Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies used for the treatment of advanced malignancies. Current ICPIs target two immune regulatory pathways: cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1) or its ligand (PD -L1).
Upon binding specific immune checkpoint proteins, ICPIs suppress the action of these checkpoints and enhance the T-cell mediated anti-tumor immune response. Unfortunately, this also leads to a wide spectrum of immunologically mediated inflammatory toxicities, collectively referred to as immune-related adverse events.
Gastrointestinal toxicities are among the most commonly encountered side effect of current ICPI therapy and show a wide spectrum of injury patterns. Colitis is the single most common form. It is more common with CTLA-4-blocking antibodies. Although colitis can present at any time during the course of ICPI therapy, it rarely develops within the first few days or years after the initiation of therapy. Gastrointestinal side effects in most cases are mild to moderate and transient. Three major histological patterns of colonic injury are well-recognized: active colitis, chronic active colitis, and microscopic colitis.
1. Acute colitis: In acute colitis, cryptitis, crypt abscesses with crypt epithelial atrophy (so-called atrophic crypt abscess), and expansion of lamina propria by inflammatory cells, including eosinophils, are the main findings. Increased crypt apoptosis occurs alone or, in 50% of cases, with active colitis. Crypt apoptosis and crypt abscess surrounded by atrophic crypt epithelia may help to distinguish ICPI-associated colitis from idiopathic inflammatory bowel disease (IBD). ICPI-associated acute colitis typically lacks the features of chronic mucosal injury such as basilar lymphoplasmacytosis or significant crypt architectural distortion.
2. Chronic active colitis: Features of ICPI-associated chronic active colitis include significant crypt architectural distortion, basilar lymphoplasmacytosis, and Paneth cell metaplasia, overlapping with those of IBD. Chronic active colitis is most frequently seen in patients on, naivolumab therapy.
3. Microscopic colitis: Microscopic colitis encompasses lymphocytic colitis and collagenous colitis that exhibit similar clinical presentations, and treatments. Unlike de nova microscopic colitis, ICPI-associated microscopic colitis shows mucosal abnormalities by endoscopy, and the patients are more symptomatic. Microscopically, ICPI-associated microscopic colitis may show changes deviating from the typical pattern of de novo microscopic colitis.
Although the histologic features of ICPI-associated colitis may vary among drug classes, the changes are largely nonspecific and can mimic other types of colitis. The main differential diagnosis for ICPI-associated colitis should include IBD, graft versus host disease, cytomegalovirus colitis, de novo microscopic colitis, celiac disease-related microscopic colitis, ischemic colitis, and other drug-induced colitis. Drug history is a critical component in the diagnostic workup. The history of malignant neoplasm is an important clue that should prompt a search for potential offending ICPIs.
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