Gastrointestinal: Immune‐related sclerosing cholangitis with pembrolizumab: Imaging and histological features

A 63-year-old female was diagnosed with squamous cell carcinoma of the lung (T4N0M0 stage IIIA). She received combination chemotherapy with carboplatin, albumin-bound paclitaxel, and pembrolizumab in July 2020. After four cycles, laboratory data revealed aspartate aminotransferase 192 IU/L (7–38 IU/L), alanine aminotransferase 248 IU/L (4–44 IU/L), alkaline phosphatase 917 IU/L (106–322 IU/L), and γ-glutamyl transferase 356 IU/L (5–50 IU/L). Serum immunoglobulin G4 (IgG4) was within normal range. Abdominal computed tomography revealed diffuse thickening of the extrahepatic bile duct without biliary stenosis and obstruction (Fig. 1a). Magnetic resonance cholangiopancreatography showed no dilation but did show irregularly narrowed intrahepatic bile ducts (Fig. 1b). Endoscopic ultrasound showed diffuse thickening of the extrahepatic bile duct, gallbladder, and cystic duct (Fig. 1c). Endoscopic retrograde cholangiopancreatography revealed a pruned tree appearance (Fig. 1d). Transpapillary biopsy of the bile duct showed no malignant cells but did show infiltration of inflammatory cells such as lymphocytes, including CD8+ T cells (Fig. 1e,f). A biopsy of the liver showed infiltration of inflammatory cells in the portal region, including CD8+ T lymphocytes (Fig. 2). The patient was diagnosed with pembrolizumab-induced sclerosing cholangitis (SC) as an immune-related adverse effect (irAE) based on these findings. The hepatic toxicity worsened to Grade 4. Ursodeoxycholic acid and prednisolone were administered. The hepatic injury temporarily improved but then worsened again. Steroid pulse therapy (methylprednisolone 1 g for 3 days) was performed, and subsequently, azathioprine was initiated. Despite these therapies, repeated acute cholangitis occurred, and the patient finally died 24 weeks after the onset of SC. Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with malignancy. However, irAEs occur in approximately 10–15% of all patients treated with ICIs. While irAE-SC is relatively rare, it is initially asymptomatic and shows only mild liver injury. In addition to imaging modality, histological examinations are essential to distinguish irAE-SC from normal drug-induced liver disorders, IgG4-SC, and irAE-hepatitis. SC is characterized by diffuse thickening of the extrahepatic bile duct, narrowing of the intrahepatic bile duct, infiltration of CD8+ T lymphocytes, and a moderate or poor response to corticosteroid therapy compared with other irAEs. SC should be considered and treated appropriately and promptly when a patient being treated with ICIs experiences liver damage.