Introduction
Immune checkpoint inhibitors (ICIs) represent a major advance in treatment of many
types of cancers and have dramatically changed the cancer therapeutic strategy. The
efficacy of ICI treatment has been confirmed, and real-world clinical experience with
its application has been gained. However, a wide spectrum of accompanying immune-related
adverse events (irAEs) have been reported, with caution advised by expert oncologists
[1 ]. These irAEs are driven by the immunologic mechanisms responsible for the therapeutic
effects of ICIs [2 ]
[3 ].
Gastrointestinal disorders are particularly common irAEs, and most patients develop
severe inflammation in the colon [4 ]
[5 ]. IrAE gastritis was first reported in 2017 [6 ], with more case reports on gastritis published later [7 ]
[8 ]
[9 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ]. All reports described the severity and rarity of this gastritis. However, details
concerning the clinical features of irAE gastritis remain sparse.
Symptoms in patients with irAE gastritis are non-specific. An accurate diagnosis should
be made, based on a combination of a patient’s clinical course and endoscopic and
histopathological findings [13 ]
[14 ]. Therefore, we retrospectively collected cases and reviewed the relevant literature
to assess the characteristics of irAE gastritis, focusing on endoscopic findings and
results of histopathological analyses.
Patients and methods
We conducted an observational retrospective study to collect information on patients
with irAE gastritis. Three hundred and fifty-nine patients were treated with ICIs
in Asahikawa Medical University Hospital from October 2018 to October 2021. Among
them, 10 patients underwent esophagogastroduodenoscopy (EGD) due to complains of gastrointestinal
symptoms after administration of an ICI. Severe gastritis was observed in four patients.
IrAE gastritis was identified based on the clinical course and endoscopic and histopathological
findings. Detailed information was collected about the patients with irAE gastritis,
including their symptoms, current treatments, and later immune therapy. The diagnostic
criteria for irAE gastritis were onset of upper gastrointestinal symptoms while a
patient was receiving ICIs, and the exclusion of other causes endoscopically and/or
histologically.
Endoscopic findings were evaluated with conventional endoscopy, chromoendoscopy, and
narrow-band imaging using gastroduodenoscopy (GIF-H290Z, GIF-HQ290 or GIF-1200N, Olympus
Optical Co., Ltd., Tokyo, Japan). Biopsy specimens were collected from the antrum
and corpus of the stomach for histological diagnosis in patients suspected of having
irAE.
Immunohistochemical analyses were further conducted for patients with irAE gastritis.
Immune subtype markers, including CD4 (1F6; Leica Microsystems, Wetzlar, Germany)
and CD8 (C8 /144B; Agilent Technology, Santa Cruz, CA, USA), and programmed cell death
ligand-1(PD-L1) antibody (SP263; Ventana Medical Systems, Tucson, AZ, USA) were used
for immunohistochemistry. Expression of PD-L1 was evaluated as the positive rate (%)
in total cells including epithelial cells and infiltrating immunocytes. Cytomegalovirus
(CMV) antibody (DDG9 + CCH2, DAKO Agilent, Carpinteria, California, United States)
was used for CMV immunohistochemistry. Warthin-Starry staining was performed to investigate
Helicobacter pylori infection.
This observational study protocol was approved by the Asahikawa Medical University
Research Ethics Committee (No. 210769). A written informed consent was obtained from
each patient with irAE gastritis.
Results
Patient characteristics
Ten patients underwent EGD due to complains of gastrointestinal symptoms after the
administration of an ICI. Severe gastritis was observed in four of 359 patients (1.1 %).
These adverse events (AEs) were graded > 2 because all patients were treated with
prednisolone (PSL). Three patients were admitted to the hospital, and the incidence
of grade 3 irAE gastritis was found to be 0.84 % (3/359).
All four of these patients were finally diagnosed with irAE gastritis, and their clinical
information is shown in [Table 1 ]. These four patients were two males and two females, with a median age of 70 years
(range 62–84), treated with ICIs due to malignant melanoma (n = 2), lung cancer (n = 1),
and gastric cancer (n = 1). Pembrolizumab had been administered to the melanoma patient
and the lung cancer patient, nivolumab to the gastric cancer patient, and nivolumab/ipilimumab
to the melanoma patient. Symptoms of irAE gastritis occurred 1 to 40 weeks after administration
of ICIs. Among the affected patients, two patients had a history of ICI treatment
and they did not develop irAE during the treatment. Common gastrointestinal symptoms,
such as nausea, vomiting, and loss of appetite, occurred in all patients, and fatigue
and heartburn were observed in one patient.
Table 1
Characteristics of patients with immune-related gastritis.
