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Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies.

抗PD-1抗体免疫治疗所致结肠炎的病理特征

Chen JH,Pezhouh MK,Lauwers GY,Masia R

Abstract

Programmed cell death protein 1 (PD-1) blocking agents are novel immunotherapeutics used for treatment of advanced-stage malignancies. They have shown promise in the treatment of several malignancies, with greater efficacy and better tolerability than cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents. However, as with anti-CTLA-4 agents, clinically significant colitis remains an important complication. Although there is growing awareness of the histopathologic features of anti-CTLA-4 therapy, there is little information on the pathologic features of anti-PD-1 colitis. We describe here the histopathologic findings in 8 patients who developed colitis while on anti-PD-1 monotherapy. The most common pattern of injury observed (5/8 cases) was an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis such as acute graft-versus-host disease or certain drug-induced colitides. The remainder of cases (3/8) showed a lymphocytic colitis-like pattern, characterized by increased intraepithelial lymphocytes and surface epithelial injury. Apoptosis was also often increased in these cases but crypt atrophy/dropout was not present. In patients who experienced recurrence of anti-PD-1 colitis, histologic features were similar to the initial insult but, in addition, features of chronicity developed that mimicked inflammatory bowel disease (basal lymphoplasmacytosis and crypt architectural irregularity, and Paneth cell metaplasia in 1 case). Awareness of the clinical scenario, however, should allow pathologists to suggest anti-PD-1 colitis. Interestingly, recurrent colitis was observed in patients who had been off anti-PD-1 therapy for many months. As anti-PD-1 agents are increasingly used in oncology, we present this series to increase awareness of anti-PD-1 colitis among pathologists, to facilitate its timely diagnosis and treatment.

摘要

程序性细胞死亡蛋白1(PD-1)抑制剂是用于治疗进展期恶性肿瘤的新型免疫疗法。在某些恶性肿瘤治疗上,它们显示出了比细胞毒性T淋巴细胞抗原4(CTLA-4)抑制剂具有更大疗效和更好耐受性的前景。然而,与抗CTLA-4抑制剂一样,临床上相当数量的结肠炎依然是一个重要的并发症。虽然对抗CTLA-4治疗导致的结肠炎病理特征认识增强,但是对于抗PD-1所致结肠炎的病理特征知之甚少。本文中,我们描述了8位接受抗PD-1单一治疗后发生结肠炎病人的病理发现。在观察的病例中(5/8例)最常见的损伤模式是活动性结肠炎伴有嗜中性粒细胞的隐窝微脓肿、显著的隐窝上皮细胞凋亡和隐窝萎缩/脱落。上述伴随特征可令人联想到其它伴有明显细胞凋亡的结肠炎,例如急性移植物抗宿主病或某些药物诱导性结肠炎。其余病例(3/8例)表现为一种淋巴细胞结肠炎样模式,以增加的上皮内淋巴细胞和表面上皮受损为特征。细胞凋亡在这些病例中也经常增多,但无隐窝萎缩/脱落。抗PD-1结肠炎复发的病人,其组织学特征与原发损害相似,除此之外,慢性进展的特点与炎症性肠病类似(基底部淋巴浆细胞增多、隐窝结构不规则,1例潘氏细胞化生)。对临床案例的认识,应该允许病理学家对抗PD-1结肠炎提出建议。令人感兴趣的是,观察病例中结肠炎复发的病人抗PD-1治疗已经结束数月。随着抗PD-1抑制剂越来越多地应用于肿瘤,我们提出该系列以求增加病理学家对抗PD-1结肠炎的认识,从而有助于及时诊断和治疗。


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