Endoscopic insights into digestive-related adverse effects of immune checkpoint inhibitors: A narrative review

Abstract

Treatment with immune checkpoint inhibitors (ICIs) is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly. The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor, programmed cell death-ligand 1 receptor, and cytotoxic T lymphocyte antigen 4 receptor. The widespread utilization of ICIs over the past several years, however, is frequently accompanied by immune-related adverse events (irAEs) that substantially impact the patient’s quality of life, particularly those affecting the digestive system, including both the upper and lower gastrointestinal tract. Based on a literature search covering databases such as PubMed, Web of Science, Embase, and the Cochrane Library, we present an insight into primary gastrointestinal irAEs, with a special focus on endoscopic manifestations. Additionally, we analyze data regarding the pathogenetic mechanisms, diagnostic approaches, histological characteristics, and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.

Key Words: Immune checkpoint inhibitors; Gastrointestinal tract; Endoscopy; Immune-related adverse events; Toxicity; Colitis; Enteritis; Gastritis

Core Tip: Inflammation of the gastrointestinal tract following immune checkpoint inhibitor administration is a frequently encountered adverse event that can significantly impact both the quality of life of the oncology patients and the overall efficacy of cancer therapy. Currently, standardized endoscopic protocols for the diagnosis and longitudinal monitoring remain unavailable. A comprehensive understanding of the macroscopic features and distinct inflammatory patterns during the endoscopy of the digestive tract is essential for the early and accurate diagnosis, contributing to the optimization of therapeutic strategies and clinical outcomes for patients with immune-related adverse events.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) are increasingly becoming the standard of care as a therapeutic modality for patients with specific types of malignancy, offering a distinct mechanism of action compared to conventional oncologic treatments. By modulating immune responses and enhancing tumor-specific T-cell pathway activation, agents such as programmed cell death-1 (PD-1) receptor, programmed cell death-ligand 1 (PD-L1) receptor, and cytotoxic T lymphocyte antigen 4 (CTLA-4) receptor inhibitors have demonstrated significant antitumor efficacy. However, their widespread application in clinical practice has been accompanied by an increasing incidence of immune-related adverse events (irAEs), resulting from T-lymphocyte activation against healthy tissues, thereby eliciting inflammatory responses across multiple organ systems. Among these, gastrointestinal (GI) involvement, particularly the lower digestive tract, constitutes one of the most frequently documented irAEs associated with ICIs. The incidence of these adverse effects continues to rise in parallel with the expanding use of ICIs in oncologic practice. Therefore, we performed a comprehensive literature review to evaluate the endoscopic manifestations of GI irAEs. Additionally, we analyzed the existing evidence regarding their underlying pathophysiological mechanisms, histopathologic features, and currently available therapeutic strategies, aiming to enhance the understanding and management of these immune-related toxicities.

PATHOPHYSIOLOGY

Although the precise pathogenetic mechanisms underlying irAEs triggering GI toxicity are not yet completely understood, the fundamental immunological processes involved appear similar at the molecular level for both the upper and lower digestive tract. Current research aims to clarify these mechanisms, investigating the role of the specific receptors targeted by ICIs and their particular role in the immune response[1].

The CTLA-4 receptor, expressed on regulatory T cells (Tregs), interacts with the integral membrane proteins cluster of differentiation (CD) 80 and CD86 on antigen-presenting cells to inhibit T cell activation[2]. Under regular conditions, Tregs become capable of restraining inflammatory responses, thereby maintaining immune homeostasis[3]. Blocking of the CTLA-4 receptor effectively “releases the brake” on the immune response, leading to increased production of CD4+ and CD8+ T cells with subsequent cytokine release, triggering an inflammatory response[4]. The PD-1 receptor is a membrane-bound protein on T cells associated with immune signal transduction and facilitates intercellular communication. Interacting with the transmembrane ligand PD-L1 inhibits the T cell receptor and CD28, an important co-receptor for the complete T cell activation[5]. PD-L1 receptor expression is found in almost all types of tumors, B and T cells, dendritic cells, and macrophages. Consequently, immune therapies targeting PD-1/PD-L1 aim to interfere with this interaction, thereby enhancing immune activation targeted towards cancer cells. However, the parallel widespread immune activation can trigger tissue inflammation, contributing to immune-related inflammatory events in the upper and lower digestive tract[6].