Case
Age
Sex
Cancer type
ICI past history
ICI medication
Time to onset for symptoms (weeks)
Symptoms
CTCAE grade
Prednisolone treatment
Time to improvement
ICI rechallenge
Relapse of gastritis
Nausea/vomiting
Loss of appetite
Other
1
84
M
Melanoma
Pembrolizumab
Nivolumab/ipilimumab
1
+
+
–
3
Div (0.5 mg/kg)
A few days
Nivolumab
+
2
75
F
Melanoma
–
Pembrolizumab
40
+
+
Fatigue
3
Div (0.5 mg/kg)
A few days
–
–
3
65
F
Lung cancer
Pembrolizumab
Pembrolizumab
15
+
+
Heartburn
3
P.O. (0.5 mg/kg)
2 weeks
–
–
4
62
M
Gastric cancer
–
Nivolumab
24
+
+
–
2
P.O. (0.5 mg/kg)
A few days
Nivolumab
+
ICI, immune checkpoint inhibitor; CTCAE, Common Terminology Criteria for Adverse Events
Endoscopic and histopathological findings at the diagnosis
Endoscopic and histopathological findings from patients with irAE gastritis are shown
in [Table 2 ]. EGD revealed various findings, such as network-pattern erosion or ulceration in
the antrum ([Fig. 1a ]), erythematous and edematous mucosa with whitish purulent discharge ([Fig. 1b ]), and fragile mucosa ([Fig. 1c ]). The whitish discharge was remarkably increased by air insufflation and mechanical
contact during endoscopic examination. Oozing caused by a slight touch was observed
in fragile mucosa ([Video 1 ]). Narrow-band imaging effectively enhanced erythema as a brownish area, and then
contrasted between the mucosa and discharge ([Fig. 1d ]).
Table 2
Endoscopic and histological findings and PD-L1 expression in patients with immune-related
gastritis.
Case
Endoscopic findings
Histological findings
Immunohistochemical findings
Erythematous and edematous mucosa
Network-pattern erosion in the antrum
Fragile mucosa
Severe inflammatory cell infiltration in the lamina propria
Fibrinopurulent exudate
Epithalaxia
Apoptosis
PD-L1 (%)
1
+
+
+
+
+
+
–
10 % <
2
+
+
+
+
–
+
+
10 % <
3
+
+
+
+
–
+
–
10 % <
4
+
–
+
+
–
+
+
1 % <
PD-L1, programmed cell death ligand-1; mCPS, modified combined positive score.
Fig. 1 Endoscopic features of immune-related adverse event (irAE) gastritis. a The network-pattern erosion and ulcer in the antrum are collectively termed a “spiderweb-like
appearance.” b Erythematous and edematous mucosa is covered with excessive whitish purulent discharge
in the whole stomach. c The fragile mucosa easily bleeds on washing with water spray. d The spiderweb-like appearance is clearly enhanced with narrow-band imaging.
Video 1 The fragile gastric mucosa of the patient with immune-related adverse event (irAE)
gastritis. The antral mucosa, which is covered with whitish purulent exudate, bleeds
easily when removed by the forceps and exposed to water jet from the endoscope.
Biopsy specimens were collected from the antrum and corpus of the stomach for histological
diagnosis. Epithalaxia and severe inflammatory cell infiltration in the epithelia
and lamina propria were observed on histology ([Fig. 2a ]). Fibrinopurulent exudate was observed on the epithelia ([Fig. 2b ]). Immunohistochemical analysis showed that the infiltrating lymphocytes were positive
for CD3, CD4, and CD8, but negative for CD20 (Supplementary Figure). Staining was
positive for PD-L1 in the immune cells and/or epithelial cells ([Fig. 2c, d ]). The positive rate was ≥ 10 % in three cases and ≥ 1 % in one case.
Fig. 2 Histological findings of immune-related adverse event (irAE) gastritis. a Epithalaxia and severe inflammatory cell infiltration in the mucosa are observed
in the biopsy specimens (H&E, × 100). b Fibrinopurulent exudate is seeping out through the deficient of mucosa (H&E, × 200).
c An immunohistochemical analysis of PD-L1 antibody (SP263) shows positive staining
on epithelial cells and infiltrating immune cells (× 200). (d) PD-L1 is positive on
the membrane of the inflammatory cells and negative in the epithelial cells ( × 200).
CMV was not detected by a specific antibody in any cases, and H. pylori was detected in the patient with gastric cancer (Case 4).
Treatment and outcome
Treatments for irAE gastritis and the clinical outcomes are shown in [Table 1 ]. Corticosteroids (0.5 mg/kg) were administered orally or intravenously. Patient
symptoms rapidly improved within a few days of administration. The dose was gradually
tapered every 1 to 2 weeks. EGD with a histological examination after treatment with
PSL revealed improvement in three cases ([Fig. 3a–f ]). In the other case, fragile mucosa remained in the lesser curvature ([Fig. 3g, h ]). While the histopathological findings remarkably improved, mild inflammatory cell
infiltration persisted in all cases.
