Nivolumab-induced tumour-like gastritis: A case report

Table 1 Case report timeline

Date	Event	Findings
December 2017	Chest CT	Tumour in the left lung (S1/2) with pleural metastases
January 2018	Fibrobronchoscopy with biopsy	Pathology report: poorly differentiated (G3) non-small lung cell adenocarcinoma, EGFR (-)
February - June	Chemotherapy treatment (Carboplatin, Paclitaxel, Bevacizumab), 6 courses
September	Chest CT	Reduction of target tumours by 16%. Stable oncologic disease
January 2019	Chest CT	Progression of the disease
January	Initiation of nivolumab treatment
December 2020	Beginning of gastrointestinal symptoms
February 2021	EGD with biopsy	EGD: Tumour-like endoscopic changes in the stomach; Histology: Chronic active (++) erosive gastritis with gland destruction and lymphoepithelial infiltration. Possible immune check-point inhibitor therapy-associated gastritis
March	Abdominal CT	Stomach changes related to chronic gastritis
March	EGD with biopsy	EGD: Progression of tumour-like endoscopic changes in the stomach; Histology: Chronic active (++) gastritis with erosions and intestinal metaplasia
March - April	First course of 20 mg/d of omeprazole
July	EGD with biopsy	EGD: Decreased diffuse inflammatory/infiltrative changes in the stomach wall; Histology: Chronic active gastritis (++) associated with immunotherapy
July - August	Second course of omeprazole 20 mg/d
September	COVID-19 infection; acute renal failure; cessation of nivolumab
October	Third course of omeprazole 20 mg/d
December	Chest CT	No progression of pulmonary disease
	Renal function improvement; Reintroduction of nivolumab
January 2022	EGD with biopsy	EGD: Gastric mucosa atrophy with focal intestinal metaplasia, gastric polyp; Histology: Hyperplastic gastric polyp
March	Acute renal failure; kidney biopsy; cessation of nivolumab	Histology: Insignificant and non-specific renal changes
May	Renal function improvement; Initiation of Atezolizumab treatment
October	Chest CT	No progression of pulmonary disease

CT: Computed tomography; EGD: Esophagogastroduodenoscopy; EGFR: Epidermal growth factor receptor.

