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Hepatotoxicity of Immune Checkpoint Inhibitors: a Histology Study of Seven Cases in Comparison with Autoimmune Hepatitis and Idiosyncratic Drug-Induced Liver Injury

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Hepatotoxicity of Immune Checkpoint Inhibitors: a Histology Study of Seven Cases in Comparison with Autoimmune Hepatitis and Idiosyncratic Drug-Induced Liver Injury Modern Pathology (2018) 31:965–973 https://doi.org/10.1038/s41379-018-0013-y ARTICLE Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury 1 2 Yoh Zen ● Matthew M. Yeh Received: 29 September 2017 / Revised: 12 November 2017 / Accepted: 3 December 2017 / Published online: 5 February 2018 © United States & Canadian Academy of Pathology 2018 Abstract The adverse effects of immune checkpoint inhibitors in various organs may be attributed to immune-mediated processes triggered by disrupted self-tolerance; however, it remains unclear whether they are similar or dissimilar to classic organ- specific autoimmune diseases. The present study aimed to compare clinicopathologic features between checkpoint inhibitor- induced liver injury and acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2) presented with liver dysfunction a median of 41 days (range 21–120) after the initiation of immunotherapy. All patients had elevated liver enzymes, whereas hyper-bilirubinemia was less 1234567890();,: common. None of the patients had antinuclear antibodies or IgG elevations. Stopping the immunotherapy and additional immunosuppression with corticosteroids normalized or decreased liver enzymes in all patients treated. Histologically, all biopsies showed predominantly lobular hepatitis with milder portal inflammation. Centrilobular confluent necrosis and plasmacytosis were observed in a single case, and were markedly less common and milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001, respectively). Bile duct injury, micro-abscesses, and extramedullary hematopoiesis were also found in one case each. Immunostaining revealed the presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor- induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production. Introduction Nivolumab and ipilimumab are now the two most com- monly used checkpoint inhibitors [2, 9, 10]. Nivolumab Immunomodulation using immune checkpoint inhibitors has recognizes programmed cell death 1 (PD-1), mainly become a promising approach for the treatment of various expressed by T lymphocytes, and blocks the interaction PD- malignant neoplasms [1, 2]. This emerging immunotherapy 1 and its ligand, programmed death ligand 1 (PD-L1) was originally used for advanced malignant melanoma, but expressed on cancer cells [1, 11]. The blockage of this has since been approved or is currently being tested in ligand–receptor interaction inhibits the inactivation of T clinical trials for many other malignancies including non- lymphocytes and enhances anticancer cytotoxic effects. small-cell lung cancers and renal cell carcinomas [3–8]. Ipilimumab targets cytotoxic T-lymphocyte-associated anti- gen 4 (CTLA4) on the surface of T lymphocytes [11]. Since the CTLA4 signal also inactivates lymphocytes, blocking CTLA4 by ipilimumab enables T lymphocytes to exert their * Yoh Zen cytotoxic effects on tumor cells [12]. Although PD-1 and [email protected] CTLA4 are mainly expressed by CD8+ cytotoxic T cells, + 1 Department of Diagnostic Pathology, Kobe University Graduate other lymphocytes including regulatory T cells and CD4 School of Medicine, Kobe, Japan T cells are also suggested to have these receptors [13–15]. 2 Department of Pathology, University of Washington School of Checkpoint inhibitors sometimes induce various adverse Medicine, Seattle, WA, USA effects including skin rashes, colitis, pancreatitis, nephritis, 966 Y. Zen, M. M. Yeh and hepatitis [16, 17]. Based on the assumption that T-cell hepatitis. All selected patients with autoimmune hepatitis inactivation by the PD-1 and CTLA4 pathways is also had >1:40 titers of antinuclear antibodies and IgG elevations involved in immune tolerance to self-antigens, adverse with clinicopathologic features meeting the criteria of defi- effects may be triggered by autoimmune reactions. There- nite autoimmune hepatitis based on the simplified scoring fore, the side effects of checkpoint inhibitors are often system [21]. As for drug-induced liver injury, consecutive referred to as “immune-mediated adverse events” in order to cases of predominantly hepatitic injury were selected. All distinguish them from usual idiosyncratic drug-induced cases of drug-induced liver injury were clinically determined organ damage [16]. Although