IgG4-Related Disease
A Reminder for Practicing Pathologists
Steven C. Weindorf, MD; John Karl Frederiksen, MD, PhD
 IgG4-related disease (IgG4-RD) is a systemic autoimmune
fibroinflammatory disease that produces sclerotic, tumefac-
tive masses containing dense lymphoplasmacytic infiltrates
rich in immunoglobulin (Ig) G4þ plasma cells. Initially
characterized as a form of autoimmune pancreatitis, the
distinctive histopathology of IgG4-RD has now been de-
scribed in almost every organ system. However, because the
clinical manifestations of IgG4-RD are diverse and nonspe-
cific, the disease may go unsuspected until a biopsy or
resection specimen is obtained to diagnose a presumed
malignancy. Pathologists thus play a key role in the diagnosis
of IgG4-RD, and familiarity with its histopathologic features is
essential to preventing the irreversible comorbidities associ-
ated with this treatable disease. This brief review outlines the
epidemiology, clinical manifestations, and histopathology of
IgG4-RD, with the aim of furthering pathologists’ awareness
of and ability to diagnose this disorder.
(Arch Pathol Lab Med. 2017;141:1476–1483; doi:
10.5858/arpa.2017-0257-RA)
I gG4-related disease (IgG4-RD) is a systemic autoimmune
disorder characterized by elevated serum immunoglob-
ulin (Ig) G4 levels and tumorlike fibroinflammatory masses
with distinctive histopathologic features that almost always
include infiltrates of IgG4þ plasma cells. Described initially
as a form of sclerosing autoimmune pancreatitis (now
designated as type I autoimmune pancreatitis),1–3 the
disease has since been recognized as having the capacity
to affect nearly every organ system. Indeed, IgG4-RD is
notable for unifying several historical and seemingly organ-
specific fibrosing diseases into a single process (Figure 1).
The designation of IgG4-RD as a distinct disease entity
was proposed in 2003.1 Much literature has been published
since then (Figure 2), including many recommendations
regarding its diagnosis and management.4,5 Despite these
advances, however, the pathophysiology of IgG4-RD
Accepted for publication July 10, 2017.
From the Department of Pathology, University of Michigan, Ann
Arbor. Dr Frederiksen is now with the Department of Pathology,
Jackson Memorial Hospital, Miami, Florida.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented in part at the New Frontiers in Pathology meeting;
October 13–15, 2016; Ann Arbor, Michigan.
Reprints: John Karl Frederiksen, MD, PhD, Department of
Pathology, Jackson Memorial Hospital, Holtz 2042C, 1611 NW
12th Ave, Miami, FL 33136 (email: john.frederiksen@jhsmiami.org).
1476 Arch Pathol Lab Med—Vol 141, November 2017
remains poorly understood. Moreover, as some6,7 have
observed, diagnosis of the disease suffers from a paradoxical
combination of underrecognition and overrecognition—
underrecognition due to unfamiliarity, and overrecognition
due to overeagerness to demonstrate familiarity. Accurate
and timely recognition of the characteristic histopathologic
features of IgG4-RD, and differentiation from its mimics, is
important because it is eminently treatable, yet debilitating
and potential deadly if left unchecked. Pathologists in
particular play a crucial role by alerting clinicians to the
possibility of a diagnosis of IgG4-RD, since it may be
unsuspected clinically until a resection specimen arrives
(Figure 3, A through H). This brief review will summarize
the clinical features, histopathology, and differential diag-
nosis of IgG4-RD, with an eye toward increasing patholo-
gists’ awareness of this unique disorder.
EPIDEMIOLOGY AND CLINICAL FEATURES
The incidence of IgG4-RD across all organ systems is
difficult to determine, since the disease has only recently
been described and global population-based data are
lacking. In Japan, where the disease has been characterized
extensively, one study examining the incidence of autoim-
mune pancreatitis reported a rate of 0.8 per 100 000
individuals.8 More recently, a rate for all forms of IgG4-
RD of 0.28 to 1.08 per 100 000 individuals was estimated in
Japan from the number of patients with IgG4-RD who
presented to 2 hospitals within a single prefecture over the
course of several years.9 These rates may rise as additional
data accumulate and physicians become more familiar with
and able to recognize the disease.10
Unlike most autoimmune diseases, IgG4-RD is more
prevalent in middle-aged and elderly males, although the
extent of this male predominance varies with the anatomic
site of involvement. At least in Japanese populations, IgG4-
related autoimmune pancreatitis has a male to female ratio
of 3–4:1,11 but this ratio decreases nearly to unity in the
context of head and neck disease.12 The most common
clinical manifestation is the development of a mass lesion
that produces site-specific symptoms and raises suspicion
for malignancy. The effects range from simple swelling of
the affected organs (salivary and lacrimal glands, lymph
nodes) to obstruction (pancreaticobiliary, ureteral), organ
dysfunction (pituitary insufficiency secondary to hypophy-
sitis, kidney disease), and even frank medical emergency
(aortic dissection, pachymeningitis, pancreatitis). Apart from
the mass effects, a small number of patients may experience
constitutional symptoms such as fever and weight loss.10
IgG4-Related Disease—Weindorf & Frederiksen
Figure 1. Some of the many clinical manifestations of IgG4-related disease, including the names of historic fibrosing diseases (italicized)
subsequently linked to the disorder. Abbreviation: IgG4, immunoglobulin G4.

