title: Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study.
abstract: BACKGROUND
  Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal.
  
  
  METHODS
  This autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune-related end-organ damage due to lymphocytic myocarditis was found.
  
  
  CONCLUSIONS
  Autopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity.
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland ; Translational Research Unit (TRU), Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3010 Bern, Switzerland.
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Division of Medical Oncology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Sacha I
authors.initials: SI
authors.lastname: Rothschild
authors.affiliation: Department of Medical Oncology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Zihler
authors.affiliation: Division of Medical Oncology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.affiliation: Institute of Radiology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Berenika
authors.initials: B
authors.lastname: Willi
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Niels
authors.initials: N
authors.lastname: Willi
authors.affiliation: Department of Medical Oncology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Michèle
authors.initials: M
authors.lastname: Voegeli
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Gieri
authors.initials: G
authors.lastname: Cathomas
authors.affiliation: Division of Medical Oncology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Mühlemattstrasse 11, CH-4410 Liestal, Switzerland.
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
keywords: Anti-tumor T cell response; Antibody; Autoimmunity; Autopsy; Immune checkpoint inhibitors; Immunotherapy; Ipilimumab; Melanoma; Nivolumab