Histological Features of Celiac-Disease-like Conditions Related to Immune Checkpoint Inhibitors Therapy: A Signal to Keep in Mind for Pathologists.

Rachele Del Sordo,Illuminato Carosi,Paola Parente,Celeste Clemente,Vassilios Lougaris,Angelo Sidoni,Vincenzo Villanacci,Umberto Volta,Mattia Facchetti,Gabrio Bassotti

doi:10.3390/diagnostics12020395

Abstract

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, are finding increasing application in the treatment of malignant neoplasms. The widespread clinical use of these drugs, however, resulted in the discovery of side effects. The occurrence of celiac disease (CD) after ICIs therapy has been reported in the literature, but its incidence remains unknown and the role of ICIs in its onset is not yet clear. In this review, we examine the published data on this topic in order to better understand and define this entity from a histological point of view. We performed an electronic literature search to identify original reports in which CD or pathological CD-like conditions were documented histologically in patients treated with ICIs. We identified ten papers. A total of twenty-five patients were included in these publications, eleven of them receiving a serologic and histological diagnosis of CD, and four a histological diagnosis of CD-like conditions, in which pathogenesis appears to be multifactorial. ICIs can cause a CD-like enteropathy and biopsies with clinical integration are crucial to diagnose this condition. CD rarely has been observed during treatment with ICIs and its morphological aspects are similar to ICIs-CD enteropathy. Moreover, the onset of ICIs-CD may have a distinct immune mechanism compared to classical CD. Thus, the pathologists must make a histological diagnosis of CD with caution and only in adequate clinical and serological context.

Highlights

Biological therapy development in inflammatory bowel disease (IBD) has allowed for the identification of several novel compounds that can interfere with distinct immunological pathways [1,2]
We summarize celiac disease (CD) and CD-like histological features in patients with Immune checkpoint inhibitors (ICIs) therapy reported in the literature and comment on the possible immune-related pathogenic mechanisms in order to better understand the relationship between ICIs and the development of CD and CD-like alterations, including the histological diagnostic approach
Twenty-five patients were described in these publications with eleven of them receiving a diagnosis of CD confirmed by serological and histological assessment

Summary

Introduction

Biological therapy development in inflammatory bowel disease (IBD) has allowed for the identification of several novel compounds that can interfere with distinct immunological pathways [1,2] Among these compounds, immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, have been added to increasing treatment indications among patients affected by malignancies [3]. Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, have been added to increasing treatment indications among patients affected by malignancies [3] The rationale for their implementation in this setting originates from the observation that CTLA-4, PD-1, and PDL-1 are overexpressed in the tumour microenvironment, on tumour cells, and T cells intermingled with neoplastic cells [4]. The Food and Drug Administration has approved several monoclonal antibodies blocking CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab), and PDL-1 (atezolizumab, avelumab, durvalumab) for treatment of solid tumours, such as melanomas [6], non-small cell lung carcinoma [7], squamous cell carcinoma of the head and neck [8], urothelial carcinoma [9], gastroesophageal cancer [10], renal cell carcinoma [11], colorectal cancer with high microsatellite instability status (MSI-H) or mismatch repair deficient (MMRd) profile [12], hepatocellular carcinoma [13], classic Hodgkin’s lymphoma [14], and Merkel cell carcinoma [15]

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