Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

Abstract

Aims Immune checkpoint inhibitors (ICIs) improve survival across a range of malignancies but are also associated with a spectrum of gastrointestinal (GI) immune‐related adverse events (GI‐irAEs). The aims of this study were to explore the diagnostic value of gastric and duodenal biopsies and to address considerations in the differential diagnosis. Methods and results We identified 39 patients who were treated with ICIs and had a subsequent upper GI biopsy. We recorded clinical data and endoscopic findings, and reviewed their gastric, duodenal and colonic biopsies. Twenty‐one (54%) patients were treated with an anti‐programmed cell death protein 1 (PD‐1)/anti‐programmed cell death ligand 1 antibody alone, and 17 (44%) patients were treated with a combination of anti‐cytotoxic T‐lymphocyte‐associated protein‐4 and anti‐PD‐1 antibodies. Thirty‐two (82%) patients presented with diarrhoea. Gastric alterations included periglandular inflammation and granulomas, and duodenal changes included villous blunting, intraepithelial lymphocytosis, granulomas, and neutrophilic activity. We recognised four patterns of colonic injury: (i) acute self‐limiting colitis; (ii) lymphocytic colitis; (iii) collagenous colitis; and (iv) apoptosis‐only. Twenty‐nine (74%) and 10 (26%) patients were diagnosed clinically as positive and negative for GI‐irAEs, respectively. Gastric periglandular inflammation (P = 0.004) and an increased number of colonic lamina propria mononuclear cells (P = 0.04) correlated with the clinical diagnosis of a GI‐irAE. Histological alterations associated with ICI injury were more often identified in upper GI biopsies (71%) than in colonic biopsies (65%). Conclusions The morphological spectrum of ICI‐related GI disease is broad, and mimics a range of infectious and inflammatory diseases. Gastric periglandular inflammation represents one of the more characteristic histological features of GI‐irAEs. The study underscores the importance of a comprehensive review of upper and lower GI biopsies for the diagnosis of GI‐irAEs.

Morphological spectrum of immune check‐point inhibitor therapy‐associated gastritis

“…It must be emphasised that any empirical treatment prior to obtaining biopsies may alter the morphological appearance and make it much more difficult for pathologists to favour one diagnosis over another. A recent study included 39 patients on immune check‐point inhibitor therapy and clinically suspected GI irAE where gastric biopsies were available for review . Of these, 22 were reported as positive for mucosal ‘injury’ and granulomas were present in 31% of patients.…”

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

“…Upper gastrointestinal symptoms such as abdominal pain, nausea, and vomiting are relatively common for patients receiving CPI treatment. [12][13][14][15] However, histopathologic patterns of upper gastrointestinal tract (stomach and duodenum) CPI injury have not been well characterized until recently. [12][13][14][15] The most common abnormality reported on endoscopy is erythema followed by erosions.…”

Systematic review with meta‐analysis: effectiveness of anti‐inflammatory therapy in immune checkpoint inhibitor‐induced enterocolitis

“…For example, many studies included patients with any gastrointestinal symptom, 14,22,25,27,35,37,41,[60][61][62] while others were more stringent and only included patients exhibiting at least CTCAE grade 2 40,63,64 or 3 23,34 diarrhoea, endoscopic and/or histological evidence of inflammation, 16,33,42,44,[65][66][67] patients requiring corticosteroids 24,30 or having some response to immunosuppressive therapy. 68 Moreover, there was marked variation between studies Finally, in the subgroup analysis we included some studies where not all the study group belonged to the covariate being analysed. It may be argued that this may 'dilute' the true effect size, but reassuringly when we removed these studies and only analysed those that exclusively reported patients with melanoma, or a particular checkpoint inhibitor regimen there were no considerable differences in the response rate seen (data not shown).…”