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

Immune checkpoint inhibitors are a major breakthrough in the field of oncology. Targets for approved immune checkpoint inhibitors are cytotoxic T-lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death receptor 1/ programmed cell death ligand 1 (PD-1/PD-L1). Five patients (four males and one female) were treated with immune checkpoint inhibitors for advanced melanoma (stage III). None of them had prior history of autoimmune disorders, AIDS, or sarcoidosis. The PET/CT imaging studies showed new onset lymphadenopathy suspicious for malignancy. Four patients had cutaneous melanoma and one had vaginal melanoma. Three patients were treated with single agent (two Nivolumab, one Ipilimumab) and two with double agents (Ipilimumab and Pembrolizumab, or Ipilimumab and Nivolumab). PET/CT showed mediastinal multistational lymphadenopathy in four cases and peri-portal lymphadenopathy in one patient. Ultrasound-guided fine needle aspiration (FNA) biopsy showed numerous sarcoid-like granulomatous inflammation, while the fungal and mycobacterial infections were excluded. Cytomorphologically, the granulomas were numerous, mostly large, cellular and non-necrotizing. Multi-nucleated giant were rare or not seen at all. Cell blocks did not show any fibrosis. Other adverse effects included mouth sores, flu-like symptoms, arthritis, muscle aches, skin rashes, mild and severe colitis. The treatment was stopped and patients received prednisone. One patient developed severe adrenal insufficiency, which prolonged prednisone tapering. Their condition improved and lymphadenopathy was resolved in follow-up imaging. Sarcoid-like granulomatous inflammation is an adverse event in patients treated with immune checkpoint therapy such as Ipilimumab and Nivolumab. It can present as enlarged lymph nodes in PET/CT imaging suspicious for malignancy. FNA can serve as a minimally invasive tool to investigate the underlying cause of lymphadenopathy in this subset of patients.