Figure 2. The yearly number of PubMed

citations since 2000 containing the search
term IgG4-related. Abbreviation: IgG4, im-
munoglobulin G4.

Arch Pathol Lab Med—Vol 141, November 2017 IgG4-Related Disease—Weindorf & Frederiksen 1477
Figure 3. IgG4-related disease involving the submandibular gland. The specimen was taken from a 46-year-old woman with a 3-month history of a
right submandibular gland mass and mild regional neck lymphadenopathy. Her medical history included Graves disease and asthma. Nineteen
months earlier she underwent a lacrimal gland biopsy for periorbital swelling. Lymphoma had been suspected, but flow cytometry was negative, and
the biopsy was interpreted as sclerosing inflammatory pseudotumor with numerous active lymphoid follicles. Sections of the excised right
submandibular gland mass (A) show serous salivary gland tissue and adjacent nodular lymphoid tissue consisting of reactive germinal centers (B)

1478 Arch Pathol Lab Med—Vol 141, November 2017 IgG4-Related Disease—Weindorf & Frederiksen
Other patients are asymptomatic, and a mass lesion is only
found incidentally on imaging. With such diverse clinical
presentations, it is perhaps not surprising that the possibility
of a systemic autoimmune disease may be overlooked in
favor of alternative diagnoses during initial or even
subsequent evaluations.
PATHOPHYSIOLOGY
The etiology of IgG4-RD remains obscure, and it is easier
to describe the inflammatory response in affected patients
than to identify definitive causative mechanisms. Evidence
suggests that the disease is associated with both T helper 2
(Th2) and regulatory T-cell (Treg) immune responses. Th2
responses are linked to the development of allergies and
bronchial asthma, conditions that are more prevalent in
patients with IgG4-RD.13,14 They are characterized by CD4þ
T cells secreting the cytokines interleukin (IL)–4, IL-5, and
IL-13, and they promote class switching to IgG4, increased
IgE synthesis, and eosinophilia. Regulatory CD4þ T cells
(Tregs), in contrast, secrete cytokines such as IL-10 and
transforming growth factor b (TGF-b), leading to immuno-
modulatory or immunosuppressive effects. Serum from
patients with IgG4-RD shows elevated mRNA expression
of IL-4, IL-5, and IL-10, as well as increased concentrations
of IgG4 and IgE.15 Tissue sections of salivary glands,16
lacrimal glands,16 and pancreas17 from patients with IgG4-
RD show high mRNA expression of Th2- and Treg-
associated cytokines. Circulating Treg-type CD4þ T cells
are increased in the peripheral blood of patients with IgG4-
related autoimmune pancreatitis.18 Treg cells (as defined by
immunohistochemical expression of the Treg-related tran-
scription factor Foxp3) are also increased in liver biopsies
from patients with IgG4-RD.19
These findings suggest a possible model10,20 in which an
unknown immunologic trigger induces an aberrant Th2-
type immune response leading to peripheral blood and
tissue eosinophilia and increased IgE production. At the
same time, Treg cells, perhaps to ameliorate the Th2
response, are stimulated to secrete IL-10, which (along
with IL-4) induces class switching to IgG4, and TGF-b, a
known stimulator of fibroblast activity. Repeated cycles of
antigenic stimulation and cytokine secretion then produce
the histopathologic findings of tissue fibrosis and a
lymphoplasmacytic infiltrate rich in IgG4þ plasma cells.
However, direct evidence that Th2-associated cytokines
truly drive the inflammation in IgG4-RD is still lacking, and
no convincing environmental trigger (infectious or other-
wise) or autoantigen has been identified. Other possible
predisposing conditions or contributors to IgG4-RD path-
ogenesis include specific human leukocyte antigen (HLA)
alleles and single-nucleotide polymorphisms within some
non-HLA genes.21,22
Also puzzling is the precise role of IgG4 in the disease.