Fig. 3 Endoscopic appearance of immune-related adverse event (irAE) gastritis before (a, c, e, g ) and after (b, d, f, h ) treatment with prednisolone. Four cases (Case 1: a, b ; Case 2: c, d ; Case 3, e, f ; Case 4: g, h .) showed marked improvement in endoscopic features. Case 1 was cited from a previous
publication [25 ].
In two cases, retreatment with the same ICI was attempted to suppress the regrowing
cancer, after the patient’s initial epigastric symptoms had completely resolved. The
patient in Case 1 ([Table 1 ]), who had received nivolumab/ipilimumab, was administered nivolumab monotherapy.
The patient in Case 4 was administered nivolumab monotherapy again. Both patients
developed loss of appetite and nausea again 10 to 12 weeks after rechallenge with
ICIs. EGD revealed relapse of irAE gastritis, characterized by erythematous and edematous
mucosa with whitish purulent discharge, and PSL retreatment rapidly improved their
symptoms.
Discussion
The number of reported cases of severe irAE gastritis has been increasing in recent
years [15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]. Previously reported cases with severe irAE gastritis are summarized in [Table 3 ]. These reports showed that irAE gastritis developed during administration of ICI
monotherapy in most cases. Our study included three patients who developed irAE gastritis
with ICI monotherapy. Incidence of irAE colitis was shown to be higher in the combination
therapy group than in the monotherapy group [21 ]. In our study, three patients developed irAE gastritis with ICI monotherapy, while
one patient developed it with ICI combination therapy. IrAE gastritis seems to develop
more frequently with ICI combination therapy, as well as irAE colitis reported in
a previous review [22 ].
Table 3
Characteristics of 36 cases of ICI-related gastritis in previous reports.
Age
Median (range)
63.5 (16–93)
Sex
n
(Male:female)
20:16
Type of tumor
n (%)
Malignant melanoma
16 (44)
Lung cancer
10 (28)
Others
11 (31)
Type of ICI
n (%)
Pembrolizumab
14 (39)
Nivolumab
11 (31)
Ipilimumab + nivolumab
7 (19)
Ipilimumab
2 (0.6)
Nivolumab + lag3 inhibitor
1 (0.3)
Ipilimumab + pembrolizumab
1 (0.3)
Treatment cycles
Median (range)
2.5 (1–80)
Symptoms
n (%)
Abdominal pain (epigastric pain)
19 (53)
Nausea/vomiting
14 (39)
Loss of appetite
11 (31)
Diarrhea
9 (25)
Weight loss
4 (1.1)
No symptom
2 (0.6)
Endoscopic findings
n (%)
Erythema
16 (44)
Erosion/ulcer
15 (43)
Edematous
7 (20)
White exudate
6 (17)
Friable
8 (23)
Normal
4 (1.1)
Granularity
3 (0.9)
Hemorrhagic gastritis
2 (0.6)
Histological findings
n (%)
Inflammatory cell infiltration
29(85)
(lymphocytes, neutrophils, eosinophils, plasma cell)
Apoptosis
10(29)
Decreased glands
4 (12)
Treatment
n (%)
Prednisolone (0.5–1.0 mg/kg) IV/PO
31 (89)
Infliximab
2 (6)
Proton pump inhibitor
1 (3)
ICI switch
1 (3)
No treatment
1 (3)
ICI, immune checkpoint inhibitor; IV, intravenous; PO, per oral.
To obtain an accurate diagnosis, this study indicates that it is important to be alert
for three characteristic endoscopic findings: 1) network-pattern erosion or ulcer
in the antrum; 2) erythematous and edematous mucosa with excessive whitish purulent
discharge in the whole stomach; and 3) extremely fragile mucosa. Among these findings,
the first may be the most specific, and indeed, three of the four patients in our
study had this finding. It was unique, enabling it to be distinguished from other
etiologies, while the other finding was common findings in gastritis induced by other
etiologies. For instance, the second finding can be observed in gastritis caused by
severe H. pylori infection [23 ]. However, the whitish purulent discharge in irAE gastritis was exacerbated by air
insufflation and endoscopic contact while performing an endoscopic examination. Furthermore,
there were some patients in whom a large amount of whitish purulent discharge covered
the mucosal surface, resulting in pseudo-membranous formation. This appearance was
described as “fibrin-covered superficial erosions” in a previous report involving
endoscopic evaluation of gastrointestinal toxicity [15 ]
[16 ]
[24 ]. Finally, the third finding was quite characteristic as well. The mucosa of our
patients bled easily, even when exposed to the low-pressure water jet from the endoscope.
