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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 Pathologyvolume 31pages965973 (2018) | Download Citation

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 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.

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References

  1. 1.

    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.

  2. 2.

    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

  3. 3.

    Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.

  4. 4.

    Melosky B, Chu Q, Juergens R, et al. Pointed progress in second-line advanced non-small-cell lung cancer: The rapidly evolving field of checkpoint inhibition. J Clin Oncol. 2016;34:1676–88.

  5. 5.

    Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

  6. 6.

    Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

  7. 7.

    Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase ii trial. J Clin Oncol. 2015;33:1430–7.

  8. 8.

    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

  9. 9.

    Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 2008;26:5275–83.

  10. 10.

    Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

  11. 11.

    Melero I, Hervas-Stubbs S, Glennie M, et al. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95–106.

  12. 12.

    O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer. 2007;110:2614–27.

  13. 13.

    Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206:1717–25.

  14. 14.

    Quezada SA, Simpson TR, Peggs KS, et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med. 2010;207:637–50.

  15. 15.

    Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–29.

  16. 16.

    Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.

  17. 17.

    Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: A systematic review of case reports. PLoS ONE. 2016;11:e0160221.

  18. 18.

    Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31:1071–7.

  19. 19.

    Johncilla M, Misdraji J, Pratt DS, et al. Ipilimumab-associated Hepatitis: Clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol. 2015;39:1075–84.

  20. 20.

    Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40.

  21. 21.

    Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76.

  22. 22.

    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–9.

  23. 23.

    Simonelli M, Di Tommaso L, Baretti M, et al. Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Immunotherapy. 2016;8:1363–9.

  24. 24.

    Huffman BM, Kottschade LA, Kamath PS, et al. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: Natural progression and management. Am J Clin Oncol. 2017. https://doi.org/10.1097/COC.0000000000000374.

  25. 25.

    Lindros KO. Zonation of cytochrome P450 expression, drug metabolism and toxicity in liver. Gen Pharmacol. 1997;28:191–6.

  26. 26.

    Oinonen T, Lindros KO. Zonation of hepatic cytochrome P-450 expression and regulation. Biochem J. 1998;329(Pt 1):17–35.

  27. 27.

    Gelsomino F, Vitale G, Ardizzoni A. A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event. Invest New Drugs. 2017. https://doi.org/10.1007/s10637-017-0484-6.

  28. 28.

    Kawakami H, Tanizaki J, Tanaka K, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs. 2017;35:529–36.

  29. 29.

    Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41:134–7.

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Author information

Affiliations

  1. Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan

    • Yoh Zen
  2. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA

    • Matthew M. Yeh

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Yoh Zen.

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DOI

https://doi.org/10.1038/s41379-018-0013-y

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