IgG4 is the least common IgG subtype, comprising less than
5% of total IgG,23 and is usually viewed as an anti-
inflammatory molecule. IgG4 binds C1q and the Fcc
separated by thick intervening bands of sclerosis in a storiform pattern. The sclerotic areas (C) contain a lymphoplasmacytic inflammatory infiltrate
with frequent eosinophils. The infiltrate surrounds the ducts and glands of the salivary acinar structures without forming lymphoepithelial lesions.
Immunohistochemical stains show abundant IgGþ plasma cells (D), nearly all of which are also IgG4þ (E). Re-evaluation of the patient’s prior lacrimal
gland biopsy (F) and immunohistochemical stains for IgG (G) and IgG4 (H) demonstrate similar results. Following the submandibular gland biopsy,
the patient was found to have a serum IgG4 concentration that exceeded 1000 mg/dL (reference range, 8–150 mg/dL) (hematoxylin-eosin, original
magnifications 3 20 [A and F], 3100 [B], and 3400 [C]; immunoperoxidase, original magnification 320 [D, E, G, and H]). Abbreviations: IgG,
immunoglobulin G; IgG4, immunoglobulin G4.
Arch Pathol Lab Med—Vol 141, November 2017
receptor with relatively low affinity,24,25 and consequently
is not expected to be as effective as other IgG subclasses at
activating complement or promoting phagocytosis. In
addition, owing to unstable inter–heavy chain disulfide
bonds,26 IgG4 can exchange its Fab arms with other IgG4
molecules, rendering it functionally monovalent. Because
IL-10, a cytokine produced by Treg cells, promotes class
switching to IgG4, one possibility is that the infiltrates of
IgG4þ plasma cells in IgG4-RD result from Treg cells
attempting to dampen the immune response. However,
whether the IgG4þ plasma cells damage tissue directly or
represent the byproduct of an exaggerated immune re-
sponse remains unclear.
HISTOPATHOLOGY
For several reasons, histopathologic evaluation of affected
tissues remains a critical component in the diagnosis of
IgG4-RD. The histologic pattern is highly characteristic
(with certain caveats described below), and immunohisto-
chemistry demonstrating increased IgG4þ plasma cells is
important and necessary confirmatory evidence. Moreover,
considering the diverse clinical presentations associated
with IgG4-RD, histopathology can both exclude malignancy
and alert clinicians to the presence of a separate (and
treatable) disease that may have been unsuspected. The
major histologic features associated with IgG4-RD have
been well described5,10,27,28 and include (1) a dense
lymphoplasmacytic inflammatory infiltrate with increased
numbers of IgG4þ plasma cells and often increased
eosinophils; (2) a storiform pattern of fibrosis; and (3)
obliterative vasculitis.
The Inflammatory Infiltrate
While IgG4-RD is usually described in terms of increased
IgG4þ plasma cells, T cells (predominantly CD4þ) actually
comprise the bulk of the inflammatory infiltrate (Figure 4,
A and B). Other components include small aggregates of B
cells (which may be distributed in germinal centers,
depending on anatomic location), along with interspersed
macrophages and the requisite IgG4þ plasma cells (Figure
4, C and D). These may be diffusely increased (Figure 3, E
and H) or distributed in variably dense patches (Figure 4,
D). Tissue eosinophilia is usually present (Figure 3, C). Not
characteristic are epithelioid granulomas, multinucleated
giant cells, overt necrosis, and neutrophilic infiltrates in
sites other than the lung (see below). If present, these
findings should prompt consideration of alternative diag-
noses.
The number of IgG4þ plasma cells should be quantified in
some manner, either as the number per high-power field or
as the IgG4þ:IgGþ plasma cell ratio. The absolute number of
IgG4þ plasma cells often varies with anatomic site, and
many organ-specific cutoff values of IgG4þ plasma cells per
high-power field have been proposed.5,27 These range from
greater than 10 to greater than 200 IgG4þ plasma cells, with
values in most sites falling somewhere between 10 and 50.
IgG4-Related Disease—Weindorf & Frederiksen 1479
Figure 4. A, Dense lymphoplasmacytic inflammatory infiltrate in pericardial tissue taken from a patient with IgG4-related mediastinitis. B, Most of
the cells in the infiltrate are T cells. C, Higher magnification view of the infiltrate showing many plasma cells. D, In this case, the IgG4þ plasma cells
exhibit a patchy distribution (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [C]; CD3, immunoperoxidase, original magnification
3100 [B]; IgG4, immunoperoxidase, original magnification 3100 [D]). Abbreviation: IgG4, immunoglobulin G4.

