Giant IgG4-Related Pseudotumor of the Esophagus Resected with Endoscopic Submucosal Dissection: A Case Report and Review of the Literature
Nese EKINCI1, Duygu UNAL KOCABEY1, Eylul GUN1, Fatih ASLAN2
1Department of Pathology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, IZMIR, TURKEY
2Department of Gastroenterology, Koc University Hospital, ISTANBUL, TURKEY
Keywords: IgG4, IgG4-related disease, Esophagus, Endoscopic submucosal dissection, Autoimmune
IgG4-related disease (IgG4-RD) is a systemic autoimmune disorder that has been defined in various organs. The disease is characterized
by typical clinicopathological features including a dense lymphoplasmacytic infiltrate rich in IgG4 positive plasma cells, storiform fibrosis,
obliterative phlebitis, and often an elevated serum IgG4 level. Esophageal IgG4-RD is rare, and its presentation as a solid mass is even more rare.
Only 15 previous cases of IgG4-related esophageal disease have been described. We herein present a case of giant IgG4-related pseudotumor
of the esophagus resected with endoscopic submucosal dissection (ESD) and a review of the literature. The patient was a 67-year-old man who
was admitted to our hospital for assessment of progressive dysphagia. Upper gastrointestinal endoscopy revealed a 9 cm mass in the cervical
esophagus. In the previous two hospitals, the patient’s mass could not be diagnosed despite repeated biopsies. Because of concerns regarding
malignancy, endoscopic submucosal dissection was performed. Histopathological examination showed dense lymphoplasmacytic infiltration
with predominant IgG4-positive plasma cells on a sclerotic background. The patient was diagnosed with IgG4-RD. During the follow-up, no
residual mass was detected but the patient was diagnosed with lung adenocarcinoma. We present a unique case of giant IgG4-related pseudotumor
of the esophagus. Resection with ESD of such a big mass of IgG4-RD in the esophageal region has never been reported before in the literature.
IgG4-related disease (IgG4-RD), originally described in the
pancreas by Sarles et al. in 1961 1,
is a fascinating clinical
entity of unknown etiology characterized by high serum
IgG4 concentrations and tumefaction or tissue infiltration
by IgG4-positive plasma cells. The disorder is recognized as a
systemic disease characterized by specific histopathological
findings that include the presence of predominant
IgG4-positive plasma cells in a background of intense
lymphoplasmacytic infiltration, storiform fibrosis, and
obliterative phlebitis 2
. It has been reported in almost any
organ and tissue in the body including the pancreatobiliary
system, lacrimal glands, salivary glands, central nervous
system, thyroid, lungs, liver, gastrointestinal tract, kidney,
prostate, retroperitoneum, arteries, lymph nodes, skin,
and breast 3
. The clinical presentation depends on the
site of involvement 6
. Involvement of the esophagus is
extremely rare. Sometimes esophageal IgG4-RD may mimic
malignancy both clinically and radiologically, especially
when it forms a mass 7
. We herein present a unique
case of giant IgG4-related pseudotumor of the esophagus
resected with endoscopic submucosal dissection (ESD) and
a review of the literature.
A 67-year-old Caucasian man presented with progressive
dysphagia to solids over the last 2 years. His past medical
history was uneventful. He had no other autoimmune
diseases. He was an ex-smoker with a smoking history of
43 pack-years. The patient had previously visited 2 different
hospitals, where he underwent upper gastrointestinal
endoscopy, neck computed tomography (CT), and FDGpositron
emission tomography (PET) because of the
suspicion of malignancy. Upper gastrointestinal endoscopy
revealed a mass-forming lesion prolapsing into the lumen
of the cervical esophagus. The neck CT demonstrated a
suspicion of gastrointestinal stromal tumor (GIST) and no
concomitant lymphadenopathy. FDG-PET showed that the
SUVmax of the mass was 10.0. Because of the suspicion
of esophageal cancer, multiple biopsies were taken from
the mass. However, the biopsy specimens were evaluated
as squamous epithelial hyperplasia and inflammatory
granulation tissue histologically which did not explain the
tumoral nature of the lesion.
The patient presented to the gastroenterology department of
our hospital. The physical examination was unremarkable.
All laboratory data were within normal limits. Upper
gastrointestinal endoscopy revealed an approximately 9 cm
polypoid tumor partially obstructing the esophageal lumen,
located about 15 cm from the incisors (Figure 1). Because
of the obstruction and the concerns regarding malignancy,
endoscopic removal of the lesion was planned.
