In Search of a Histopathological Pattern of Immune-Mediated Gastritis from Nivolumab Therapy: A Case Report with Literature Review

A B S T R A C T

Immunotherapy with checkpoint inhibitors is associated with termed inflammatory and immune-related side effects (irAE). Upper gastrointestinal symptoms are infrequent and appear mainly in patients on combination therapy with two checkpoint inhibitor drugs. We present the case of a patient with IIIB stage cutaneous melanoma treated with Nivolumab in monotherapy who developed an immune-mediated gastritis. Histopathologically, due to the paucity of published cases, no specific pattern of Nivolumab-immune-mediated gastritis has been described. We have reviewed the literature and compared the histopathology of the cases available in the literature.

Keywords

Checkpoint inhibitors, immune-mediated gastritis, histopathological pattern

Introduction

Immunotherapy with checkpoint inhibitors is increasingly used as an oncological treatment and has improved the prognosis in several types of cancer. Despite important clinical benefits, checkpoint inhibition is associated with termed inflammatory and immune-related side effects (irAE), including dermatologic, gastrointestinal, hepatic and endocrine events. Upper gastrointestinal symptoms are infrequent and appear mainly in patients on combination therapy with two checkpoint inhibitor drugs. We present the case of a patient with IIIB stage cutaneous melanoma treated with Nivolumab in monotherapy who developed abdominal pain and nausea, compatible with immune-mediated gastritis.

Case Report

A 59-year-old male under follow-up by the dermatology department for IIIB stage cutaneous melanoma in the frontal region with Nivolumab since November 2019. In May 2020, the patient presented with occasional abdominal pain unrelated to ingestion, without vomiting, but with hyporexia and a weight loss of about 2 kg in the prior 3 weeks. Physical examination revealed pain and nausea on palpation in the epigastrium. Laboratory tests showed no elevation of acute phase reactants or other significant findings. During treatment with Nivolumab, the patient presented clinical stability with mild symptoms that only partially subsided with symptomatic treatment. After completing the immunotherapy, and as part of the oncological pathology follow-up, a PET-CT scan was performed in January 2021, which showed a slight diffuse increase in metabolic activity on the gastric walls, especially significant in the walls of the antral region (SUVmax 13.85), and which appeared to be associated with a narrowing of the lumen. The study was completed with a gastroscopy in which an erythematous antral mucosa with a thickened appearance and cobblestone pattern was observed, with no other macroscopic lesions at the level of the body or fundus.

Pathology showed lymphocytic gastritis with the presence of relevant intraepithelial T-type lymphocytosis, mostly CD8 positive (Figures 1A & 1B) with neutrophilic activity and occasional karyorrhexis (Figure 2). No intestinal metaplasia, bacilli or nuclear positivity for EBV by in situ hybridisation was observed. Although no malignant cells had been observed with morphological techniques, an immunohistochemical study was requested due to the patient’s history (S100, Melan A, HBM45), which was negative. In addition, tissue transglutaminase analysis was requested to rule out lymphocytic gastritis in the atypical context of coeliac disease, which was negative. Based on these findings, the diagnosis was lymphocyte-mediated gastritis secondary to the checkpoint inhibitor, which persisted two months after the end of treatment. A new control gastroscopy was performed in March 2021, showing an image compatible with antral predominant gastritis that anatomopathologically corresponds to chronic superficial gastritis, with no other characteristics suggestive of immune-mediated gastritis. At the follow-up visit, the patient reported clear clinical improvement, without abdominal pain or nausea and with weight gain.

Figure 1: A) Gastric mucosa with lymphocytic gastritis affecting foveolar epithelium. Hematoxylin-eosin. Magnification 100x. B) Gastric mucosa with lymphocytic gastritis CD8 positive. Immunohistochemistry CD8 antibody. Magnification 100x.

Figure 2: High power view of the inflammatory cells showing diffuse lymphocytosis (arrow heads) and also neutrophilic focal activity (arrows) and occasional karyorrhexis. Hematoxylin-eosin. Magnification 400x.

Discussion

Immunotherapy with immune checkpoint inhibitors has revolutionised cancer treatment in the last decade, improving prognosis in several types of cancer, including - as with the case presented here - cutaneous melanoma. Despite significant clinical benefits, these treatments are associated with inflammatory and immunological side effects (irAEs), including dermatological, gastrointestinal, hepatic and endocrine effects [1, 2]. Side effects in the upper gastrointestinal tract may be present even if patients do not express any symptoms [3]. A study of enterocolitis in 39 patients treated with immunotherapy showed that 9 of 22 patients in whom gastroscopy was performed had coexisting gastritis, although it is not specified whether they had symptoms [4]. In the specific case of anti-PD-1s, including Nivolumab, the incidences of decreased appetite, nausea and abdominal pain were 2.5%-13.6%, 7.0%-16.5% and 2.7%, respectively, in patients with non-gastrointestinal cancers [5]. There are very few cases reported in the literature describing gastritis as a side effect of Nivolumab monotherapy. The median time to onset of symptoms is 6-7 weeks from initiation of therapy, but the timeline can vary, with some reports of up to 6 months, such as the case described by Justin Boike and Todd Dejulio, and in the case presented here (7-month lag) [6].