IRAES

Regardless of the advantages that ICIs offer against certain types of malignancies, they can excessively activate the immune system, resulting in a spectrum of adverse events that range from mild skin reactions to potentially fatal cardiac events[7]. It is estimated that a significant proportion of patients receiving ICI will experience some form of irAEs, with a small subset developing severe complications[8]. The frequency and severity of these side effects differ among various immune checkpoint therapies[9]. Moreover, combination regimens involving anti-CTLA-4 and anti-PD-1 for the treatment of patients with advanced melanoma were associated with a higher incidence of irAEs, often presenting longer and with greater severity[10].

The effectiveness of ICIs in targeting cancer cells has been widely studied; conversely, the immunological mechanisms underlying irAEs remain partially understood. Current investigations focus on pathways resulting in immune cell profile alterations, intraepithelial lymphocyte infiltration, B cell activation with consequent antibody production, and a cascade of pro-inflammatory cytokines as the main pathogenetic mechanisms[11,12]. The adverse events correlated with ICIs display significant heterogeneity and may implicate numerous organs simultaneously[13]. Common manifestations encompass dermatologic reactions, respiratory system involvement, GI symptoms, and disruption of the endocrine glands, such as the onset of type 1 diabetes mellitus, adrenal insufficiency, or hypothyroidism[14]. Therefore, comprehensive patient monitoring with clinical and laboratory evaluation for instant symptom identification is recommended[15]. In certain instances, more severe adverse events may emerge, including colitis, hepatitis, pancreatitis, pneumonitis, and occasionally myocarditis and hypophysitis[16].

Adverse events occurring during the treatment session are classified as acute, while those emerging at the end of the treatment are considered delayed. Events persisting beyond 12 weeks after therapy discontinuation are classified as chronic, with manifestations from the musculoskeletal and endocrine systems commonly distinguished in this category[17].

GI IRAES

Ranking as the second most frequent irAEs coming after dermatological events, digestive-related manifestations as a consequence of ICI toxicity[18], potentially involve not only the upper and lower GI tract but also the liver, pancreas, and biliary system[19,20]. The severity of each event is assessed using the Common Terminology Criteria for Adverse Events (CTCAE) established by the United States National Cancer Institute, which employs a grading scale ranging from 1 to 5[21]. Diagnosing GI irAEs necessitates a comprehensive approach, including blood and fecal samples analysis to rule out other infectious or inflammatory potential causes, alongside clinical evaluation and endoscopic investigation[22,23]. While radiological imaging is not routinely the gold-standard diagnostic tool for luminal GI adverse events due to its low negative predictive value, it serves a fundamental role in excluding complications, like bowel perforation[24], and in evaluating the pancreas and hepatobiliary system in circumstances of suspected drug toxicity[25,26] (Figure 1).

Figure 1  Main endoscopic features of immune-related adverse events of checkpoint inhibitors in the digestive system.

UPPER GI TRACT

Clinical manifestations

Clinical manifestations from the upper GI tract display a wide variation, with epigastric pain and vomiting being the most frequently reported symptoms[27,28]. Additional symptoms may encompass early satiety, nausea, weight loss, and in infrequent cases dysphagia, hematemesis, and melena. These symptoms can be secondary due to immune toxicity of the esophagus, stomach, duodenum, and small bowel mucosa[29]. The onset of these symptoms typically ranges from a few weeks to months after immunosuppressive therapy initiation[30]. The precise role of upper GI endoscopy, as well as the optimal timing of its performance following symptom onset, has not been fully defined and is often guided by local or national diagnostic protocols. Nevertheless, esophagogastroduodenoscopy (EGD) serves as a valuable diagnostic tool, contributing to the objective documentation of inflammation, mapping of the affected areas of the upper digestive tract, and assessment of disease severity[29]. Table 1 presents the most common upper digestive tract symptoms associated with the use of ICIs categorized by severity according to the CTCAE criteria (Table 1).

Table 1 Classification of upper gastrointestinal symptom severity according to the Common Terminology Criteria for Adverse Events.

