Identification of characteristic subepithelial surface granulomatosis in immune‐related adverse event‐associated enterocolitis

Abstract

Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune‐related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis‐like pattern and a graft vs host disease‐like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call “subepithelial surface granulomatosis” (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.

Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review

“…These results are consistent with the current literature, reporting the highest incidence in thoracic and mediastinal lymph nodes (92.9%), followed by the lungs (50%) and skin (10.7%) [8,23]. Other less frequently involved organs include the spleen and subepithelial surface granulomatosis observed in the colon [24][25][26].…”

Immunopathological basis of immune-related adverse events induced by immune checkpoint blockade therapy

“…Recently, we identified characteristic subepithelial surface granulomatosis (SSG) in the colon tissue of patients treated with ICIs [71]. In practice, it is helpful to adopt immunohistochemical staining for PD-L1 to identify granuloma cells, although they can be identified with ordinary hematoxylin and eosin staining (Figure 3(A)) [72].…”

Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors

“…3). Histopathologic patterns of ICI-induced colitis reported in the literature are summarized in Table 2 [20,22,23]. Chen et al [20] reported that histopathologic patterns of acute colitis with increased apoptosis and lymphocytic colitis are characteristic of ICI colitis.…”

“…Zhang et al [22] added 2 types of colitis, namely, collagenous colitis and apoptosis-only colitis. Furthermore, Kubo et al [23] reported that the histopathologic features of ICI colitis can be classified into 2 categories, ulcerative colitis-like colitis and graft-versus-host disease-like colitis. Based on these histologic characteristics, it can be concluded that ICI colitis is divided into acute colitis due to innate immunity and chronic colitis induced by alterations in acquired immunity.…”