Histopathologically, due to the paucity of published cases, no specific pattern of Nivolumab-immune-mediated gastritis has been described. In the present case, the gastritis is notable for its lymphocytic pattern with intraepithelial CD8 T-type lymphocytosis accompanied by neutrophilic activity and occasional karyorrhexis. In three other cases of immune-mediated gastritis from Nivolumab in monotherapy, two present intraepithelial lymphocytosis, with one indicating the predominance of CD3+ without specifying a CD4 or CD8 subtype and the other demonstrating highly reactive changes of the glandular epithelium with inflammation in the crypts [3, 6]. The third case presents focal gastritis in the antrum and body, without intraepithelial lymphocytosis, eosinophils or apoptosis (Table 1) [7]. No controlled clinical studies on the treatment of upper GI symptoms have been published. Review of the literature shows that most symptoms are mild and can be resolved with symptomatic treatment, as in the case described here. In severe cases, treatment similar to that of immune-mediated colitis is recommended, with corticosteroids at 1-2 mg/kg body weight or biologic treatments in case of no response. Due to the increasing indications and use of immunotherapy, we must be aware of its potential adverse effects to have a high clinical suspicion in patients on active or recent treatment with checkpoint inhibitors and presenting with compatible symptomatology.

Table 1: Characteristics and histopathological findings of immune-mediated gastritis secondary to Nivolumab in monotherapy.

Tumor

Gastritis pattern

Other diagnoses

Year

Melanoma

Intraepithelial lymphocytosis, neutrophilic activity, apoptosis, crypt abscesses

Absent

2020 [3]

Hodgkin lymphoma

Intraepithelial lymphocytosis with predominance of CD3

Esophagitis

2017 [6]

Melanoma

Lymphohistocyte aggregates around actively inflamed glandular epithelium

Duodenitis

Colitis

2020 [7]

Melanoma

Intraepithelial CD8 T-type lymphocytosis accompanied by neutrophilic activity and occasional karyorrhexis

Absent

2021


Conflicts of Interest

None.

Article Info

Article Type
Case Report and Review of the Literature
Publication history
Received: Tue 17, Aug 2021
Accepted: Thu 04, Nov 2021
Published: Thu 11, Nov 2021
Copyright
© 2023 Flor M Fernández-Gordón Sánchez. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.COR.2021.10.03

Author Info

Corresponding Author
Flor M Fernández-Gordón Sánchez
Division of Gastroenterology and Hepatology, Doce de Octubre University Hospital, Madrid, Spain

Figures & Tables

Table 1: Characteristics and histopathological findings of immune-mediated gastritis secondary to Nivolumab in monotherapy.

Tumor

Gastritis pattern

Other diagnoses

Year

Melanoma

Intraepithelial lymphocytosis, neutrophilic activity, apoptosis, crypt abscesses

Absent

2020 [3]

Hodgkin lymphoma

Intraepithelial lymphocytosis with predominance of CD3

Esophagitis

2017 [6]

Melanoma

Lymphohistocyte aggregates around actively inflamed glandular epithelium

Duodenitis

Colitis

2020 [7]

Melanoma

Intraepithelial CD8 T-type lymphocytosis accompanied by neutrophilic activity and occasional karyorrhexis

Absent

2021


Science Repository

Figure 1: A) Gastric mucosa with lymphocytic gastritis affecting foveolar epithelium. Hematoxylin-eosin. Magnification 100x. B) Gastric mucosa with lymphocytic gastritis CD8 positive. Immunohistochemistry CD8 antibody. Magnification 100x.


Science Repository

Figure 2: High power view of the inflammatory cells showing diffuse lymphocytosis (arrow heads) and also neutrophilic focal activity (arrows) and occasional karyorrhexis. Hematoxylin-eosin. Magnification 400x.



References

1.     Postow M (2020) Toxicities associated with checkpoint inhibitor immunotherapy. UpToDate.

2.     European Association for the Study of the Liver (2019) EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 70: 1222-1261. [Crossref]

3.     Vindum HH, Agnholt JS, Nielsen AWM, Nielsen MB, Schmidt H (2020) Severe steroid refractory gastritis induced by Nivolumab: A case report. World J Gastroenterol 26: 1971-1978. [Crossref]

4.     Marthey L, Mateus C, Mussini C, Nachury M, Nancey S et al. (2016) Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease. J Crohns Colitis 10: 395-401. [Crossref]

5.     Wang ZH, Shen L (2018) Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors. Chronic Dis Transl Med 4: 1-7. [Crossref]

6.     Boike J, Dejulio T (2017) Severe Esophagitis and Gastritis from Nivolumab Therapy. ACG Case Rep J 4: e57. [Crossref]

7.   Johncilla M, Grover S, Zhang X, Jain D, Srivastava A (2020) Morphological spectrum of immune check-point inhibitor therapy-associated gastritis. Histopathology 76: 531-539. [Crossref]