Nivolumab-induced Sarcoid-like Granulomatous Reaction in a Renal Cell Carcinoma Patient

Abstract Nivolumab is an anti-PD-1 antibody that blocks the interaction between PD-1 and PD-1 ligand, allowing antigen-specific T cells to recognize and mount a response against tumor cells. The most common pulmonary side effects of Nivolumab include pneumonitis, pleural effusions and eosinophilic pneumonia. 69yo male with high grade renal cell carcinoma initially treated with right nephrectomy and pazopanib. One year after diagnosis, radiologic evidence showing disease progression to the liver and lungs was identified. This prompted the oncology team to start immunotherapy with nivolumab every 2 weeks. Patient initially responded well to treatment as evidenced by stable lung nodules and resolution of the liver lesion on imaging obtained at 18 months and 2.5 years after nivolumab initiation. Patient remained on this regimen for 4 years. However, surveillance CT scan identified left hilar lymphadenopathy, hypermetabolic on PET scan. Pulmonary service was consulted for fine needle aspiration of these lymph nodes. Patient underwent bronchoscopy with endobronchial ultrasound (EBUS) for transbronchial needle aspiration (TBNA) of stations 11L and 7. Right middle lobe bronchoalveolar lavage (BAL) was also performed. Pathology results from lymph node biopsy resulted as noncaseating granulomatous changes in both stations, with no mycobacteria identified. Cytology results were negative for malignant cells; AFB and GMS stains were negative. The diagnosis of granulomatosis secondary to nivolumab was given to this patient. Oncology team stopped this agent indefinitely. Repeat bronchoscopy with EBUS and TBNA eight months later showed fibrotic changes with rare noncaseating granulomas in the same lymph node stations. Granulomatosis, or sarcoid-like reaction is a rare complication caused by nivolumab. The pathogenesis has not been established. It is hypothesized that pathogenesis is related to an indirect enhanced release of IFN-γ. One key feature of sarcoid-like reaction is intrathoracic lymphadenopathy which has been identified in less than 10% of the patients treated with nivolumab. Most of these cases have been reported in melanoma patients. Patients are generally asymptomatic and these lesions are typically found incidentally. Other pulmonary radiographic findings reported include ground glass opacities, irregular nodular parenchymal opacities and peripheral interstitial opacities. Diagnosis is made with tissue biopsy showing noncaseating granulomas with elevated CD4:CD8 ratios. Treatment options include systemic steroid therapy and discontinuing this medication. In this case, discontinuing nivolumab lead to tissue transformation from noncaseating granulomas to fibrous tissue eight months later. Obtaining tissue when new or worsening lymphadenopathy is identified in cancer patients is imperative as this can signify cancer progression.