Click Here to Zoom
|Figure 1: Macroscopic examination of the resected specimen
revealed a polypoid tumor that measured 9x7x5 cm with mucosal
surface erosion. Insert: Endoscopic view of upper esophagus
demonstrated intraluminal mass (arrow) partially obstructing the
He underwent a successful ESD. After marking the lesion,
a mixture of saline, indigocarmin and hyaluronic acid was
locally injected into the submucosal space to elevate the
lesion. The borders were marked circumferentially using
a needle knife tip (DualKnifeTM; Olympus, Tokyo, Japan)
and careful dissection of the lateral borders and submucosal
space was performed. En bloc removal of the lesion was
performed successfully and it was sent to the pathology
department for histological evaluation. Cauterization for
bleeding was accomplished and enteral feeding was started
in order to allow the esophageal mucosa to heal.
Gross examination of the resected specimen revealed a
polypoid tumor that measured 9x7x5 cm with mucosal
surface erosion and a tan-white, solid, partially rubbery cut
surface (Figure 1). Histological examination showed dense
lymphoplasmacytic inflammation, lymphoid follicles with
prominent germinal centers, and proliferation of small
vessels on a sclerotic background beneath the ulcerated
squamous epithelium (Figure 2). The inflammation
consisted of abundant plasma cells admixed with some
eosinophils (Figure 3). Stromal sclerosis resembling
storiform fibrosis that is characterized by a whorled pattern
of fibrosis was observed (Figure 4). Blood vessels showed
partially luminal obliteration by aggregated inflammatory
cell infiltration but there was no manifest obliterative
phlebitis (Figure 5). There were reactive mucosal changes
adjacent to the ulcer. Immunohistochemically, cytokeratin
AE1/AE3, CD117, ALK, CD3, CD20, bcl2, CD10, CD38,
kappa, lambda, IgG and IgG4 stains were performed. Stains
for cytokeratin AE1/AE3, CD117, ALK were all negative in
the lesion. A possible lymphoproliferative neoplasm was
excluded by CD3, CD20, bcl2 and CD10 staining. CD38
revealed abundant plasma cells demonstrating a polyclonal
staining pattern including the expression of both kappa and
lambda. IgG4 immunostaining revealed 60 IgG4+ plasma
cells per high-power field (HPF) (Figure 6). The ratio of
IgG4+/IgG+ plasma cells was > 40%.
Click Here to Zoom
|Figure 2: Low-power view shows dense lymphoplasmacytic
inflammation and lymphoid follicles with prominent germinal
centers on a sclerotic background beneath the squamous
epithelium (H&E; x20).
Click Here to Zoom
|Figure 4: The stromal sclerosis resembling storiform fibrosis
Click Here to Zoom
|Figure 5: The blood vessel showing partial luminal obliteration by
aggregated inflammatory cell infiltration (H&E; x100).
Click Here to Zoom
|Figure 6: Dense infiltration of IgG4-positive plasma cells (IHC;
With the help of histopathological findings raising concern
for IgG4-RD, the serum IgG4 level was checked afterwards.
Ten days after the ESD procedure, the patient’s serum IgG4
level was found to be elevated at 179 mg/dL (reference
range, 0-125 mg/dL). Based on comprehensive diagnostic
criteria for IgG4-RD (10), the patient was finally diagnosed with a IgG4-related pseudotumor of the esophagus. He
was discharged from the hospital after an uneventful postprocedural
course. A written consent form was obtained
from the patient’s relatives.
The patient did not receive any medication including corticosteroid
therapy after the ESD procedure. He underwent
neck and thorax CT two months after the ESD procedure.
Neck CT showed no residual mass but unexpectedly the
thorax CT showed a solid mass with an irregular spiculated
contour of 24 mm size in the perihilar area of the lower lobe
in the left lung. FDG-PET showed that SUVmax of the mass
was 14.68 and there were concomitant hypermetabolic
lymph nodes in the mediastinum. Due to the suspicion of
lung cancer, bronchoscopy was performed. However, the
mass could not be sampled despite repeated bronchoscopies.
Bone scintigraphy showed a lesion suspicious in terms
of metastasis in the left iliac crest. Biopsy taken from the
lesion was evaluated as adenocarcinoma favoring the lung
as primary origin. The patient received chemotherapy
but unfortunately, 21 months after the ESD procedure,
he passed away with unknown cause, and no autopsy was
IgG4-RD is an immune-mediated fibroinflammatory condition
that has been described in a variety of organs 11
According to the comprehensive diagnostic criteria for
3 criteria were proposed for a diagnosis of
involvement with diffuse/localized swelling
or masses in single or multiple organs; 2
serum IgG4 concentration (≥135 mg/dl); 3
findings that include a ratio of IgG4+/IgG+ plasma
cells > 40% and >10 IgG4+ plasma cells/HPF in addition
to marked lymphoplasmacytic infiltration and fibrosis. A
diagnosis of IgG4-RD is definite in patients who fulﬁll the
comprehensive diagnostic criteria for IgG4-RD 10
. As our
case fulfilled all 3 criteria and was a solid pseudotumor, our
patient was diagnosed as definite IgG4-related pseudotumor
of the esophagus.
