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Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis

Larsen, Brandon T. MD, PhD*; Chae, June M. MD; Dixit, Anuj S. MD; Hartman, Thomas E. MD; Peikert, Tobias MD; Roden, Anja C. MD§

The American Journal of Surgical Pathology: October 2019 - Volume 43 - Issue 10 - p 1331–1340
doi: 10.1097/PAS.0000000000001298
Original Articles

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, but are associated with immune-related adverse events. Clinically, pneumonitis is a well-recognized complication, but its histopathologic features are poorly understood. Institutional archives were searched for patients having ICI therapy and subsequent lung tissue sampling. After excluding infectious cases, 9 patients (5 women, median: 59 y) were identified with clinically suspected ICI-related pneumonitis. Clinical history, imaging, and pathology slides were reviewed. Patients received pembrolizumab (6 cases), nivolumab (1), ipilimumab followed by pembrolizumab (1), or pembrolizumab followed by nivolumab (1); the latter experienced pneumonitis with both agents. Treatment duration ranged from 1 to 33 cycles (median: 8). Three patients received concurrent chemotherapy and 1 received radiation; the remainder received ICI monotherapy. Symptoms were nonspecific; 2 patients were asymptomatic. Thoracic imaging showed bilateral ground glass or nodular opacities in all cases, often with pleural effusion. Histologically, organizing pneumonia was seen in 7 patients, all with subclinical or mild disease, admixed with vague non-necrotizing airspace granulomas in 3 cases; all 6 patients with follow-up did well. One patient had acute fibrinous pneumonitis and 1 had diffuse alveolar damage; both died. All 9 cases showed foamy macrophages and pneumocyte vacuolization; 6 had rare eosinophils. ICI-related pneumonitis presents as bilateral ground-glass opacities or nodules, and usually manifests as organizing pneumonia histopathologically, often with vague non-necrotizing airspace granulomas. Foamy macrophages and pneumocyte vacuolization are characteristic and rare eosinophils are often seen. Less commonly, acute fibrinous pneumonitis or diffuse alveolar damage can occur, which may be fatal.

*Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ

Division of Pulmonary and Critical Care Medicine

Departments of Radiology

§Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Brandon T. Larsen, MD, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, 13400 E. Shea Blvd., Scottsdale, AZ 85259 (e-mail:

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