Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.