Sarcoidosis-like reaction induced by immune checkpoint inhibitors in patients with advanced melanoma: a report of two cases and a brief review of the literature
Abstract
Introduction. Immunotherapy is associated with a wide range of adverse events. A drug-induced sarcoidosis-like reaction is a systemic granulomatous reaction that is no different from sarcoidosis and occurs in a certain temporal relationship with the initiation of the drug. Case report. The first presented patient was a 61-year-old male with stage IIIC BRAF-positive melanoma treated with adjuvant nivolumab therapy. After four cycles of therapy, enlarged mediastinal lymph nodes were confirmed using computed tomography. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy showed chronic granulomatous inflammation. After 12 cycles, grouped brownish-red papules and plaques covered with whitish scales were observed in the skin of both knees, and a histopathology finding indicated a sarcoidosis-like reaction. He was treated with oral prednisone, 60 mg daily in decreasing doses, and after 16 months, the enlarged mediastinal lymph nodes and skin lesions disappeared completely. The second presented patient was a 45-year-old male with stage IIIC BRAF-positive melanoma treated with adjuvant pembrolizumab therapy. After four cycles, enlarged mediastinal lymph nodes were observed. Bronchoscopy with bronchoalveolar lavage revealed granulomatous inflammation, and transbronchial biopsy confirmed sarcoidosis. Therapy with oral prednisone 40 mg daily in decreasing doses was performed in the next three months, and immunotherapy was continued. The enlarged mediastinal lymph nodes resolved after completion of adjuvant therapy. Conclusion. In most cases, a diagnosis of a sarcoidosis-like reaction requires a biopsy of the suspected lesions. It is not usually necessary to stop immunotherapy, but sometimes standard corticosteroid therapy is indicated. An interdisciplinary approach is important to distinguish true disease progression from adverse drug reaction.
References
Smith H, Easterling R, Ma J, Moodabagil M, Meara A, Owen DH, et al. Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival. Respir Med 2024; 227: 107640.
Chopra A, Nautiyal A, Kalkanis A, Judson MA. Drug-Induced Sarcoidosis-Like Reactions. Chest 2018; 154(3): 664–77.
Danlos FX, Pagès C, Baroudjian B, Vercellino L, Battistella M, Mimoun M, et al. Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient with Advanced Melanoma. Chest 2016; 149(5): e133–6.
Lomax AJ, McGuire HM, McNeil C, Choi CJ, Hersey P, Karikios D, et al. Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis. Int J Rheum Dis 2017; 20(9): 1277–85.
Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006; 174(7): 795–802.
Daïen CI, Monnier A, Claudepierre P, Constantin A, Eschard JP, Houvenagel E, et al. Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford) 2009; 48(8): 883–6.
Gkiozos I, Kopitopoulou A, Kalkanis A, Vamvakaris IN, Judson MA, Syrigos KN. Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors. J Thorac Oncol 2018; 13(8): 1076–82.
Melin A, Routier É, Roy S, Pradere P, Le Pavec J, Pierre T, et al. Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma. Cancers (Basel) 2022; 14(12): 2937.
Reule RB, North JP. Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab. J Am Acad Dermatol 2013; 69(5): e272–3.
Suozzi KC, Stahl M, Ko CJ, Chiang A, Gettinger SN, Siegel MD, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep 2016; 2(3): 264–8.
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.
Chanson N, Ramos-Casals M, Pundole X, Suijkerbuijk K, José de Barros E Silva M, Lidar M, et al. Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation. Eur J Cancer 2021; 158: 208–16.
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.
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 (Basel) 2023; 15(9): 2561.
Hans S, Dercle L, Champiat S, Voisin AL, Noémie C, Marabelle A, et al. Sarcoidosis-like reaction mimics progression in patients treated with immune checkpoint inhibitors. Ann Oncol 2019; 30(5): 1302P.
Rambhia PH, Reichert B, Scott JF, Feneran AN, Kazakov JA, Honda K, et al. Immune checkpoint inhibitor-induced sarcoidosis-like granulomas. Int J Clin Oncol 2019; 24(10): 1171–81.
Nishino M, Hatabu H, Sholl LM, Ramaiya NH. Thoracic complications of precision cancer therapies: a practical guide for radiologists in the new era of cancer care. Radiographics 2017; 37(5): 1371–87.
Cornejo CM, Haun P, English J 3rd, Rosenbach M. Immune checkpoint inhibitors and the development of granulomatous reactions. J A Acad. Dermatol 2019; 81(5): 1165–75.
Tetzlaff MT, Nelson KC, Diab A, Staerkel GA, Nagarajan P, Torres-Cabala CA, et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: A marker of therapy response in a subset of melanoma patients. J Immunother Cancer 2018; 6(1): 14.
Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis statement committee. American thoracic society. European respiratory society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J 1999; 14(4): 735–7.
Llabres M, Brito-Zerón P, Ramos-Casals M, Sellares J. Synthetic pharmacotherapy for pulmonary sarcoidosis. Expert Opin Pharmacother 2019; 20(11): 1397–404.
Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5(1): 95.
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol 2018; 36(17): 1714–68.
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.
Berthod G, Lazor R, Letovanec I, Romano E, Noirez L, Mazza Stalder J, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol 2012; 30(17): e156–9.
Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol 2012; 30(2): e7–10.
Wilgenhof S, Morlion V, Seghers AC, Du Four S, Vanderlinden E, Hanon S, et al. Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor. Anticancer Res 2012; 32(4): 1355–9.
Andersen R, Nørgaard P, Al-Jailawi MK, Svane IM. Late development of splenic sarcoidosis-like lesions in a patient with metastatic melanoma and long-lasting clinical response to ipilimumab. Oncoimmunology 2014; 3(8): e954506.
Murphy KP, Kennedy MP, Barry JE, O’Regan KN, Power DG. New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing CTLA4 monoclonal antibody treatment. Oncol Res Treat 2014; 37(6): 351–3.
Martínez Leboráns L, Esteve Martínez A, Victoria Martínez AM, Alegre de Miquel V, Berrocal Jaime A. Cutaneous sarcoidosis in a melanoma patient under ipilimumab therapy. Dermatol Ther 2016; 29(5): 306–8.
Koelzer VH, Rothschild SI, Zihler D, Wicki A, Willi B, Willi N, et al. Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors - an autopsy study. J Immunother Cancer 2016; 4: 13.
Reuss JE, Kunk PR, Stowman AM, Gru AA, Slingluff CL Jr, Gaughan EM. Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature. J Immunother Cancer 2016; 4: 94.
Montaudié H, Pradelli J, Passeron T, Lacour JP, Leroy S. Pulmonary sarcoid-like granulomatosis induced by nivolumab. Br J Dermatol 2017; 176(4): 1060–3.
Reddy SB, Possick J, Kluger HM, Galan A, Han D. Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma. J Immunother 2017; 40(8): 307–11.
Dunn-Pirio AM, Shah S, Eckstein C. Neurosarcoidosis following Immune Checkpoint Inhibition. Case Rep Oncol 2018; 11(2): 521–6.
Nishino M, Sholl LM, Awad MM, Hatabu H, Armand P, Hodi FS. Sarcoid-Like Granulomatosis of the Lung Related to Immune-Checkpoint Inhibitors: Distinct Clinical and Imaging Features of a Unique Immune-Related Adverse Event. Cancer Immunol Res 2018; 6(6): 630–5.
Faviez G, Bousquet E, Rabeau A, Rouquette I, Collot S, Goumarre C, et al. Sarcoid-like granulomatosis in cancer patients treated with immune checkpoints inhibitors. Rev Mal Respir 2018; 35(9): 963–7. (French)
Laroche A, Alarcon Chinchilla E, Bourgeault E, Doré MA. Erythema Nodosum as the Initial Presentation of Nivolumab-Induced Sarcoidosis-Like Reaction. J Cutan Med Surg 2018; 22(6): 627–9.
Yatim N, Mateus C, Charles P. Sarcoidosis post-anti-PD-1 therapy, mimicking relapse of metastatic melanoma in a patient undergoing complete remission. Rev Med Interne 2018; 39(2): 130–3.
Jespersen H, Bjursten S, Ny L, Levin M. Checkpoint inhibitor-induced sarcoid reaction mimicking bone metastases. Lancet Oncol 2018; 19(6): e327.
Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, Naegeli MC, Goldinger SM, Barysch M, et al. Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res 2018; 28(3): 230–6.
Lu Y. FDG PET/CT Course of Pembrolizumab - Associated Multiorgan Sarcoidosis. Clin Nucl Med 2019; 44(2): 167–8.
Fukuchi K, Hikawa M, Sano Y, Kasuya A, Aoshima M, Tatsuno K, et al. Sarcoid-like reaction and vitiligo occurring after nivolumab therapy in a patient with metastatic melanoma. J Dermatol 2019; 46(10): e359–60.
Cervantes J, Rosen A, Dehesa L, Dickinson G, Alonso-Llamazares J. Granulomatous Reaction in a Patient with Metastatic Melanoma Treated with Ipilimumab: First Case Reported with Isolated Cutaneous Findings. Actas Dermo-Sifiliográficas 2019; 110(1): 43–9.
Toumeh A, Sakhi R, Shah S, Arudra SK, De Las Casas LE, Skeel RT. Ipilimumab-Induced Granulomatous Disease Occurring Simultaneously With Disease Progression in a Patient With Metastatic Melanoma. Am J Ther 2016; 23(4): e1068–71.
Lidar M, Giat E, Garelick D, Horowitz Y, Amital H, Steinberg-Silman Y, et al. Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev 2018; 17(3): 284–9.
Burillo-Martinez S, Morales-Raya C, Prieto-Barrios M, Rodriguez-Peralto JL, Ortiz-Romero PL. Pembrolizumab-Induced Extensive Panniculitis and Nevus Regression: Two Novel Cutaneous Manifestations of the Post-immunotherapy Granulomatous Reactions Spectrum. JAMA Dermatol 2017; 153(7): 721–2.