Condition	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Abdominal pain	Mild pain	Moderate pain; Limiting instrumental ADL	Severe pain; Limiting self-care ADL
Dysphagia	Symptomatic, able to eat a regular diet	Symptomatic and altered eating or swallowing	Severely altered eating/swallowing; Tube feeding, TPN, or hospitalization indicated	Life-threatening consequences; Urgent intervention indicated	Death
Vomiting	Intervention not indicated	Outpatient IV hydration; Medical intervention indicated	Tube feeding, TPN, or hospitalization indicated	Life-threatening consequences	Death
Upper GI hemorrhage	Mild symptoms; Intervention not indicated	Moderate symptoms; Intervention indicated	Transfusion indicated; Invasive intervention indicated; Hospitalization	Life-threatening consequences; Urgent intervention indicated	Death

GI: Gastrointestinal; ADL: Activities of daily living; IV: Intravenous; TPN: Total parenteral nutrition.

Esophagus

Endoscopic features: Endoscopic findings from the esophagus have not been extensively described in the literature, mainly due to their low incidence, with the available data largely derived from isolated case reports. The clinical and endoscopic presentation exhibits considerable heterogeneity in both the anatomical distribution and morphological features[31]. Reported lesions have been described throughout the entire esophagus, from the proximal to the distal part, as well as at the gastroesophageal junction (GEJ). The findings are nonspecific and include mucosal edema, diffuse erythema, mucosal erosions, linear or circumferential ulcers with or without luminal narrowing, and inflammation of the GEJ[31-34]. Additionally, one case report has described inflamed mucosa that may be misinterpreted as Barrett’s esophagus[35], while another report has documented fibrotic stenosis of the GEJ[36], both of which occurred following the use of PD-1 inhibitors. Although esophageal inflammation does not always present with the characteristic endoscopic appearance of classic reflux esophagitis, the Los Angeles classification system can be used to describe the extent of the affected mucosa[31].

Histopathological findings: The scarce histological data on esophageal lesions associated with ICI therapy indicate two predominant pathological patterns. The first involves lymphocytic inflammation, characterized by infiltration of the squamous epithelium primarily by CD3+ lymphocytes, with or without the presence of apoptotic keratinocytes[37,38]. The second pattern is marked by acute inflammation with neutrophil predominance, ulceration, and granulation tissue formation[31,39].

These histopathological findings are derived from a limited number of case reports, lack specificity, and are insufficient for establishing a definitive diagnosis, as comparable mucosal alterations can be observed in other pathological conditions. Consequently, the differential diagnosis should consider disorders that cause lymphocytic or ulcerative esophagitis, including inflammatory bowel disease (IBD), radiation-induced and gastroesophageal reflux esophagitis, as well as infectious conditions, in particular, herpes simplex virus and cytomegalovirus (CMV) infections[40].

Stomach

Endoscopic features: Endoscopic evaluation in patients presenting with upper digestive tract-related symptoms following ICI therapy reveals a diverse range of unspecific findings, varying in both presentation and severity. In mild cases, endoscopic features typically include slight mucosal erythema and edema while lesions, such as gastric erosions and ulcers, may also be observed[41].

In a systematic review of observational studies involving 258 patients with ICI-associated gastritis, Su et al[42] demonstrated that mucosal erythema was the most prevalent endoscopic finding, observed in approximately 56% of patients, followed by mucosal edema and erosions. In severe cases of gastritis, reported findings from Sugiyama et al[43] include diffuse erythema, gastric mucosal friability with deep ulcers and hemorrhages as characteristic endoscopic features. However, these findings were based on a limited sample of 4 patients. Necrotizing gastritis can occur in uncommon instances. Notably, normal endoscopic appearance may be exhibited in a handful of cases despite symptomatic presentation, necessitating histopathological evaluation for the diagnosis of gastritis[44].

Histopathological findings: Histopathological findings from gastric biopsies are often nonspecific and exhibit variability, making differentiation from other conditions remarkably challenging due to microscopic resemblance[45]. As previously mentioned, histologic inflammatory changes can also be observed in patients with completely normal endoscopic appearance. Common histopathological findings consist of chronic inflammatory response characterized by lymphoplasmacytic infiltration of the lamina propria[46], increased number of intraepithelial neutrophils, and, occasionally, formation of neutrophilic glandular abscesses[47]. Additionally, non-caseating granulomas and peri-glandular inflammation can occur, complicating the distinction between Crohn’s disease with gastric involvement[48].

Given these overlapping features, a comprehensive differential diagnosis combining clinical, endoscopic, and histological findings is essential. Diseases such as Helicobacter pylori, lymphocytic, and infectious gastritis, particularly those associated with CMV and Epstein-Barr virus, should be carefully evaluated. Crohn’s disease must also be considered, especially in cases where granulomas are present[40].

