Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Tisch Cancer Institute at Mount Sinai, New York, NY, USA.
Mod Pathol. 2021 Apr;34(4):823-833. doi: 10.1038/s41379-020-00679-5. Epub 2020 Sep 28.
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.
纳武利尤单抗是一种免疫检查点抑制剂（ICI），已批准用于治疗多种癌症，包括肝细胞癌（HCC）。在接受纳武利尤单抗治疗非肝脏肿瘤的患者中，肝损伤是已知的并发症。迄今为止，在 HCC 患者中，尚未很好地描述肿瘤和非肿瘤肝脏的形态变化。我们确定了 20 名接受纳武利尤单抗治疗 HCC 后行部分肝切除术或肝移植的患者。从病历中获得了人口统计学、实验室值和影像学结果。评估了所有切除标本的切片，以评估肿瘤坏死、肿瘤浸润淋巴细胞（TIL）和肝损伤特征。研究中的患者包括 16 名男性和 4 名女性，中位年龄为 56 岁。基础肝病为乙型肝炎病毒（HBV）的有 10 例，丙型肝炎病毒（HCV）的有 6 例，未知/其他的有 4 例。12 例患者在新辅助治疗中接受纳武利尤单抗治疗，8 例患者在接受肝移植前接受纳武利尤单抗治疗，通常联合其他疗法。在复查切除标本时，有 3 例（均来自新辅助组）患者的治疗反应归因于纳武利尤单抗，表现为明显的治疗反应。在 20 例中有 17 例 TIL 存在。在新辅助组中显示治疗反应的 1 例病例中，非坏死性肉芽肿和非肿瘤肝脏中的明显胆管上皮内淋巴细胞（IEL）。在接受长期纳武利尤单抗治疗（32 剂）的移植组中有 1 例患者显示胆管损伤和明显的胆管反应。我们的发现表明，纳武利尤单抗在包括新辅助治疗在内的一部分患者中有效。在接受纳武利尤单抗治疗的病例中，肉芽肿和胆管 IEL 是罕见的发现，但如果出现，可能表明对治疗有潜在反应。胆管损伤和胆管反应可能是长期纳武利尤单抗治疗的表现。未来的前瞻性和纵向研究，包括预处理肿瘤活检，可能有助于识别有望对 ICI 治疗有反应的患者，并进一步描述 ICI 相关肝损伤的模式。
