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.

Case presentation: 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.

Keywords: Anti-tumor T cell response; Antibody; Autoimmunity; Autopsy; Immune checkpoint inhibitors; Immunotherapy; Ipilimumab; Melanoma; Nivolumab.

Fig. 1

Time axis. Line graph illustrating disease progression and therapeutic intervention between initial diagnosis in August 2012 and death from metastatic melanoma in September 2015

Fig. 2

Morphological progression from initial diagnosis. a Melanoma ex naevo (08/2012) b local recurrence (08/2013) with deep in transit metastasis and c sentinel node metastasis d skin metastasis (10/2014) e dedifferentiated melanoma at autopsy f intratumoral CD8-positive T-cell infiltrates at autopsy as detected by immunohistochemistry; scale bars as indicated

Fig. 3

Lung damage patterns. a CT Thorax: Pulmonary metastasis before therapy with Ipilimumab (02/2015) b CT Thorax: pulmonary metastasis regression, ground glass opacities after Ipilimumab (04/2015) c sarcoid-like reaction d elastica stain showing epithelioid granulomas surrounded by fibrotic rings e CD8-positive T-cell infiltrates surrounding giant cell granulomas as detected by immunohistochemistry f diffuse alveolar damage; scale bars as indicated

Fig. 4

Lymphocytic myocarditis and hepatic T-cell infiltration. a Normal-sized heart with normal coronary arteries in frontal view b patchy myocardial fibrosis and mononuclear infiltrates c myocardial CD8-positive T-cell infiltrates as detected by immunohistochemistry e mild hepatic portal T-cell infiltrates f lobular hepatic CD8-positive T-cell infiltrates and g sinusoidal infiltration by CD68+ histiocytic as detected by immunohistochemistry; scale bars as indicated

Fig. 5

Meningoencephalitis and bone marrow lymphocytosis. a Meningeal lymphocytosis with b a predominantly CD8+ T-cell infiltrate as demonstrated by immunohistochemistry and c extension into the brain parenchyma; d Hypercellular bone marrow with e an increase in CD3+ and f CD8+ T-lymphocytes as detected by immunohistochemistry; scale bars as indicated