Duodenum

Endoscopic features: Endoscopic data on duodenal inflammation in patients with irAEs following ICI therapy are primarily derived from case series and case reports. Duodenal involvement may manifest as an isolated finding or occur alongside concurrent gastritis[49]. Common endoscopic features include diffuse or patchy erythema, erosions, mucosal friability, and ulcers of varying sizes[32,47]. In individual instances, pseudopolyp formation[50] and characteristics of hemorrhagic duodenitis have also been described[51]. Finally, hyperemic mucosa has also been reported in a rare case of a neonate following in-utero exposure to ICIs[52].

Histopathological findings: The histopathological alterations observed in ICI-related duodenitis closely resemble those of celiac disease, posing a significant diagnostic challenge. This complexity is further exacerbated by case reports of ICI-induced de novo celiac disease, characterized by the presence of tissue transglutaminase antibodies and clinical remission following the initiation of a gluten-free diet[53,54]. Microscopic investigation typically reveals villous blunting accompanied by neutrophilic infiltration of the villi. Additionally, expansion of the lamina propria with infiltrating lymphocytes, plasma cells, and occasionally neutrophils are frequent findings. The primary histopathological distinction between ICI-related duodenitis and celiac disease lies in the presence of an acute inflammatory mucosal response with neutrophilic infiltration, a feature that is not characteristic of celiac disease[46,47].

LOWER GI TRACT

Clinical manifestations

The GI tract, particularly the lower segment, is the most frequently affected system in irAEs associated with ICI treatment[55]. In a meta-analysis encompassing 8863 patients, Wang et al[56] reported that the incidence of all-grade colitis resulting from CTLA-4 blockade was approximately 9.1%, while inhibitors of PD-1 and PD-L1 were associated with lower incidences of 1.4% and 1.0%, respectively. Furthermore, the combination of PD and CTLA-4 inhibition resulted in a higher incidence of all-grade colitis, reaching up to 13.6%, suggesting that combination therapy or the use of CTLA-4 inhibitors is more likely to induce lower GI symptoms.

Tran et al[57], in a more recent meta-analysis involving a total of 12661 patients, presented that the highest incidence of all-grade diarrhea occurred in patients treated with combination strategy, reaching 24.1%. A similarly high incidence was observed in patients receiving CTLA-4 inhibitor treatment, with a rate of 20.1% contrary to inhibition of the PD-1 axis that was associated with significantly lower incidence, at 4.1%.

Symptom onset from the lower GI tract can occur within weeks to months after treatment initiation, with a maximum reported delay of up to one year, particularly following anti-PD-1 therapy[58]. The predominant symptom of lower GI irAEs is watery diarrhea, frequently accompanied by fecal urgency and abdominal pain[59,60]. Additional symptoms, including nausea, fever, rectal bleeding, and proctalgia, are reported less frequently and often coexist with diarrhea[61]. Fatal complications, such as colonic perforation and death, are rare[62,63]. In severe cases, symptoms can become debilitating, with patients experiencing stool frequency exceeding 20 episodes per day. Symptom severity is evaluated using the CTCAE grading system (Table 2), which considers stool frequency, abdominal pain intensity, and the presence of inflammatory diarrheas, with mucus and blood in the stool[64].

Table 2 Classification of lower gastrointestinal symptom severity according to the Common Terminology Criteria for Adverse Events.

Condition	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Anal pain	Mild pain	Moderate pain; Limiting instrumental ADL	Severe pain; Limiting self-care ADL
Colitis	Asymptomatic; Clinical or diagnostic observations only; Intervention not indicated	Abdominal pain; Mucus or blood in stool	Severe abdominal pain; Peritoneal signs	Life-threatening consequences; Urgent intervention indicated	Death
Diarrhea	Increase of < 4 stools per day over baseline; Mild increase in ostomy output compared to baseline	Increase of 4-6 stools per day over baseline; Moderate increase in ostomy output; Limiting instrumental ADL	Increase of ≥ 7 stools per day over baseline; Hospitalization indicated; Severe increase in ostomy output; Limiting self-care ADL	Life-threatening consequences; Urgent intervention indicated	Death
Upper GI hemorrhage	Mild symptoms; Intervention not indicated	Moderate symptoms; Intervention indicated	Transfusion indicated; Invasive intervention indicated; Hospitalization	Life-threatening consequences; Urgent intervention indicated	Death

GI: Gastrointestinal; ADL: Activities of daily living.

