IgG4-Related Lymphadenopathy.

Abstract

Lymphadenopathy is frequently observed in patients with immunoglobulin G4-related disease (IgG4-RD) and sometimes appears as the first manifestation of the disease. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great histological diversity, with at least 5 histological subtypes. Indeed, lymph node biopsy may be performed under the suspicion that the lymphadenopathy is a malignant lymphoma or other lymphoproliferative disorder. The diagnosis of IgG4-RD is characterized by both elevated serum IgG4 (>135 mg/dL) and histopathological features, including a dense lymphoplasmacytic infiltrate rich in IgG4(+) plasma cells (IgG4(+)/IgG(+) plasma cell ratio >40%). However, patients with hyper-interleukin (IL-) 6 syndromes such as multicentric Castleman's disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node involvement and often fulfill the diagnostic criteria for IgG4-RD. Owing to these factors, IgG4-RD cannot be differentiated from hyper-IL-6 syndromes on the basis of histological findings alone. Laboratory analyses are crucial to differentiate between the 2 diseases. Hyper-IL-6 syndromes are characterized by elevated serum levels of IgG, IgA, IgM, and C-reactive protein (CRP); thrombocytosis; anemia; hypoalbuminemia; hypocholesterolemia. In contrast, IgG4-RD does not share any of these characteristics. Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses.

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Hindawi Publishing Corporation
International Journal of Rheumatology
Volume 2012, Article ID 572539, 8 pages
doi:10.1155/2012/572539
Review Article
IgG4-Related Lymphadenopathy
YasuharuSatoand TadashiYoshino
Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
Correspondence should be addressed to Yasuharu Sato, satou-y@cc.okayama-u.ac.jp
Received 28 November 2011; Accepted 30 March 2012
Academic Editor: Yoh Zen
Copyright © 2012 Y. Sato and T. Yoshino. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Lymphadenopathy is frequently observed in patients with immunoglobulin G4-related disease (IgG4-RD) and sometimes appears
as the first manifestation of the disease. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great
histological diversity, with at least 5 histological subtypes. Indeed, lymph node biopsy may be performed under the suspicion that
the lymphadenopathy is a malignant lymphoma or other lymphoproliferative disorder. The diagnosis of IgG4-RD is characterized
by both elevated serum IgG4 (>135mg/dL) and histopathological features, including a dense lymphoplasmacytic infiltrate rich
in IgG4+plasma cells (IgG4+/IgG+plasma cell ratio >40%). However, patients with hyper-interleukin (IL-) 6 syndromes such
as multicentric Castleman’s disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node
involvement and often fulfill the diagnostic criteria for IgG4-RD. Owing to these factors, IgG4-RD cannot be differentiated from
hyper-IL-6 syndromes on the basis of histological findings alone. Laboratory analyses are crucial to differentiate between the
2 diseases. Hyper-IL-6 syndromes are characterized by elevated serum levels of IgG, IgA, IgM, and C-reactive protein (CRP);
thrombocytosis;anemia;hypoalbuminemia;hypocholesterolemia.Incontrast,IgG4-RDdoesnotshareanyofthesecharacteristics.
Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses.
1.Introduction
Immunoglobulin G4-related disease (IgG4-RD) frequently
involves lymph nodes in a localized or systemic fashion [1–
3]. Indeed, approximately 80% of patients with autoimmune
pancreatitis (IgG4-related pancreatitis) has lymphadenopa-
thy, most commonly involving the mediastinal and intraab-
dominal lymph nodes [4]. Moreover, lymphadenopathy
sometimes appears as the first manifestation of IgG4-RD [1–
3].
IgG4-RD is an inflammatory condition characterized
by a dense lymphoplasmacytic infiltrate rich in IgG4+
plasma cells; an IgG4+/IgG+plasma cell ratio of >40% is
an important diagnostic criterion for the disease [3, 5].
Patients with IgG4-related lymphadenopathy occasionally
show systemic lymphadenopathy and elevated serum levels
of IgG4 and IgE, and less often show low titers of various
autoantibodies [1–3, 5, 6]. Therefore, the disease often
shares clinical characteristics with malignant lymphoma,
multicentric Castleman’s disease, and immune-mediated
conditions [1–3, 7, 8]. However, the patients often show
an excellent response to steroid therapy and do not show
the B symptoms of fever, fatigue, weight loss, and night
sweats. Moreover, no monoclonal immunoglobulin gene
rearrangement is observed [1, 3].
Recently, several studies dealing with the morphologi-
cal and immunohistological findings of IgG4-related lym-
phadenopathy have been performed [1–3]. Furthermore,
these studies have shown that lymphadenopathies are histo-
logicallydistinctfromtheeffectsofIgG4-RDonotherorgans
(i.e., storiform fibrosis and obliterative phlebitis are usually
absent) [1–3]. From this histological diversity, we consider
the presence of 5 subtypes of IgG4-related lymphadenopa-
thy (Table 1): multicentric Castleman’s disease-like, reac-
tive follicular hyperplasia-like, interfollicular expansion and
immunoblastosis, progressively transformed germinal center
(PTGC-) type, and inflammatory pseudotumor-like IgG4-
related lymphadenopathy [1–3].

