in Personalized Medicine, 3D and Telemedicine, Robotic Assisted and Minimally Invasive Surgery-Leonardo da Vinci, 5800 Pleven, BulgariaDepartment of Pathology, Military Medical Academy, 1606 Sofia, BulgariaDepartment of Medical Oncology, Medical University of Sofia, University Hospital “Tsaritsa Yoanna”, 1527 Sofia, BulgariaBackground: 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.https://www.mdpi.com/1718-7729/32/5/255intrahepatic cholangiocarcinomasynchronous iCCAsmall-ductlarge-ductmolecular heterogeneitytargeted therapy |
| spellingShingle | Savelina Popovska Vladislav Nankov Boriana Ilcheva George Dimitrov Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series Current Oncology intrahepatic cholangiocarcinoma synchronous iCCA small-duct large-duct molecular heterogeneity targeted therapy |
| title | Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series |
| title_full | Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series |
| title_fullStr | Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series |
| title_full_unstemmed | Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series |
| title_short | Molecular and Pathological Heterogeneity of Synchronous Small and Large Duct Intrahepatic Cholangiocarcinoma—A Case Series |
| title_sort | molecular and pathological heterogeneity of synchronous small and large duct intrahepatic cholangiocarcinoma a case series |
| topic | intrahepatic cholangiocarcinoma synchronous iCCA small-duct large-duct molecular heterogeneity targeted therapy |
| url | https://www.mdpi.com/1718-7729/32/5/255 |
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