Alternatively, an elevated IgG4þ:IgGþ plasma cell ratio may
be more specific for IgG4-RD, with most authors recom-
mending a ratio greater than 40% as characteristic.5,27–30 The
ratio may be especially useful in evaluating specimens that
lack large absolute numbers of IgG4þ plasma cells, such as
small needle biopsy samples or specimens consisting
predominantly of paucicellular fibrosis.
Storiform Fibrosis
This pattern is defined by dense, wirelike strands of
fibrotic collagen deposition radiating outward from a central
point (Figure 3, A and F; Figure 5, A and B). The collagen
fibers contain fibroblasts and myofibroblasts, and may
resemble similar arrangements associated with fibrohistio-
cytic malignancies. In cases of long-standing fibrosis, a
sparsely cellular or acellular fibrotic pattern may predom-
inate (Figure 5, B).
Obliterative Vasculitis
Inflammatory infiltrates fill both the walls and lumina of
the affected vessels, producing partial or complete obliter-
ation (Figure 6, A and B). Veins are most often involved, and
fully obliterated veins may sometimes be identified by their
1480 Arch Pathol Lab Med—Vol 141, November 2017
proximity to adjacent arteries, which are usually spared.
However, arteritis is sometimes observed, especially in the
lung, and elastic stains may be required to highlight the
residual vessel walls (Figure 6, B). Despite the dense
inflammatory infiltrate, necrotizing vasculitis is not charac-
teristic.
Caveats and Differential Diagnosis
While the histopathologic and immunohistochemical
findings are distinctive, they are not always present to the
same extent within each affected organ. Salivary and
lacrimal glands, for example, may show more of a thick,
collagenous pattern of fibrosis (Figure 3, A and F). These
organs are also less likely to feature obliterative vasculitis,
and the inflammatory infiltrates may manifest instead as
many lymphoid follicles, albeit with increased numbers of
IgG4þ plasma cells. In the lung,31 plasma cell–rich infiltrates
are often distributed along vessels and lymphatic channels,
and may surround bronchioles concentrically. In contrast to
other tissues, the infiltrates may include small neutrophilic
aggregates within alveolar spaces, although abscess forma-
tion and necrosis are not characteristic. Typical storiform
fibrosis may be absent, and obliterative vasculitis affects
IgG4-Related Disease—Weindorf & Frederiksen
Figure 5. A, Storiform fibrosis from the lacrimal gland biopsy shown in Figure 3, F. B, Storiform fibrosis within periureteral tissue in a case of IgG4-
related retroperitoneal fibrosis. The specimen consists largely of fibrotic tissue with a sparsely cellular inflammatory infiltrate (hematoxylin-eosin,
original magnification 3 100 [A and B]). Abbreviation: IgG4, immunoglobulin G4.
Figure 6. Obliterative phlebitis in a case of IgG4-related pancreatitis (type I autoimmune pancreatitis). A, Hematoxylin-eosin stain. B, Movat
pentachrome stain demonstrating residual elastic fibers (original magnification 3 100 [A and B]). Abbreviation: IgG4, immunoglobulin G4.

both pulmonary arteries and veins. Some of the most
variable IgG4-related morphologies occur in lymph nodes,
in which 5 separate patterns are recognized and typical
storiform fibrosis is again often absent.7 Since not all
histologic features may be present within a given specimen,
core needle biopsies may not sample the most important
diagnostic areas, and therefore larger specimens should be
obtained whenever possible. In addition, owing to their
highly variable patterns of involvement, enlarged lymph
nodes may not be optimal specimens for diagnosing IgG4-
RD prospectively.32,33
Further complicating interpretation is the observation that
increased numbers of IgG4þ plasma cells is not a finding
specific to IgG4-RD. Many other benign and malignant
processes may also feature increased IgG4þ plasma cells,27,34
including granulomatosis with polyangiitis,35 multicentric
Castleman disease,36 Rosai-Dorfman disease,37 marginal
zone lymphoma,38–41 pancreatic adenocarcinoma,42,43 and
even reactive lymphadenopathy,44 to name just a few.
Additionally, the histologic patterns of both these and other
Arch Pathol Lab Med—Vol 141, November 2017
entities sometimes overlap with that of true IgG4-RD. These
mimics include lymphoproliferative/histiocytic disorders
(multicentric Castleman disease, Rosai-Dorfman disease,
lymphoma), autoimmune disorders (Sjögren syndrome in
salivary and lacrimal glands, primary sclerosing cholangitis
in the liver), spindle cell neoplasms (inflammatory myofi-
broblastic tumor, desmoid fibromatosis), and infections
(especially within the lung). Thus, a specimen with
increased IgG4þ plasma cells and IgG4-RD–like histology
must also be interpreted within the context of the associated
clinical history. In some cases, judicious use of additional
immunohistochemical or special stains may also provide
important diagnostic clues.