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Table 1: Histological subtypes of IgG4-related lymphadenopathy.
Histological typeDistribution of IgG4+plasma cells
Interfollicular
Interfollicular
Interfollicular
Intragerminal center
Interfollicular
Lymphadenopathy
Systemic
Localized
Systemic
Localized/systemic
Localized
I
II
III
IV
V
Multicentric Castleman’s disease-like
Reactive follicular hyperplasia-like
Interfollicular expansion and immunoblastosis
PTGC-type
Inflammatory pseudotumor (IPT-) like
PTGC; progressively transformed germinal centers.
Table 2: Distinction between IgG4-related disease and hyper-IL-6 syndromes.
IgG4-related disease
IgG↑(IgG4↑), IgE↑
Elevated
Normal (∼sightly elevated)
Normal (∼sightly elevated)
No
No
No
No
Hyper-IL-6 syndromes
IgG↑(IgG1∼IgG4↑), IgA↑, IgM -/↑, IgE↑
Normal (∼sightly elevated)
Elevated
Elevated
Yes
Yes
Yes
Yes
Serum immunoglobulin
Serum IgG4/IgG ratio
Serum IL-6
Serum CRP
Thrombocytosis
Anemia
Hypoalbuminemia
Hypocholesterolemia
Hyper IL-6 syndromes; multicentric Castleman’s disease, rheumatoid arthritis, and other immune-mediated conditions.
2.Clinicaland Pathological Featuresof
IgG4-RelatedLymphadenopathy
2.1. Type I: Multicentric Castleman’s Disease-Like. This type
is frequently characterized by systemic lymphadenopathy
[1–3]. Histologically, the lymph node shows interfollicular
expansion with normal to hyperplastic germinal centers,
penetrated by blood vessels. Abundant plasma cells and
scattered eosinophils are apparent in the interfollicular
zone (Figure 1). Although these features are similar to the
features of multicentric Castleman’s disease (MCD), MCD is
usually characterized by the presence of small and regressive
germinalcentersandnoeosinophilinfiltration[8].However,
pathological diagnosis is difficult, because MCD sometimes
fulfillsthediagnosticcriteriaforIgG4-RD,namely,abundant
IgG4+plasma cell infiltration (i.e., IgG4+/IgG+plasma cell
ratio >40%) and elevated serum IgG4 levels [8]. Therefore,
the 2 diseases cannot be differentiated on the basis of
histological findings alone, and laboratory analyses are
critical for a definitive diagnosis (Table 2).
2.2. Type II: Reactive Follicular Hyperplasia-Like. The lymph
nodes usually exhibit reactive follicular hyperplasia, and
sinuses are intact. The reactive follicles comprise a germinal
center surrounded by a discrete mantle zone. The inter-
follicular zone contains a small to moderate number of
mature plasma cells, with small lymphocytes and eosinophils
(Figure 2). This type is frequently found in the regional
lymph nodes of IgG4-RD [1, 2].
2.3. Type III: Interfollicular Expansion and Immunoblasto-
sis. This type is also frequently characterized by systemic
lymphadenopathy [1–3]. Histologically, the lymph nodes
show marked interfollicular expansion with prominent high
endothelial venules and patent sinuses. The lymphoid fol-
licles are usually normal to atrophic. A mixed infiltrate of
small lymphocytes, immunoblasts, immature plasma cells,
mature plasma cells, and scattered eosinophils is observed
(Figure 3). The morphological features overlap with those
of atypical lymphoplasmacytic and immunoblastic prolifer-
ation (ALPIBP), which is a characteristic lymphadenopathy
observed in patients with rheumatoid arthritis (RA), sys-
temic lupus erythematosus (SLE), and other autoimmune
diseases [9].
This type is somewhat similar to angioimmunoblastic T-
cell lymphoma. However, it is noteworthy that these lesions
lack clusters of clear cells and definite cytologic atypia typical
of the lymphoma. Moreover, CD21+follicular dendritic
cell proliferation, the presence of CD10+T-cells, and T-cell
receptor gene rearrangement are not observed [1–3].
2.4. Type IV: Progressively Transformed Germinal Centers
(PTGC)-Type. PTGC is a benign condition of unknown
origin characterized by reactive follicular hyperplasia in the
lymph nodes [10, 11]. Recently, we were the first to report
cases of patients with IgG4-RD in PTGC of lymph nodes
(PTGC-type IgG4-related lymphadenopathy) [3]. In this
type, the lymph nodes demonstrate numerous lymphoid
follicles with hyperplastic germinal centers and a distinct
mantle zone but no expansion of the interfollicular zone.
PTGCs are also apparent, appearing as round to oval
structures with diameters 2 or 3 times the diameter of the
other reactive follicles. They are predominantly composed of
small lymphocytes, centrocytes, centroblasts, and numerous
mature plasma cells and plasmacytoid cells. The interfollicu-
larzoneshowsinfiltrationbynumerouseosinophils,whereas

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International Journal of Rheumatology3
(a)(b)
(c)(d)
Figure1:IgG4-relatedlymphadenopathy(typeI).(a)Thelymphnodeshowsinterfollicularexpansionwithnormaltohyperplasticgerminal
centers.(b)Thegerminalcentersarepenetratedbybloodvessels.(c)Alargenumberofmatureplasmacellswithsmalllymphocytesareseen.
(d) Immunostaining shows numerous IgG4+cells in the interfollicular zone.
(a) (b)(c)
Figure 2: IgG4-related lymphadenopathy (type II). (a) The lymph node shows reactive follicular hyperplasia with intact sinuses. (b) A small
to moderate number of mature plasma cells with small lymphocytes and eosinophils are present. (c) Immunostaining shows numerous
IgG4+cells in the interfollicular zone.

