Paradoxical hyperprogressive disease in MSI-high intrahepatic cholangiocarcinoma treated with pembrolizumab

Cholangiocarcinoma carries a poor prognosis, and surgical resection remains the only curative option. Microsatellite instability-high (MSI-H) is a rare molecular subtype in intrahepatic cholangiocarcinoma (ICC). Although immune checkpoint inhibitors (ICIs) are effective in MSI-H malignancies, responses are variable. We report a rare case of MSI-H ICC that developed hyperprogressive disease (HPD) following pembrolizumab.

An 81-year-old man with a history of endoscopic submucosal dissection for esophageal cancer underwent surveillance computed tomography (CT), which revealed a liver mass with intrahepatic bile duct dilation. Tumor markers were elevated (CA19-9: 214.9 U/mL). Suspecting ICC, liver resection was performed, achieving R0 resection. However, recurrence in the liver and hilar lymph nodes occurred within months. Systemic chemotherapy was ineffective. Genomic profiling (FoundationOne® CDx) revealed MSI-H, and pembrolizumab was initiated. After two cycles, rapid tumor progression was observed, with a ≥ twofold increase in tumor growth rate, consistent with HPD, along with new liver, bone, and peritoneal metastases. The patient died shortly thereafter.

This case highlights the paradoxical response to ICIs in ICC, demonstrating that MSI-H status does not preclude HPD. Further investigation of the tumor immune microenvironment is warranted.