Table 2 Summary of nivolumab-induced gastritis case reports

Ref.	Main symptoms	Time of onset (in relation to nivolumab therapy)	Radiologicall findings	EGD findings	Pathology findings	Treatment	Outcomes
Johncilla et al[2], 2019	Nausea, vomiting, diarrhea	Two doses	-	Gastric erythema and erosions	Focal enhancing gastritis (pyloric antrum and body)	Prednisone, infliximab	Improved symptoms
Zhang et al[17], 2019	Diarrhea, nausea, vomiting	Avg. 8 doses	-	Erythema (with or without erosions) - 64% of patients, periglandular inflammation -20%, polyps - 2%	Periglandular inflammation, granuloma, diffuse inflammation, neutrophilic abscess	Steroids, infliximab	-
Placke et al[4], 2021	Weight loss, nausea, heartburn	118 d	-	Severe erythematous gastritis	Lymphoplasmocytic cells, granulocyte infiltration	Pantoprazole, prednisone	Improvement in symptoms (after circa 6 d)
Shi et al[3], 2017	Vomiting, nausea	17 cycles	PET/CT and MRI - unremarkable	Diffusely friable, erythematous, denuded gastric mucosa	Neutrophilic abscesses, expansion of the lamina propria with lymphocytes and plasma cells	Pantoprazole and ranitidine; cessation of nivolumab	No improvement after pantoprazole and ranitidine therapy; improvement after nivolumab cessation
Boike et al[10], 2017	Dysphagia, diarrhea	6 mo	PET/CT - FDG uptake in the esophagus and stomach wall	Gastric erythema, thick mucoid secretions	Lymphoplasmocytic infiltration in lamina propria and epithelium	Prednisone and PPI	Improved symptoms after 2 d
Alhatem et al[6], 2019	Loss of appetite, diarrhea, bloating	Few months	-	Barrett’s esophagus, antral gastritis	Transmural inflammation, cryptitis, dysplasia	Prednisone; cessation of nivolumab for 6 wk	Improved symptoms; no recurrence after resuming nivolumab therapy
Woodford et al[5], 2021	Epigastric pain, intermittent anorexia and nausea	4 cycles (nivolumab and ipilimumab combination)	CT - stomach wall thickening	Erythema, friable gastric mucosa	Active chronic inflammation, distortion of glandular architecture	Pantoprazole; methylprednisone	Pain aggravation after 2 wk. Recurrent gastritis 12 mo later
Bazarbashi et al[14], 2020	Mild epigastric discomfort	4 doses of nivolumab monotherapy (16 wk) then switched to nivolumab and + ipilimumab combination (2 doses, 4 wk)	Abdominal and pelvic CT - unremarkable	Hemorrhagic and inflamed gastric mucosa with exudate	Active chronic inflammation, intraepithelial lymphocytosis, increased apoptotic activity	Prednisone	Improved symptoms. Continual endoscopically observed resolution of inflammation
Rovedatti et al[7], 2020	Epigastric pain, loss of appetite	12 cycles	-	Diffuse ulcerations covered with fibrin-like membranes, erythematous friable gastric mucosa	Lymphoplasmocytic and neutrophilic infiltration, microabscesses, apoptotic bodies, reactive epithelial cell atypia	Prednisone, pantoprazole, cessation of nivolumab	Improved symptoms. Endoscopic and histologic remission.
Vindum et al[8], 2020	Anorexia, vomiting, nausea, epigastric pain, weight loss	6 doses	PET/CT - FDG-uptake in the gastric wall	Erythematous gastric mucosa with fibrinous erosions	Chronic active pangastritis. Neutrophilic and lymphocytic epithelial infiltration, crypt abscesses, lymphoplasmacytic infiltration in lamina propria	1st admission – low dose prednisone; 2nd admission - high dose methylprednisone (80 mg), pantoprazole	Improved symptoms after 3 mo of treatment. Radiological and clinical remission
Mubder et al[15], 2020	Anorexia, nausea, vomiting, abdominal pain	3 mo	Abdominal and pelvic CT - unremarkable	Active gastritis	Severe acute gastritis with necro-inflammatory debris. Glandular destruction, lymphoplasmacytic infiltration	-	-
Martínez-Acitores de la Mata et al[16], 2020	Epigastric pain, hyporexia, vomiting	2.5 yr	Abdominal CT - unremarkable	Exudate, diffuse congestion, edema, erythema, friable mucosa in the stomach	Glandular destruction, crypt abscesses, inflammatory cell infiltration.	PPI, cessation of nivolumab	Improved symptoms
Ferrian et al[18], 2021	Epigastric pain, nausea, anorexia	32 mo	-	Erythema, friable gastric mucosa	Crypt destruction, erosions, neutrophilic, lymphoplasmacytic, and eosinophilic infiltration in the lamina propria	Prednisone, cessation of nivolumab	Improved symptoms. Radiological and clinical remission
Ebisutani et al[13], 2020	Left-sided epigastric pain, nausea, anorexia	7 mo	CT - thickening of the gastric wall	Erythema, edema, white membrane in the gastric mucosa	Lymphocytic and neutrophilic infiltration of the lamina propria and epithelium	Prednisone, cessation of nivolumab	Improved symptoms. Endoscopic and clinical remission
Kobayashi et al[9], 2017	Epigastric pain, hematemesis	10 cycles, 4 mo	-	Hemorrhagic gastritis, white membrane on mucosa	Lymphoplasmacytic and neutrophilic infiltration	Prednisone	Improved symptoms after few days. Clinical and endoscopic remission
Tomiyasu et al[11], 2021	Diarrhea, nausea, anorexia, weight loss	11 courses	PET/CT - diffuse FDG accumulation in stomach wall and duodenum	Multiple white granular elevations in the stomach	Eosinophilic infiltration of mucosa	Prednisone, cessation of nivolumab	Improved symptoms
Cǎlugǎreanu et al[12], 2019	Vomiting, epigastric pain, weight loss	26 courses	PET/CT – diffuse FDG uptake in the stomach wall	Ulcerative and hemorrhagic gastritis	Lymphoplasmacytic infiltration with scattered neutrophils and eosinophils	Methylprednisone and PPI, cessation of nivolumab	Resolved after 8 wk
Tsuji et al[20], 2022	Anorexia, epigastric discomfort, vomiting	10 mo	CT - diffuse thickening of the stomach wall; EUS - mucosal thickening	Mucosal edema, erosions	Inflammatory cell infiltration of the lamina propria	Prednisone, cessation of nivolumab	Improved symptoms. Radiological and endoscopic remission
Samonis et al[21], 2022	Anorexia, gastric discomfort and pain, vomiting	6 mo	PET/CT - intense metabolic uptake in the stomach	Erythematous gastritis, friable mucosa, edema, mucous exudate	Inflammatory cell infiltration of the lamina propria	Prednisone and PPI	Improved symptoms. Endoscopic remission

CT: Computed tomography; EGD: Esophagogastroduodenoscopy; EGFR: Epidermal growth factor receptor; EUS: Endoscopic ultrasound; FDG: Fluorodeoxyglucose; MRI: Magnetic resonance imaging; PET: Positron emission tomography; PPI: Proton pump inhibitor.