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

Abstract

Context.— Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. Objectives.— To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. Data Sources.— Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. Conclusions.— The pathologic manifestations of CPI therapy–induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we here discuss the pathologic features and differential diagnosis of CPI therapy–induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy; and administration of steroids or other immunosuppressive agents, based on severity of injury.

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis

“…CD n (%) Control n (%) CD8 + T cells are the effectors of ICI anti-tumour effects, and high levels of CD8 + T cell infiltration in tumours before and during ICI treatment are associated with improved ICI efficacy [23]. The extent of CD8 + T cell mucosal infiltration in CIC reported in this study is comparable to heavy CD8 + T cell infiltration previously described in non-intestinal sites of autoimmune inflammation [24][25][26][27].…”

Pathologic Diagnosis of Nonalcoholic Fatty Liver Disease

“…The anti-PD-1 antibodies, such as nivolumab and pembrolizumab, have been successfully used to treat patients with multiple advanced malignancies. 25 The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied 25,27 but anti-PD-1 therapy-induced steatohepatitis has been reported by our group. 25 Specifically, a steatohepatitic pattern (Figure 2, D) of injury was observed in 1 of 8 cases in our study.…”

Novel and rare forms of oesophagitis

“…It should be noted that a lymphocyte-predominant oesophagitis can also be associated with the use of check-point inhibitor therapy. 70…”

“…Multiple studies have also demonstrated an association between smoking and the risk of LO, 58,61,69 although the underlying mechanism for this remains unclear. It should be noted that a lymphocyte‐predominant oesophagitis can also be associated with the use of check‐point inhibitor therapy 70 …”