Clinicopathologic Characteristics of Immune Checkpoint Inhibitor-related Pancreatitis

Abstract

The advent of immune checkpoint inhibitors (ICIs), although associated with adverse events, has heralded a new era in cancer therapy. ICI-related pancreatitis is a rare adverse effect of ICIs. The nonspecific clinical manifestations have posed diagnostic challenges, and the detailed histologic features remain largely unknown. This study aims to characterize the clinical and histopathologic features of ICI-related pancreatitis to increase awareness and improve diagnostic accuracy. We retrospectively identified 5 specimens from 4 patients from our database and consultation practice. We reviewed demographic, clinical, serological, and radiologic data and examined each specimen's histologic features. Patients (2 female, 2 male) were all prescribed anti-PD-1 monoclonal antibodies (1 on Nivolumab and 3 on Pembrolizumab) for metastatic melanoma, unresectable colon cancer, metastatic pancreatic adenocarcinoma, and urothelial carcinoma. The onset of ICI-related pancreatitis ranged from 28 to 473 days after ICI initiation. All 4 patients showed elevated amylase and/or lipase. Two patients presented with the chief complaint of abdominal pain. The other 2 initially asymptomatic patients showed hypointense mass lesions on imaging resembling malignant processes. The most common histologic findings were acinar-centric mixed inflammatory infiltrate (5/5 specimens) followed by atrophy (4/5 specimens) and fibrosis (4/5 specimens). Storiform fibrosis was identified in one patient who was biopsied twice. Other findings included edema (3/5 specimens) and acinar-to-ductal metaplasia (3/5 specimens). Granulocytic epithelial lesion was identified in 2 specimens. No obliterative phlebitis or granulomas were identified. By immunohistochemistry, the inflammatory infiltrates were predominately composed of CD3+ T cells with a variable CD4 to CD8 ratio. Neutrophils and eosinophils were readily identifiable with rare plasma cells. Management included stopping the ICI and starting steroids. Whereas 1 patient lacked follow-up information, 2 patients showed marked improvement. One patient succumbed to severe ICI-related myocarditis. In conclusion, ICI-related pancreatitis shows overlapping clinical-radiologic features with malignancy and autoimmune pancreatitis with the potential for chronic injury. Although ICI-related pancreatitis lacks the classic histologic features of autoimmune pancreatitis, there is considerable histologic overlap, particularly on small biopsies. Therefore, correlation with the patient's medications is critical when evaluating pancreatic specimens with nonspecific chronic pancreatitis histologic patterns.

Keywords: immune checkpoint inhibitor; pancreatitis; pathology.