CLINICAL DIAGNOSIS, TREATMENT,
AND THE ROLE OF THE PATHOLOGIST
Beyond the histologic findings, the clinical diagnosis of
IgG4-RD requires additional correlation with laboratory and
radiologic evaluations. According to the proposed Compre-
hensive Diagnostic Criteria for IgG4-RD,29 a definite
IgG4-Related Disease—Weindorf & Frederiksen 1481
diagnosis of IgG4-RD may be made by demonstrating (1)
organ involvement; (2) a serum IgG4 level exceeding 135
mg/dL; and (3) greater than 10 IgG4þ plasma cells per high-
power field and an IgG4þ:IgGþ plasma cell ratio of at least
40% on histologic tissue sections. In contrast, if organ
involvement is present along with only 1 of the remaining 2
criteria, a diagnosis of IgG4-RD is considered ‘‘possible’’ or
‘‘probable.’’ Confirmation then depends upon the radiologic
appearance of the affected organ or organs, organ-specific
histologic criteria, or the responsiveness of patient symp-
toms to a trial of steroids. An elevated serum IgG4 level
(.135 mg/dL) is suggestive of IgG4-RD but is not specific,
and may be found in patients with chronic sinusitis,
pneumonia, other autoimmune diseases, and certain ma-
lignancies.45 Moreover, although the negative predictive
value for an elevated serum IgG4 is high (96%),45 occasional
patients will have a normal level despite characteristic IgG4-
RD histology on a tissue biopsy.
Once the diagnosis of IgG4-RD has been established,
most patients’ symptoms respond within several weeks to
an initial course of glucocorticoids. For IgG4-related
autoimmune pancreatitis, both retrospective46,47 and pro-
spective48 studies have demonstrated the efficacy of
glucocorticoids at inducing an initial remission. Subsequent
management may include observation or maintenance
therapy with either steroids or steroid-sparing immuno-
modulatory agents. For nonresponders or for patients
unable to tolerate steroids, B-cell depletion with rituximab
has shown efficacy in retrospective studies.49–51
The availability and efficacy of therapy for IgG4-RD,
along with its myriad clinical presentations, further
highlight the pathologist’s critical role as both caregiver
and guide to treatment. Patients with symptomatic, active
IgG4-RD require treatment.4 Some—those with aortitis,
retroperitoneal fibrosis, proximal biliary strictures, hyper-
trophic pachymeningitis, pancreatic enlargement, or peri-
carditis—require treatment urgently to prevent irreversible
disease-related complications or death. Accurate and
timely diagnosis of this condition opens the door to
treatment and helps to avoid both complications and
unnecessary surgical procedures (such as the Whipple
resections that furnished so many autoimmune pancrea-
titis specimens before IgG4-RD was recognized). The chief
responsibilities of the pathologist are awareness of the
disease, recognition of its characteristic histology, and
appropriate communication with the clinical team. Be-
cause histology constitutes only a part of the diagnostic
criteria (albeit a major one), one consensus statement
recommends a 3-tiered approach to reporting on suspect-
ed IgG4-RD specimens.5,27 Cases ‘‘histologically highly
suggestive of IgG4-RD’’ show, in addition to increased
IgG4þ plasma cells, at least 2 of the following: a dense
lymphoplasmacytic infiltrate, fibrosis (usually storiform),
and obliterative vasculitis (usually phlebitis). Cases show-
ing ‘‘probable histologic features of IgG4-RD’’ may show
only 1 of these features, may be insufficiently large (needle
cores), or may derive from an anatomic site not typically
associated with IgG4-RD. The remaining cases may be
described as having ‘‘insufficient histopathologic evidence
of IgG4-RD,’’ with the caveat that the diagnosis is not
excluded. While not providing a definitive diagnosis, these
designations at a minimum alert the clinical team to the
possibility of IgG4-RD, which may prompt further
diagnostic laboratory and radiologic evaluations.
1482 Arch Pathol Lab Med—Vol 141, November 2017
CONCLUSIONS
IgG4-RD is a systemic autoimmune disease with distinc-
tive histopathology and protean clinical implications.
Histopathologic examination of affected tissues is crucial
for diagnosis, partly because the pattern is so distinctive, but
also because the disease may be unsuspected owing to its
diverse and nonspecific clinical presentations. Pathologists’
familiarity with and prompt recognition of the features of
IgG4-RD allows clinicians to institute proper treatment and
avoid unnecessary comorbidities.
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