Nivolumab-induced sarcoid-like reaction or sarcoidosis?

Sarcoid-like reactions associated with the immunotherapy are rare adverse events. The first case of a sarcoid-like reaction related to the use of checkpoint inhibitors was described in 2008 in a patient with melanoma receiving ipilimumab therapy. The gastrointestinal tract is most frequently affected, with less frequent involvement of mediastinal lymph nodes and the lungs, and very rarely the thyroid gland. These changes present significant diagnostic challenges, as it is impossible to differentiate a sarcoid reaction from the progression of the underlying oncological disease without morphological verification. Moreover, a sarcoid reaction can develop in parallel with the progression of the primary disease, further complicating the diagnosis. In the presented case, a patient with progressive melanoma developed mediastinal lymphadenopathy and lung involvement with severe respiratory symptoms 10 months after initiating immunotherapy. To confirm the diagnosis, transbronchial lymph node biopsy and cryobiopsy of lung tissue were performed. Histological examination revealed epithelioid cell granulomas, confirming the diagnosis of a sarcoid-like reaction and enabling the initiation of pathogenetic therapy with methylprednisolone. However, in our case, there were two relapses of sarcoidosis 6 months and a year after discontinuation of immune therapy against the background of discontinuation of steroid treatment, which may indicate the initial induction of sarcoidosis by immune therapy with further chronization of the process. Thus, given the increasing role of immunotherapy in oncology, knowledge about the potential development of various immunopathological reactions is important for determining treatment strategies. This clinical case highlights the importance of raising awareness among clinicians about the possibility of such complications during immunotherapy.

1. Chuchalin AG, Avdeev SN, Aisanov ZR, Baranova OP, Borisov SE, Geppe NA et al. Sarcoidosis: federal clinical guidelines for diagnosis and treatment. Pulmonologiya. 2022;32(6):806–833. (In Russ.) https://doi.org/10.18093/0869-0189-2022-32-6-806-833.

2. Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology. 2009;218(1):69–70. https://doi.org/10.1159/ 000161122.

3. Cohen Aubart F, Lhote R, Amoura A, Valeyre D, Haroche J, Amoura Z, Lebrun-Vignes B. Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database. J Intern Med. 2020;288(3):356–362. https://doi.org/10.1111/joim.12991.

4. Apalla Z, Kemanetzi C, Papageorgiou C, Bobos M, Manoli M, Fotiadou C et al. Challenges in sarcoidosis and sarcoid-like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case. Dermatol Ther. 2021;34(1):e14618. https://doi.org/10.1111/dth.14618.

5. Tarhini AA, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield LH, Kirkwood JM. Baseline circulating IL-17 predicts toxicity while TGF-beta1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015;3:39. https://doi.org/10.1186/s40425-015-0081-1.

6. Moller DR. Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 1999;16(1):24–31. Available at: https://pubmed.ncbi.nlm.nih.gov/10207939/.

7. Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax. 2011;66(2):144–150. https://doi.org/10.1136/thx.2010.140319.

8. Mortaz E, Rezayat F, Amani D, Kiani A, Garssen J, Adcock IM, Velayati A. The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis. Iran J Allergy Asthma Immunol. 2016;15(4):334–339. Available at: https://ijaai.tums.ac.ir/index.php/ijaai/article/view/695.

9. Doyle AM, Mullen AC, Villarino AV, Hutchins AS, High FA, Lee HW et al. Induction of cytotoxic T lymphocyte antigen 4 (CTLA-4) restricts clonal expansion of helper T cells. J Exp Med. 2001;194(7):893–890. https://doi.org/10.1084/jem.194.7.893.

10. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–275. https://doi.org/10.1126/science.1160062.

11. von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B, Ribas A. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med. 2009;7:35. https://doi.org/10.1186/1479-5876-7-35.

12. D’Addio F, Riella LV, Mfarrej BG, Chabtini L, Adams LT, Yeung et al. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance. J Immunol. 2011;187(9):4530–4541. https://doi.org/10.4049/jimmunol.1002031.

13. Tirumani SH, Ramaiya NH, Keraliya A, Bailey ND, Ott PA, Hodi FS, Nishino M. Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. Cancer Immunol Res. 2015;3(10):1185–1192. https://doi.org/10.1158/2326-6066.CIR-15-0102.

14. Cabanié C, Ammari S, Hans S, Pobel C, Laparra A, Danlos FX et al. Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case-control study. Eur J Cancer. 2021;156:46–59. https://doi.org/10.1016/j.ejca.2021.07.015.

15. Eljilany I, Noor A, Paravathaneni M, Yassine I, Lee SJ, Othus M et al. Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review. Cancers. 2023;15(9):2561. https://doi.org/10.3390/cancers15092561.