Neutrophil Infiltration and Acinar-ductal Metaplasia Are the Main Pathological Findings in Pembrolizumab-induced Pancreatitis

Abstract

The histopathological findings of immune checkpoint inhibitor (ICI)-induced pancreatitis have rarely been reported. A 56-year-old man with squamous cell carcinoma of the lung with bone metastasis was being treated with pembrolizumab, an anti-programmed cell death protein-1 antibody. After 13 doses, he was referred to our department due to pancreatitis. Despite characteristic symptoms of acute pancreatitis, imaging findings were similar to those of autoimmune pancreatitis. However, a histological examination showed neutrophil-based inflammatory cell infiltration and acinar-ductal metaplasia. Immunostaining showed CD8positive T lymphocyte infiltration. This case revealed the characteristic histopathology of pembrolizumabinduced pancreatitis, which was previously poorly understood.

Immune Checkpoint Inhibitor-induced Pancreatitis with Pancreatic Enlargement Mimicking Autoimmune Pancreatitis: A Case Report and Review of the Literature

“…Ofuji et al and Hirota et al described similarities between ICI-induced pancreatitis and type 2 AIP, as these patients had complications of colitis, and revealed the predominant neutrophilic infiltrate without an IgG4-positive cell infiltrate histologically ( 30 , 33 ). Furthermore, Hirota et al reported that neutrophilic infiltrates and ADM are features of ICI-induced pancreatitis ( 33 ). However, in ICI-induced pancreatitis, there are no reports of typical histological findings associated with type 2 AIP, the so-called granulocytic epithelial lesions that accompanied pancreatic duct destruction by neutrophilic infiltration ( 41 ).…”

“…Five patients had predominantly neutrophilic infiltrates, five had predominantly lymphocytic infiltrates, and two had both types of infiltrates. Ofuji et al and Hirota et al described similarities between ICI-induced pancreatitis and type 2 AIP, as these patients had complications of colitis, and revealed the predominant neutrophilic infiltrate without an IgG4-positive cell infiltrate histologically (30,33). Furthermore, Hirota et al reported that neutrophilic infiltrates and ADM are features of ICI-induced pancreatitis (33).…”

“…Similarly, ICI-induced pancreatitis may not require strong activation of helper T cells or immunoglobulin production. Ikemoto et al and Hirota et al reported that irAE-induced pancreatitis showed significant infiltration with CD8 lymphocytes ( 32 , 33 ). However, in the present patient, CD4 cells may have played an important role in the pathogenesis, as there were multinucleated giant cells and reaction-forming granulomas with dense fibrosis, which may explain why a predominant infiltration of CD8+ T cells was not observed.…”

Gradient inflammation in the pancreatic stump after pancreaticoduodenectomy: Two case reports and review of literature

“…Moreover, no previous studies have reported increased ductal permeability in patients with pancreatitis. However, a case study has documented the presence of neutrophil-predominant inflammatory cell infiltration, ADM, and fibrosis in a patient with pancreatitis induced by pembrolizumab[ 24 ]. Our study showed that the blood-duct barrier was destroyed, and the ducts formed by ADM served as sites for the transmigration of neutrophils and RBCs through the duct wall.…”

Pancreatic injury following immune checkpoint inhibitors: A systematic review and meta-analysis

“…The infiltration of the pancreas by CD3+T lymphocytes, CD8+T lymphocytes, cytotoxic particle-associated RNA binding protein (TIA1+), granulase B+ and neutrophils is believed to be involved in the mechanism of ICIs-PI. This reaction leads to pancreatic cell damage, pancreatic acinar-duct metaplasia, decreased pancreatic function, and pancreatic atrophy ( Di Giacomo et al, 2009 ; Liu et al, 2021 ; Hirota et al, 2022 ). The study found that the co-suppressive immune checkpoint receptors CTLA-4 and PD-1 are closely related to the occurrence of acute pancreatitis ( Xie et al, 2021 ).…”