Small intestine

Endoscopic features: The anatomical challenge of accessing the small intestine beyond the Treitz ligament significantly limits the possibility of rapid endoscopic evaluation in patients presenting with symptoms suggestive of inflammation following ICI therapy. Consequently, corticosteroid treatment is often initiated empirically, restricting therapeutic assessment to clinical response rather than direct visualization of mucosal changes.

So far, only a small number of case reports have documented small bowel lesions detected through endoscopic imaging in patients with symptoms and negative findings on EGD and colonoscopy. These reports describe nonspecific mucosal findings, including mucosal atrophy, erosions, ulcers, and diffuse erythema affecting both the jejunal and ileal regions[65-68].

Additionally, a prospective observational study by Shimozaki et al[69] investigated intestinal involvement in 23 asymptomatic patients who underwent panenteric capsule endoscopy eight weeks after initiating ICI therapy. The study identified mucosal abnormalities in eight patients, including edema, ulcers, and erosions in the jejunum and/or ileum, highlighting the potential for subclinical small bowel involvement in this patient population.

Histological findings: To date, histological data from small bowel biopsies, apart from those obtained from the terminal ileum, remain unreported in the literature for patients with ICI-related inflammation of the jejunum and/or ileum. The only available pathologic findings are derived from resected segments of the small intestine, which have demonstrated nonspecific lesions, including erosions, mucosal ulcerations, lymphocytic and polymorphonuclear infiltration of the lamina propria, and architectural distortion[70,71].

Terminal ileum

Endoscopic features: The terminal ileum represents a distinct site of involvement in ICI-induced inflammation, as it is part of the lower GI tract that is easily accessible via ileocolonoscopy. Inflammation of the terminal ileum most commonly occurs in conjunction with extensive or right-sided colonic involvement[72,73], whereas isolated terminal ileitis is a rare finding on colonoscopy[74,75]. A unique case in which terminal ileum inflammation resulted from reactivation of tuberculosis following ICI therapy in a patient with nasopharyngeal carcinoma has also been reported in the literature[76].

Data derived from two retrospective studies involving patients with lower GI symptoms following treatment with CTLA-4 inhibitors indicate that individuals with inflammatory involvement of the terminal ileum often present with nonspecific endoscopic findings, including ulcerations, mucosal edema, and diffuse erythema[77,78] (Figure 2A). However, these findings are based on limited patient cases, and the available data remain sparse. Larger observational studies and meta-analyses are required to provide a more comprehensive understanding of the small bowel manifestations following ICI therapy.

Figure 2 Endoscopic features of immune checkpoint inhibitor-related inflammation. A: Terminal ileum with mild mucosal erythema and formation of superficial aphthous ulcerations; B: Mild colitis: Diffuse mucosal erythema with decreased vascular pattern; C: Moderate colitis: Marked erythematous, edematous, and friable mucosa with scattered superficial ulcerations, and loss of the vascular pattern; D: Severe colitis: Extensive mucosal ulceration with fibrin coating, absence of colonic haustration, complete obliteration of the vascular pattern, and fibrin deposition.

Histopathologic findings: Histopathological analysis of terminal ileum biopsies reveals lesions similar to those observed in other regions of the small intestine. The most frequently reported microscopic findings include villous blunting, neutrophil-predominant inflammation, increased intraepithelial lymphocytosis, and lamina propria expansion. These findings are largely nonspecific and may overlap with other inflammatory conditions of the small bowel[79].

Colon

Endoscopic features: During an ileocolonoscopy, a broad spectrum of inflammatory lesions can be observed in patients with suspected ICI-related colitis, ranging from normal-appearing mucosa to severe inflammation[80]. Endoscopic findings often include features commonly associated with IBD, such as diffuse mucosal ulcerations[81] or solitary superficial and deep ulcers[82]. Moreover, a non-ulcerative inflammatory pattern characterized by erythema, erosions, mucosal edema, exudates, loss of vascular pattern, and mucosal friability is commonly distinguished[83,84] (Figure 2B-D). Inflammatory changes may present as either segmental or diffuse involvement of the colonic mucosa[85]. ICI-related colitis predominantly affects the left colon, making sigmoidoscopy a valuable diagnostic tool. In contrast, isolated right-sided colonic inflammation is rare[86]. However, a significant proportion of patients exhibit extensive colonic involvement on endoscopy, which may be underestimated if only the left colon is assessed[87,88].