In IgG4-related pancreatitis, especially in resection
specimens, it has been reported that >30 IgG4+ plasma cells
per HPF have acceptable specificity, and >50 IgG4+ plasma
cells per HPF is highly specific. However, it is emphasized
that the appropriate cut-off point may vary from organ to
In 2019, American College of Rheumatology/European
League Against Rheumatism developed the classification
criteria for IgG4-RD as validated in a wide cohort of patients
13. The classification criteria for IgG4-RD are divided
into 4 steps that include entry criteria, exclusion criteria,
inclusion criteria, and total inclusion points. These steps
contain the details from clinical, serological, radiological,
and pathological evaluations. However, to obtain a relatively homogeneous population of patients, the organs or sites
such as esophagus that are involved only rarely in IgG4-RD
were excluded from that study.
Esophageal involvement of IgG4-RD (IgG4-RDE) was
uncommonly reported in the literature. To our knowledge
only 15 cases 7–9,14–18 have been described as IgG4-
RDE in the literature previously (Table I). Previous reports
indicated that IgG4-RDE is more frequent in males
and occur from a young age to elderly patients. Clinical
symptoms of IgG4-RDE primarily include dysphagia and
weight loss and more rarely odynophagia, epigastric pain,
and acid reflux. Three of the 15 cases presented with an
intraluminal esophageal mass 7–9, while 1 patient had an
esophageal nodule 14. Operated cases were all removed
with esophagectomy or esophagogastrectomy 7,14–16.
In previous reports, the size of the IgG4-RDE mass in cases
with one ranged from 1.5 cm to 3.9 cm 7,8. The current
case is the largest of IgG4-RDE cases with a mass in the
literature. Furthermore, our case is the first one that was
removed with a successful ESD.
In 2017, a series of IgG4-RDE cases that consisted of 8
subjects was compared with chronic esophagitis, not
otherwise specified, by Obiorah et al. Storiform fibrosis and
high-density lymphoplasmacytic infiltrate were present in
all cases with IgG4-RDE, while obliterative phlebitis was
found in only 3 of 8 cases 14. It was reported that the
mean number of IgG4+ plasma cells/HPF in the cases with
IgG4-RDE was 66.9 and the mean IgG4:IgG ratio was 0.76.
Both the number of IgG4+ plasma cells/HPF and the ratio
of IgG4:IgG were significantly higher thanin the cases with
chronic esophagitis, not otherwise specified. However, the
serum IgG4 level was measured in only 3 of the cases with
IgG4-RDE and found to be normal.
Steroid therapy is an effective and primary choice for
the treatment of IgG4-RD 19. In our case, successful
en bloc resection of the tumor with ESD was performed,
so that the precise diagnosis could be made. ESD is an
effective treatment of choice for superficial neoplasms
of the gastrointestinal system and associated with lower
morbidity than the surgical alternative. Esophageal ESD is a
difficult procedure owing to the narrow lumen and thinner
wall of the esophagus 20. Furthermore, even though the
procedure of ESD seems to be difficult to achieve in a lesion
with a giant size of 9 cm as in our study, the endoscopists
in our facility are highly skilled in this regard and therefore
this lesion was successfully removed in one piece. This
happens to be the first case to report the use of ESD for the
treatment of a patient with an IgG4-related pseudotumor.
IgG4-RD is considered an autoimmune disorder, and
malignancy is associated with the dysregulated immune
system 21. Some cohorts of patients with IgG4-RD have
proposed that a history of cancer may be associated with
the development of IgG4-RD 22–24. In patients with
IgG4-RD, the most common malignancies are prostate
cancer and hematological malignancies 22,23). In our
case, metastatic lung cancer was found during the follow
up. Although the relationship between malignancy and the
IgG4RD is unclear, there are some possible explanations.
The explanations contain the triggering of malignancy by
autoantigen expression leading to IgG4-RD, common risk
factors, and genetic predispositions for both IgG4-RD and
In conclusion, IgG4-RDE can present with a mass and
may lead to a misdiagnosis of malignancy, both clinically
and radiologically. Diagnosis of IgG4-RDE requires
a careful sampling of the lesion in order to perform a
correct histopathological examination. However, it may
be difficult to diagnose IgG4-RDE with small endoscopic
biopsy specimens in some patients. In cases of suspicion,
the biopsy/resection specimens should be stained with
IgG4 and IgG immunohistochemically and the serum
IgG4 level of the patient should be checked. In patients
with an esophageal mass, consideration of IgG4-RDE in
the differential diagnosis by the clinicians and pathologists
will ensure the correct diagnosis and prevent unnecessary
CONFLICT of INTEREST
None of the authors have any conflicts of interest to declare.
Concept: NE, Design: NE, DUK, Data collection or
processing: DUK, EG, Analysis or Interpretation: NE,
FA, Literature search: NE, DUK, Writing: NE, DUK, EG,
Approval: NE, DUK, EG, FA.
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