Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

Abstract

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

Keywords: cholangiocarcinoma; pathobiology; therapeutic approaches.

Figure 1

Gross photograph of (a) Intrahepatic CCA’s both mass-forming lesions and periductal infiltrative, (b) perihilar CCA-affected both right and left hepatic ducts.

Figure 2

Photomicrographs show (A) iCCA-LD composed of glands with abundant desmoplastic stroma, perineural invasion, and portal vein thrombosis with tumor infiltration. (B) iCCA-LD showing malignant glands lined by cuboidal dysplastic cells having intracytoplasmic mucin; (C) perihilar CCA with tumor arising from the segmental intrahepatic duct, extrahepatic bile duct is normal; (D) tumor was composed of large glands lined by cuboidal–columnar cells with abundant intraluminal mucin; (E) iCCA-SD composed of small cuboidal cells without any mucin with hyperchromatic nuclei forming anastomosing cords; (F) perihilar CCA with an intraductal papillary configuration; (G) iCCA infiltration into adjacent hepatocytes; (H) bile duct showing evidence of biliary epithelial neoplasia-low grade with a papillary pattern that is a precursor lesion for extrahepatic CCA (H&E-A-H, 4×-A,F, ×20-B,D, ×1.25-C, ×10 F,G,H original magnification).