ICIs, including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death-1 (PD-1) receptors/programmed cell death-Ligand-1 (PD-L1) antibodies, are used to enhance anti-tumor immunity by blocking immune checkpoint proteins and are used in the treatment of many types of tumors, which has significantly prolonged advanced tumor patients’ survival and fundamentally changed the existing treatment paradigm for tumor patients (1, 2). Immunotherapy for breast cancer (BC) has also made significant progress in recent years with the approval of various ICIs, especially in early-stage and metastatic TNBC (3). However, in addition to the remarkable efficacy, immune-related adverse events (irAEs) have been observed in 30-60% of patients treated with ICIs, involving almost any organ of the body, including the skin, gastrointestinal (GI) tract, liver, thyroid, heart, etc. (4) Here, we present a rare case of ICI-associated gastritis with extensive exfoliation of gastric mucosa triggered by Pembrolizumab.

The patient is a 44-year-old woman who was admitted to the hospital with “nausea and vomiting for more than 4 months”, accompanied by anorexia, upper abdominal pain, without obvious black stools or blood in the stool. She was diagnosed with TNBC 10 months ago, and was treated with totally 12 cycles of Pembrolizumab (the last dose was administered one month ago). She was diagnosed with Helicobacter pylori (Hp) infection but remained untreated for one year and had been diagnosed with psoriasis for many years. She denied any consumption of non-steroidal anti-inflammatory drugs (NSAIDs), alcohol, or narcotics, and she did not have a past history of diabetes mellitus or hypertension.

Physical examination showed vital signs were stable, only slight tenderness in the upper abdomen, but no rebound pain. Laboratory tests showed elevated alanine aminotransferase (161U/L, normal range 7–40 U/L), aspartate transaminase (222U/L, normal range 13-35U/L), Gamma-Glutamyl Transpeptidase (552U/L, normal range 7-45U/L), Alkaline phosphatase (546U/L, normal range 35-100U/L) and amylase in blood (249U/L, normal range 28-100U/L). Her blood sample was also tested positive for anti-Epstein-Barr(EB) virus chlamydial antigen(VCA) IgG and anti-EB virus nuclear antigen IgG, and an elevated concentration of EBV DNA (1.04×10⁴, normal value <4×10² copies/ml) was detected. The complete blood count, C-reactive protein (CRP) and carcinoma embryonic antigen levels were normal. She tested negative for human immunodeficiency virus (HIV). Abdominal computed tomography did not demonstrate thickening of the gastric wall or enlarged lymph nodes in the abdominal cavity ( Figures 1A, B ). Magnetic resonance cholangiopancreatography showed a slight widening of the upper part of the common bile duct with a tortuous course, but no definite obstruction was found. The first look of her esophagogastroduodenoscopy in our hospital is as shown in Figures 1C, D . Endoscopic biopsy of the stomach suggested that the vast majority of glandular components disappeared and were replaced by inflammatory granulation tissue, with lymphocytes and eosinophilic granulocytes infiltration. Immunohistochemistry showed that CD3, CD4 and CD8 were positive. Rapid urease test of the stomach tissue was positive; The Epstein-Barr encoding region in situ hybridization suggested scattered positive. Cytomegalovirus was not found in the stomach tissue.

Among gastrointestinal injuries of irAEs, ICI-associated colitis is one of the most commonly reported one. Statistically, 5%-40% of ICI-treated patients develop ICI-associated colitis, and patients often present with diarrhea, abdominal pain, fever, blood in the stool and other symptoms (10). Comparatively, the incidence of ICI-associated gastritis is relatively low, with several retrospective studies based on large samples reporting a prevalence of approximately 0.35%-1.46% (11, 12), but it can lead to serious complications, such as gastric hemorrhage.

The mechanism by which ICIs trigger irAEs is unclear. It may include: imbalance of immune tolerance, cross-antigen presentation, production of multiple cytokines, off-target effects, and alterations in the microbiota (13). Both cellular and humoral immunity are involved in the development of irAEs.

The onset of ICI-associated gastritis ranges from 2 weeks to 156 weeks after initiation of immune therapy, with a median interval of 29.3 weeks. Symptoms are varied, with nausea, vomiting, and abdominal pain as common manifestations, sometimes accompanied by bloating and dyspepsia (14). Gastroscopy is a reliable means of diagnosis and manifestations such as erythema, edema, and ulceration of the gastric mucosa can be observed (15). Histopathological examination usually observes diffuse inflammation characterized by plasma cells and granulocyte infiltration with abundant eosinophils, and concurrent crypt abscesses in the epithelium and lamina propria. Serological findings and abdominal CT scan are not specific. Clinical management for ICI-associated gastritis is based on individualized assessment of clinical parameters. In asymptomatic patients, a wait-and-see approach may be appropriate. Immunotherapy is usually discontinued after the development of gastritis of grade 2 and above. In a few cases of isolated gastritis, symptoms improved with proton pump inhibitor therapy alone. However, in most cases, steroids are the first-line empirical medication. Immunosuppressive agents, such as TNF-α inhibitors (e.g., infliximab) or integrin blockers (e.g., vedolizumab) (16, 17), may be used steroid-resistant gastritis if there is no improvement within 2 to 3 days after intravenous steroid administration (18).

Diffuse gastric inflammatory lesions in patients undergoing ICI therapy continue to underscore the need to consider potential diagnosis of ICI-associated gastritis. As the clinical use of ICIs expands further, clinicians need to pay more attention to this category of adverse events and be sufficiently vigilant to avoid irreversible consequences. Gastroscopy is recommended as a first-line diagnostic modality, with prompt pharmacological intervention once diagnosed.