Liver biopsy findings in patients on immune checkpoint inhibitors


Immune checkpoint inhibitors (ICI) can induce a durable response against a wide range of malignancies but cause immune related adverse events. The purpose of this study was to evaluate whether the pattern of inflammation in a liver biopsy in patients on ICIs is likely to be related to ICIs or other causes, and whether the pattern correlates with LFT abnormalities, imaging findings, and responsiveness to steroids. Cancer patients on ICIs who underwent liver biopsy were identified. Clinical data were obtained from electronic records. Liver biopsies were recorded as hepatitic, cholangitic, mixed, steatotic, or as mild nonspecific changes. In total, 28 liver biopsies had a predominantly hepatitic pattern of inflammation, including 11 biopsies with granulomas and 10 with endothelialitis. Eight biopsies had a mixed hepatocytic and cholangitic pattern of injury, including 6 with granulomas and 4 with endothelialitis. Sixteen patients had a predominantly cholangitic pattern, with portal-based inflammation. Three patients had a pattern resembling fatty liver, and five had mild nonspecific changes. The three most common histologic patterns correlated with the pattern of LFT abnormalities. The majority of patients with a cholangitic pattern had competing causes for elevated LFTs, including disease progression or concomitant chemotherapy. The cholangitic pattern was more likely to have bile duct dilatation or narrowing on liver imaging. The pattern of inflammation, degree of lobular injury, or presence of granulomas or endothelialitis did not predict response to steroids or the need for secondary immunosuppression. In this retrospective study, the pattern of inflammation did not predict the need for steroids, the length of time that steroids is required, or the need for secondary immunosuppression. A cholangitic pattern was seen when the pattern of LFTs was cholestatic, and was associated with imaging abnormalities of the bile duct, but a similar pattern was seen in bile duct obstruction and other drug reactions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Zone 3 hepatitis and necrosis with numerous histiocytes adjacent to an injured central vein.
Fig. 2: Medium power view of a liver biopsy with panlobular inflammation, but with focal area of necrosis in the lobule.
Fig. 3: Steatosis in an area of injury around a central vein with aggregates of histiocytes surrounding an injured vein.
Fig. 4: Fibrin ring granuloma in ICI hepatitis.
Fig. 5: An hepatic vein surrounded by mononuclear inflammatory cells and granulomatous inflammation (lower right).
Fig. 6: Liver biopsy in a patient with a cholangitic pattern and likely ICI-related cholangitis.
Fig. 7: Liver biopsy in a patient with a cholangitic pattern and disease progression in the liver causing bile duct compression, and likely contributing to the LFT abnormalities.
Fig. 8: Medium power view of a liver biopsy demonstrating a steatohepatitic pattern of injury.


  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

    Kurashima Y, Kiyono H. Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol. 2017;35:119–47.

    CAS  Article  Google Scholar 

  3. 3.

    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage iii melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.

    CAS  Article  Google Scholar 

  4. 4.

    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    CAS  Article  Google Scholar 

  5. 5.

    Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colitis and hepatitis. Clin Transl Gastroenterol. 2018;9:180.

    Article  Google Scholar 

  6. 6.

    Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv264–iv266.

    CAS  Article  Google Scholar 

  7. 7.

    Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018;124:3706–14.

    CAS  Article  Google Scholar 

  8. 8.

    Pauken KE, Dougan M, Rose NR, Lichtman AH, Sharpe AH. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 2019;40:511–23.

    CAS  Article  Google Scholar 

  9. 9.

    Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36:2872–8.

    CAS  Article  Google Scholar 

  10. 10.

    Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, et al. Ipilimumab-associated hepatitis: Clinicopathologic characterization in a series of 11 cases. Am J Surgical Pathol. 2015;39:1075–84.

    Article  Google Scholar 

  11. 11.

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

    Article  Google Scholar 

  12. 12.

    Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31:965–73.

    Article  Google Scholar 

  13. 13.

    Zen Y, Chen YY, Jeng YM, Tsai HW, Yeh MM. Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes. Histopathology. 2020;76:470–80.

    Article  Google Scholar 

  14. 14.

    Hamoir C, de Vos M, Clinckart F, Nicaise G, Komuta M, Lanthier N. Hepatobiliary and Pancreatic: Nivolumab-related cholangiopathy. J Gastroenterol Hepatol. 2018;33:1695.

    CAS  Article  Google Scholar 

  15. 15.

    Kono M, Sakurai T, Okamoto K, Masaki S, Nagai T, Komeda Y, et al. Efficacy and safety of chemotherapy following Anti-PD-1 antibody therapy for gastric cancer: a case of sclerosing cholangitis. Intern Med. 2019;58:1263–6.

    Article  Google Scholar 

  16. 16.

    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. 2018;36:144–6.

    Article  Google Scholar 

  17. 17.

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

    CAS  Article  Google Scholar 

  18. 18.

    Kuraoka N, Hara K, Terai S, Yatabe Y, Horio Y. Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer. Endoscopy. 2018;50:E259–E261.

    Article  Google Scholar 

  19. 19.

    Gelsomino F, Vitale G, D’Errico A, Bertuzzi C, Andreone P, Ardizzoni A. Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury. Ann Oncol. 2017;28:671–2.

    CAS  Article  Google Scholar 

  20. 20.

    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  Google Scholar 

  21. 21.

    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.

    CAS  Article  Google Scholar 

  22. 22.

    Kashima J, Okuma Y, Shimizuguchi R, Chiba K. Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report. Cancer Immunol Immunother. 2018;67:61–65.

    Article  Google Scholar 

  23. 23.

    Doherty GJ, Duckworth AM, Davies SE, Mells GF, Brais R, Harden SV, et al. Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury. ESMO Open. 2017;2:e000268.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Joseph Misdraji.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cohen, J.V., Dougan, M., Zubiri, L. et al. Liver biopsy findings in patients on immune checkpoint inhibitors. Mod Pathol (2020).

Download citation