liver injuries caused by nivo- to be idiosyncratic and not due to drug overdose. Causative lumab and ipilimumab were originally suspected to resemble drugs were antibiotics (n = 3), anti-inflammatory agents (n classic autoimmune hepatitis [18], recent pathology papers = 3), anti-convulsants (n = 2), and herbal medicine (n = 2). raised the possibility that clinicopathologic features of All patients with autoimmune hepatitis or drug-induced liver immunotherapy-related hepatitis may not be identical to injury were negative for viral markers, with cases of drug- those of autoimmune hepatitis [19, 20]. However, these two induced liver injury also lacking antinuclear antibodies. conditions have not yet been systematically compared. In the present study, the biopsy findings of liver injuries Evaluation of liver biopsies caused by nivolumab or ipilimumab were compared with classic autoimmune hepatitis and idiosyncratic drug- Liver biopsies were reviewed in terms of the following induced liver injury in order to elucidate how checkpoint findings: portal inflammation, lobular injury, confluent inhibitor-induced liver injuries are similar or dissimilar to necrosis, eosinophilic infiltration, and plasmacytosis. The the two other conditions. degrees of portal inflammation, lobular injury, and con- fluent necrosis were examined according to Ishak’s scoring system for chronic hepatitis [22]. Although interface hepa- Materials and methods titis and fibrosis were also a part of Ishak’s scoring scheme, they are rare in acute-onset liver diseases; therefore, these Patients findings were not examined in the present study. Although Ishak’s scoring system is designed for chronic hepatitis, it This study received ethical approval from Kobe University was selected in this study because this scheme allows to Graduate School of Medicine. A search of the pathology evaluate multiple hepatitic findings in a semiquantitative database at our institutes and consultation files of the manner and also because of the lack of reliable scoring authors identified seven cases of liver injuries caused by systems for acute hepatitis. The presence or absence of >5 nivolumab (n = 5) and ipilimumab (n = 2). Five were eosinophils per high power field and >10 plasma cells per Japanese cases, while the remaining two were selected from high power field was evaluated. Other features such as bile the database in Seattle. Electronically stored clinical records duct injury were also recorded if present. and histology slides were retrospectively reviewed. Ten cases each of autoimmune hepatitis and drug-induced Immunohistochemistry liver injury were also selected for comparison (Table 1). Consecutive cases of autoimmune hepatitis that clinically All biopsy specimens were fixed in 10% buffered formalin showed an acute presentation were chosen because liver andembeddedinparaffin. Unstained slides for immuno- injuries due to checkpoint inhibitors were sudden-onset histochemistry were available in five nivolumab-treated Table 1 Characteristics of patients examined in this study Conditions n Median age Gender (Male/ Details (range) female) Checkpoint inhibitor-associated liver 7 61 (24–76) 5/2 Liver injuries caused by nivolumab (n = 5) and injury ipilimumab (n = 2). A clinical summary is available in Table 2 Autoimmune hepatitis 10 66 (20–80) 2/8 All showed an acute presentation, and had antinuclear antibodies and IgG elevations, meeting the criteria for definite autoimmune hepatitis Drug-induced liver injury 10 56 (32–76) 5/5 All presented with predominantly hepatitic liver dysfunction. Causative drugs were antibiotics (n = 3), anti-inflammatory agents (n = 3), anti-convulsants (n = 2), and herbal medicine (n = 2) Hepatotoxicity of immune checkpoint inhibitors: a histology... 967 cases and all cases of autoimmune hepatitis or drug- induced liver injury. Immunostaining was performed on a Ventana Benchmark XT (Ventana Medical Systems, Inc., Tucson, AZ) or Bond Max autostainer (Leica Micro- systems, Wetzlar, Germany) according to the manu- facturers’ protocols. Deparaffinized sections were heat- Other conditions None cholangitis (13 years) treated and incubated with primary antibodies. Immuno- Rheumatoid arthritis (3 years) histochemical staining for multiple lymphocyte markers was performed using the following antibodies: CD3 (clone F7.2.38, 1:50, Dako Cytomation, Glostrup, Den- mark), CD4 (clone 1F6, prediluted, Leica Microsystems), a CD8 (clone SP57, Roche, Ltd., Basel, Switzerland), and CD20 (clone L26, prediluted, Dako Cytomation). The numbers of lymphocytes positive for each marker were counted at three hot spots and calculated as the
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