Oozing from mucosa could be observed when the purulent discharge was removed. Endoscopic
findings of irAE gastritis in previous reports are summarized in [Table 3 ]. Some reports described the endoscopic findings in each patient, but only a few
reports clearly discussed characteristic endoscopic findings of irAE gastritis [14 ]
[25 ]. Indeed, the first finding was never mentioned in previous reports, aside from our
brief case report, in which a white fibrin-like membrane was termed “spiderweb-like
appearance” [25 ].
The present study compared endoscopic and histopathological findings. The biopsy specimens
obtained from the whitish purulent discharge showed fibrinopurulent exudate on the
epithelia in our patients. Fibrinopurulent exudate is usually observed in cases of
severe gastritis, such as that induced by severe acute H. pylori infection, causing extensive infiltration of neutrophils. IrAE gastritis may be more
destructive than H. pylori gastritis [26 ]. Presence of fibrinopurulent exudate is considered to reflect the severity of irAE
gastritis. Fragile mucosa is consistent with the histological appearance of epithalaxia
and gland depletion, which are caused by severe inflammatory cell infiltration and
destructive response ([Fig. 2a ]). One of the noteworthy histological findings in gastritis was apoptosis, which
is observed in irAE enterocolitis with different frequency [27 ]
[28 ]
[29 ]. Apoptosis is typically observed in gastric graft-versus-host-disease, the histological
criteria for which are apoptosis and gland destruction, sparse inflammatory infiltration,
and granular eosinophilic debris in the dilated gland. Therefore, the histological
distinction will be useful when endoscopic features are similar to irAE gastritis.
Differential diagnosis also includes gastric lesions such as in patients with ulcerative
colitis. Endoscopic findings of erythematous and edematous mucosa with whitish purulent
discharge may be observed in upper gastrointestinal lesions in patients with ulcerative
colitis [30 ]
[31 ]. On pathological examination, the lesions show severe inflammation with sloughed
epithelial cells, resembling a crypt abscess. Thus, a more detailed histological comparison
between ulcerative gastritis and irAE gastritis is expected in the future.
A common mechanism by which ICIs exert their effects involves activation of effector
T cells by inhibition of PD-1, PD-L1, and CTLA-4 [32 ]. It is also proposed that the proliferation of activated T cells and increase in
cytokine production, caused by a lack of self-tolerance, may result in irAEs [2 ]
[33 ]. However, the detailed mechanisms underlying manifestation of irAEs remain unclear.
Immunohistochemistry in our patients revealed that PD-L1 positivity in all four cases.
This expression was observed on epithelial cells and mesenchymal cells. The relationship
between expression of PD-L1 and irAEs needs to be evaluated in more patients. PD-L1
expression in the stomach may be associated with development of irAE gastritis. The
linkage between PD-1 and PD-L1 is inhibited by ICIs, resulting in blockade of immune
tolerance. T cells will actively attack antigens that are present on gastric epithelial
cells. This novel hypothesis will need to be assessed in a further case-control study.
While expression of tissue-based biomarkers including PD-L1 has been shown to correlate
with ICI efficacy, its association with AEs remains unclear [34 ]. One histological analysis of a patient with encephalitis induced by ICI demonstrated
prominent PD-L1 expression and robust T-cell infiltration [35 ].
Concerning the treatment, our patients were treated with intravenous or oral PSL 0.5 mg/kg/day,
which rapidly improved their symptoms within a few days to 2 weeks after administration
of PSL and the symptoms eventually disappearing. Although the time to symptom improvement
was not mentioned much in previous reports, many patients had symptom improvement
within a few days of PSL treatment. As with other irAEs, there were some PSL-refractory
cases that needed an anti-TNFα monoclonal antibody among previous cases [36 ]. Therefore, we should pay attention to improvement in symptoms after administration
of PSL.
One limitation associated with this case report is its retrospective nature and single-center
setting. Because gastritis is a relatively rare irAE, we only analyzed endoscopic
and histological findings in four collected cases. The sensitivity and specificity
of the characteristic endoscopic findings, as mentioned previously, could not be estimated,
because the endoscopic findings were not evaluated in this case series. A case-control
study or cohort study with a sufficient number of cases would help clarify the accuracy
of endoscopic findings.
Conclusions
In conclusion, we identified clinical features of irAE gastritis, including characteristic
endoscopic findings, in this case series. IrAE gastritis can be induced by any ICI
at any timing during administration of ICIs. Furthermore, symptoms of irAE gastritis
are non-specific and can resemble those induced by other etiologies, such as disease
progression and cachexia. Therefore, it is difficult to diagnose irAE gastritis based
on symptoms alone. IrAE gastritis, thus, was diagnosed by characteristic endoscopic
findings, and gastritis in patients was effectively treated with PSL. These results
suggest that an endoscopic diagnosis is quite important, so oncologists should be
aware of characteristic endoscopic findings for this entity. These findings are expected
to deepen our understanding of irAE gastritis, leading to prompt diagnosis and appropriate
treatment.