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4International Journal of Rheumatology
(a)(b)
(c)(d)
Figure 3: IgG4-related lymphadenopathy (type III). (a) The lymph node shows interfollicular expansion with normal to small germinal
centers. (b) Hypervascular proliferation is seen in the interfollicular zone. (c) A mixed infiltrate of small lymphocytes, immunoblasts,
immature plasma cells, mature plasma cells, and scattered eosinophils is observed (d) Numerous IgG4+cells are present in the interfollicular
zone.
T zones are indistinct (Figure 4). Interestingly, a unique
feature of this type is the localization of the majority of
IgG4+plasma cells in the germinal centers, with only a small
number present in the interfollicular zone [12]. However, in
a few cases of this type, IgG4+plasma cells are detected in
both the germinal centers and interfollicular zone [12].
Patients with this type have a uniform clinicopathology.
The patients initially present with asymptomatic localized
submandibular lymphadenopathy, with half of them show-
ing progression to extranodal IgG4-RD, systemic disease, or
both during the follow-up period [12].
2.5. Type V: Inflammatory Pseudotumor (IPT)-Like. In this
type, the lymph nodes show asymptomatic localized lym-
phadenopathy [13]. Histologically, most of the lymph node
is occupied by hyalinized fibrous tissue. A few residual
lymphoid follicles with hyperplastic germinal centers and a
focally dense lymphoid infiltrate are observed in the lymph
node. Small lymphocytes, plasma cells, and eosinophils
infiltrate the dense sclerotic tissue (Figure 5). This type is
rare; we have encountered only 2 cases, and no other cases
have been reported thus far [1, 13].
These histological findings are somewhat similar to
those characteristic of nodal IPT. Nodal IPT has been
histologically classified into 3 stages (i.e., Stage I, II, and III)
[14,15].IPT-likeIgG4-relatedlymphadenopathyissimilarto
lymphadenopathyinpatientswithstageIIInodalIPT[1,13].
However, IPT-like IgG4-related lymphadenopathy and nodal
IPT are clinically different, because patients with nodal IPT
usually show symptoms that are suggestive of lymphoid
malignancy (e.g., fever, fatigue, weight loss, and night
sweats) [14, 15]. In contrast, patients with IPT-like IgG4-
related lymphadenopathy show no symptoms suggestive of
lymphoid malignancy [13]. Moreover, nodal IPT is positive
forsmoothmuscleactin[14,15],whichfurtherdifferentiates
it from IPT-like IgG4-related lymphadenopathy [13].
3.Differential Diagnosis between IgG4-RD and
Hyper-Interleukin(IL-) 6 Syndromes
Hyper-IL-6 syndromes such as MCD, RA, and other
immune-mediated conditions are characterized by elevated
serum IL-6 levels [16, 17]. Moreover, IL-6 itself functions
to raise the serum levels of IgG4 and other IgG subclasses

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International Journal of Rheumatology5
(a)(b)
(c) (d)
(e)(f)
Figure 4: IgG4-related lymphadenopathy (type IV). (a) The lymph node shows marked follicular hyperplasia with PTGC. (b) The PTGCs
appear as round to oval structures 2-3 times the diameter of the other reactive follicles. (c) Numerous eosinophils infiltrate the interfollicular
zone. (d) The majority of IgG4+plasma cells reside in the germinal centers, with a small number present in the interfollicular zone. (e), (f):
The IgG4+/IgG+plasma cell ratio is >40% (e: IgG4-immunostain, f: IgG-immunostain).
[18, 19]. In fact, MCD, RA, and other immune-mediated
conditions sometimes fulfill the histological diagnostic cri-
teria for IgG4-RD (Figures 6 and 7) and are characterized
by elevated serum IgG4 levels [8, 20–23]. This complicates
diagnosis, owing to the fact that hyper-IL-6 syndromes
frequently involve lymph nodes. Because of this, laboratory
analysesarecrucialtodifferentiatebetweenthe2diseases[8].
Unlike IgG4-RD, hyper-IL-6 syndromes are characterized
by elevated serum levels of IgG, IgA, IgM, and C-reactive
protein (CRP); thrombocytosis; anemia; hypoalbumine-
mia; hypocholesterolemia (Table 2). These abnormalities are
closely related to high IL-6 levels [8, 17, 20]. On the other
hand, elevated serum IgE is often typical of IgG4-RD [1,
3, 5]. However, IL-6 plays a critical role in IL-4-driven IgE