Histological findings: Histological examination of biopsy samples reveals significant heterogeneity, encompassing multiple distinct inflammatory patterns. These patterns exhibit varying types of colonic mucosal inflammation, with some of them closely resembling the histological features of IBD or microscopic colitis, making differentiation challenging[89-91]. In Table 3 we summarize all the various histological types and their associated characteristics. Proper diagnosis requires both experience and comprehensive interpretation of microscopic findings given the overlapping histological features among various conditions such as IBD, colonic infections, drug-induced colitis, and de novo microscopic colitis[92].

Table 3 Histopathological characteristics of inflammatory patterns in biopsies from patients with immune checkpoint inhibitor-associated colitis.

Histopathological pattern	Histopathological features
Active inflammation	Neutrophil epithelial infiltration, cryptitis, crypt abscess formation, with or without mixed-cell infiltration of the lamina propria
Chronic active inflammation	Basal lymphoplasmacytosis, crypt architectural distortion, paneth cell metaplasia, cryptitis and/or crypt abscess formation
Microscopic colitis	Lymphocytic type with lymphocytic epithelial infiltration, lymphoplasmacytic lamina propria expansion or collagenous type with thickened subepithelial collagen layer
Mixed type	Combined features from the aforementioned categories

THERAPEUTIC INTERVENTIONS

A standardized treatment protocol for GI irAEs has yet to be established. In early 2021, the American Gastroenterological Association, in an expert review of the existing literature acknowledged that the evidence for managing ICI-associated enterocolitis was limited. The management strategies stated in this clinical practice guideline were predominantly based on retrospective analyses and case series[93]. In 2023, a Belgian consensus outlined a comprehensive treatment strategy for managing patients with colitis. However, evidence remains limited regarding the optimal duration of therapy, the transition between biological agents, and the management of potential colitis relapse[94]. This underscores the urgent need for large-scale prospective studies for the development of a universally accepted treatment protocol.

At the onset of GI symptoms, it is imperative to exclude other potential etiologies, with infectious causes being the most prevalent, to facilitate an early diagnosis of irAEs and initiate appropriate therapeutic interventions. For patients with mild symptoms, conservative management remains the first-line approach, including adequate hydration, dietary modifications, and supportive pharmacotherapy with agents such as loperamide or antispasmodics[95].

Notably, in cases where ICI-induced microscopic colitis is suspected or diagnosed, a conventional therapeutic strategy with approximately eight weeks of budesonide has demonstrated good efficacy[96].

In instances of more severe diarrhea accompanied by features indicative of inflammatory colitis, corticosteroid therapy is recommended in close collaboration with a gastroenterologist[97]. For cases classified as moderate, oral administration of prednisolone at a dosage of 1-2 mg/kg is generally sufficient, whereas severe presentations may necessitate hospitalization and intravenous corticosteroid administration[93].

For patients exhibiting steroid-refractory colitis or non-responders to initial therapy, treatment escalation with biologic agents, with infliximab, in a dose of 5 mg/kg is advised. Infliximab has been associated with higher response rates and faster symptom resolution, typically requiring no more than three infusions in most cases[98,99].

Emerging evidence from two case series, involving a total of 35 patients, supports the efficacy of vedolizumab, administered at a dose similar to that used in patients with IBD, either as a first or second-line biologic agent following anti- tumor necrosis factor-α[100,101]. Additionally, favorable outcomes have been reported with alternative therapeutic modalities, including tofacitinib[102], ustekinumab[103], and, in selected cases, fecal microbiota transplantation[104,105], although all the data are derived from case reports. Given the absence of a universally accepted treatment protocol, the establishment of standardized management strategies remains a priority to optimize patient outcomes and ensure high-quality care for individuals affected by ICI-induced GI toxicity.

CURRENT CHALLENGES AND FUTURE DIRECTIONS

ICI therapy has revolutionized the field of oncology, providing substantial survival benefits across a wide range of malignancies. However, as with any novel therapeutic approach, the emergence of adverse events presents a major clinical challenge. The biggest challenge is the early identification and prevention of severe irAEs while ensuring optimal oncological outcomes. This challenge has prompted extensive research into predictive biomarkers that can assess the risk of adverse events and the patient’s response to treatment.