Nandavaram S, Nadkarni A. Ipilimumab-Induced Sarcoidosis and Thyroiditis. Am J Ther 2018; 25(3): e379–80.
Tan I, Malinzak M, Salama AKS. Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy. J Immunother Cancer 2018; 6(1): 77.
Van Willigen WW, Gerritsen WR, Aarntzen EHJG. 18F-FDG PET/CT of Multiorgan Sarcoid-Like Reaction During Anti-PD-1 Treatment for Melanoma. Clin Nucl Med 2019; 44(11): 905–6.
Wang LL, Patel G, Chiesa-Fuxench ZC, McGettigan S, Schuchter L, Mitchell TC, et al. Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy. JAMA Dermatol 2018; 154(9): 1057–61.
Woodbeck R, Metelitsa AI, Naert KA. Granulomatous Tumoral Melanosis Associated with Pembrolizumab Therapy: A Mimicker of Disease Progression in Metastatic Melanoma. Am J Dermatopathol 2018; 40(7): 523–6.
Tissot C, Carsin A, Freymond N, Pacheco Y, Devouassoux G. Sarcoidosis complicating anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody biotherapy. Eur Respir J 2013; 41(1): 246–7.
Firwana B, Ravilla R, Raval M, Hutchins L, Mahmoud F. Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors. J Oncol Pharm Pract 2017; 23(8): 620–4.
Rodriguez EF, Lipson E, Suresh K, Cappelli LC, Monaco SE, Maleki Z. Immune checkpoint blocker-related sarcoid-like granulomatous inflammation: a rare adverse event detected in lymph node aspiration cytology of patients treated for advanced malignant melanoma. Hum Pathol 2019; 91: 69–76.
Chorti E, Kanaki T, Zimmer L, Hadaschik E, Ugurel S, Gratsias E, et al. Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis. Eur J Cancer 2020; 131: 18–26.
Frohlich M, Wang H, Sakr L. Sarcoid-like Reaction Discovered on EBUS-TBNA of Intrathoracic Lymph Nodes During Immunotherapy for Metastatic Melanoma. J Immunother 2020; 43(2): 75–8.
Tulbah RI, Rowe SP, Solnes LB, Javadi MS. Nivolumab-Associated Pulmonary and Bone Sarcoidosis in a Patient With Melanoma of Unknown Primary. Clin Nucl Med 2019; 44(9): e519–21.
Urrego-Callejas T, Sandoval-Álvarez S, Gómez-Wolff R, Vásquez G. Cutaneous and Pulmonary Sarcoid-Like Reaction Induced by Nivolumab: Case Report and Brief Literature Review. J Clin Rheumatol 2021; 27(8S): S460–4.
Marcoval J, Bauer-Alonso A, Fornons-Servent R, Jiménez-Colomo L, Sabaté-Llobera A, Penín RM. Subcutaneous sarcoidosis induced by pembrolizumab in a melanoma patient mimicking subcutaneous metastasis at 18F-FDG PET/CT. Rev Esp Med Nucl Imagen Mol (Engl Ed) 2021; 40(4): 255–6.
Keukeleire S, Schwarze J, Awada G, Everaert H, Van Binst AM, Cras L, et al. An atypical sarcoid-like reaction during anti-protein death 1 treatment in a patient with metastatic melanoma. Melanoma Res 2020; 30(5): 524–7.
Garanzini EM, Scaramuzza D, Spadarella G, Di Guardo L, Marchianò A. Sarcoidosis-like disease mimicking metastases during adjuvant ipilimumab therapy in advanced melanoma patient: CT scan and MRI help in managing difficult clinical decision. BJR Case Rep 2020; 6(2): 20190065.
Mobini N, Dhillon R, Dickey J, Spoon J, Sadrolashrafi K. Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature. Case Rep Dermatol Med 2019; 2019: 6702870.
Chahin M, Stack A, Siddiqi A, Shaikh M. Is it metastatic melanoma or is it sarcoidosis? Non-caseating granulomas due to pembrolizumab. BMJ Case Rep 2020; 13(12): e240701.
Pham JP, Star P, Wong S, Damian DL, Saw RPM, Whitfeld MJ, et al. Cutaneous sarcoidosis due to immune-checkpoint inhibition and exacerbated by a novel BRAF dimerization inhibitor. Skin Health Dis 2021; 1(4): e71.
O'Connor C, Finnegan P, Power DG, Bennett M, Bourke JF. Pembrolizumab-associated erythema nodosum in the treatment of metastatic melanoma. Immunotherapy 2022; 14(13): 1021–6.
Cao Y, Afzal MZ, Gutmann EJ, Shirai K. Rare immune-related adverse events in a patient with metastatic melanoma: a case report highlighting sarcoidosis-like reactions triggered by immune-checkpoint inhibitors. Melanoma Res 2024; 34(1): 70–5.