Immune Checkpoint Inhibitor‐Induced Pancreatitis

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Abstract
The increasing use of immune checkpoint inhibitors (ICI) has led to recognition of a broad spectrum of treatment‐associated inflammatory adverse events, including pancreatic injury. Histological overlap between ICI associated pancreatic injury (ICIPI) and so‐called autoimmune pancreatitis (AIP) has been suggested in isolated reports, but the extent and detailed histopathological features of this overlap remain poorly characterized. The aim of this study was to describe the clinicopathological and histological features of rare ICIPI cases with available tissues and to compare these findings with established histological patterns of AIP. Data were available for five cases. All patients except one were female. ICIPI occurred between 182–580 days after initiation of ICI therapy. All patients had received a combination ICI treatment (e.g., Ipilimumab + Nivolumab). Peak serum lipase levels ranged from 4 to 41 (µkat/L). Computed tomography demonstrated radiologic features consistent with autoimmune pancreatitis (AIP) in four cases, whereas one case raised suspicion of a metastatic lesion. Three patients were treated with steroids, following which pancreatitis (lipase and imaging) resolved. Two patients developed pancreatic atrophy or exocrine insufficiency. Two patients underwent surgical resection because of suspected cancer metastasis. Fine needle biopsy showed only nonspecific atrophy and mild chronic inflammation. In contrast, both surgical specimens demonstrated marked histological overlap with type 2 AIP, including duct‐centric inflammatory changes and granulocytic epithelial lesions, whereas increased IgG4‐positive plasma cells or other features characteristic of type 1 AIP were not identified. Our results, together with the limited published literature, suggest that ICIPI may encompass a heterogeneous spectrum of histological changes, with substantial overlap with type 2 AIP in a subset of cases. Recognition of these overlapping features is important in the histopathological diagnosis of pancreatic inflammatory lesions in patients receiving ICI therapy. Treatment of ICIPI should follow NCCN recommendations. The risk of developing a pancreatic exocrine insufficiency needs to be observed.

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