GI-related irAEs constitute a particularly significant subset due to their high incidence and high impact on patient quality of life. The lack of well-established guidelines for early detection, monitoring, and management complicates clinical decision-making. Endoscopic evaluation with EGD and ileocolonoscopy remains the cornerstone for diagnosing and assessing these complications. However, inflammatory changes induced by ICI therapy may occur even in patients with normal-appearing mucosa on endoscopy, making diagnosis more complex. Consequently, obtaining biopsies during endoscopy is essential for detecting microscopic inflammation, characterizing its pathological features, and distinguishing it from other inflammatory GI disorders[106].

Moreover, the absence of a standardized classification system for ICI-induced GI inflammation limits the consistency of diagnostic and treatment strategies. In cases of ICI-related colitis, the European Society for Medical Oncology has proposed an endoscopic classification based on observed findings. The three distinct types include IBD-like colitis, which is further categorized into ulcerative colitis-like and Crohn’s disease-like subtypes, IBD-like colitis of an unclassified nature, and microscopic colitis, either lymphocytic or collagenous[107] (Figure 3). However, a universally accepted scoring system for assessing the severity of inflammation during endoscopic evaluation remains unavailable, creating barriers to both initial assessment and longitudinal monitoring. Existing scoring systems, such as the Mayo score and ulcerative colitis endoscopic index of severity for ulcerative colitis-like colitis, as well as the simple endoscopic score for Crohn’s disease for Crohn’s disease-like colitis, have been utilized[108]. Nevertheless, the endoscopic features of ICI-induced colitis exhibit considerable variability, yet frequently resemble those seen in classical IBDs, highlighting the necessity of a disease-specific endoscopic classification.

Figure 3  European society for medical oncology classification of immune checkpoint inhibitor-associated colitis based on endoscopic and/or histological findings.

Establishing standardized endoscopic assessment methodologies and biopsy protocols is imperative to advance the field. Such standardization will enhance the understanding of ICI-induced GI toxicity at macroscopic and microscopic levels, ultimately facilitating early and accurate diagnosis. This, in turn, will enable the timely initiation of appropriate therapeutic interventions, thereby improving patient outcomes in managing ICI-related GI complications.

CONCLUSION

GI involvement is a frequent irAE associated with ICI therapy, presenting with symptoms that vary widely in both presentation and severity. These adverse events significantly impact the quality of life of oncology patients, limiting concurrently the extent to which they can continue with a potentially life-saving or life-prolonging treatment. To date, the CTCAE remains the most widely utilized tool for classifying clinical manifestations affecting the GI tract. For cases of moderate or greater severity, classified as grade 2 to 4 according to the CTCAE, endoscopic evaluation is recommended before the initiation of anti-inflammatory treatment. Simultaneously, a comprehensive diagnostic workup should be undertaken to exclude alternative etiologies, thereby facilitating the timely identification of irAEs. The endoscopic manifestations of GI irAEs exhibit considerable heterogeneity, often making differentiation from other inflammatory conditions challenging based on macroscopic findings alone. Moreover, microscopic inflammation may be present even in cases where endoscopic examination reveals no apparent abnormalities, highlighting the necessity of obtaining biopsies for accurate diagnosis. The absence of standardized diagnostic criteria, biopsy protocols, and established endoscopic monitoring classifications further complicates clinical decision-making. Given the critical need to optimize both the overall survival and quality of life of oncology patients receiving ICI therapy, we emphasize the pivotal role of endoscopic assessment in the early and accurate diagnosis of GI irAEs. A structured approach to recognizing endoscopic and histopathological features will facilitate appropriate management strategies, ultimately improving patient outcomes. Overall, large-scale prospective studies are required in the future to generate data essential for the development of clinical practice guidelines addressing the management and follow-up of patients with ICI-associated GI irAEs.

ACKNOWLEDGEMENTS

The authors would like to express their sincere gratitude to all the patients who provided their oral and written consent to publish their endoscopic findings. Their generous cooperation has significantly contributed to the completion of this manuscript. The authors also express their gratitude to Svedman FC, Senior Consultant in the Department of Oncology and Pathology at Karolinska University Hospital, Stockholm, Sweden, and researcher at Karolinska Institutet, Stockholm, Sweden, for her significant contributions to the writing of our local guidelines for the management of ICI-associated colitis, in collaboration with the Centre for Digestive Health, and co-authors Strid H and Bresso F.