Necrotizing and non-Necrotizing Granulomatous Reactions in Cancer Patients Treated with Immune Checkpoint Inhibitors: a Systematic Literature Review

Objective Immune checkpoint inhibitors (ICI) have improved cancer outcomes but often cause immune-related adverse events, including granulomatous reactions (GRs). We analyzed GRs in patients receiving anticytotoxic T-lymphocyte–associated protein 4 (anti-CTLA4), antiprogrammed cell death protein 1 (anti-PD1)/antiprogrammed death ligand 1 (anti-PDL1), and anti-CTLA4/anti-PD1 therapies. Methods We performed a literature review of GRs in patients receiving ICI. Data were extracted from 166 articles, including demographics, GR organ distribution, and pathological findings. Results In 261 patients, the mean age of GR onset was 59.3 (SD 13.0) years. The most common cancer types were melanoma (57%) and lung cancer (21%). Lymph nodes (52%) and skin (35%) were the predominantly affected organs; however, GRs also involved the liver, kidney, and bone. Granulomas were nonnecrotizing in 64% of cases and necrotizing in 15% of cases. Forty-five percent of patients were treated with systemic corticosteroids (CS), and 11% required a CS-sparing agent. Median follow-up time was 10.1 (IQR 4.0-22.2) months. Most GRs (64%) had resolved by last follow-up. Compared to those treated with combination ICI, patients treated with anti-PD1/anti-PDL1 monotherapy were older and had a longer time to onset of GR. They were less likely to be treated with CS for GRs. In patients with melanoma, necrotizing GRs were more common with combination ICI. GRs in the lungs and lymph nodes were more likely to be nonnecrotizing, and GRs in the liver were more commonly necrotizing. Conclusion GRs in patients with cancer treated with ICI can occur in many organ systems and were most commonly nonnecrotizing. Patients treated with combination ICI had more severe reactions. Most GRs resolved with CS treatment or ICI discontinuation. (PROSPERO ID: CRD42024501205)