Hindawi Publishing Corporation
International Journal of Rheumatology
Volume 2012, Article ID 572539, 8 pages
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, firstname.lastname@example.org
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
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);
Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses.
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 . Moreover, lymphadenopathy
sometimes appears as the first manifestation of IgG4-RD [1–
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-
(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].
2International Journal of Rheumatology
Table 1: Histological subtypes of IgG4-related lymphadenopathy.
Histological type Distribution of IgG4+plasma cells
Multicentric Castleman’s disease-like
Reactive follicular hyperplasia-like
Interfollicular expansion and immunoblastosis
Inflammatory pseudotumor (IPT-) like
PTGC; progressively transformed germinal centers.
Table 2: Distinction between IgG4-related disease and hyper-IL-6 syndromes.
Normal (∼sightly elevated)
Normal (∼sightly elevated)
IgG↑(IgG1∼IgG4↑), IgA↑, IgM -/↑, IgE↑
Normal (∼sightly elevated)
Serum IgG4/IgG ratio
Hyper IL-6 syndromes; multicentric Castleman’s disease, rheumatoid arthritis, and other immune-mediated conditions.
2.Clinicaland Pathological Featuresof
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
pathological diagnosis is difficult, because MCD sometimes
IgG4+plasma cell infiltration (i.e., IgG4+/IgG+plasma cell
ratio >40%) and elevated serum IgG4 levels . 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
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) . 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-
International Journal of Rheumatology3
(d) Immunostaining shows numerous IgG4+cells in the interfollicular zone.
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.
4International Journal of Rheumatology
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
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 . However, in
a few cases of this type, IgG4+plasma cells are detected in
both the germinal centers and interfollicular zone .
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 .
2.5. Type V: Inflammatory Pseudotumor (IPT)-Like. In this
type, the lymph nodes show asymptomatic localized lym-
phadenopathy . 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)
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 . Moreover, nodal IPT is positive
it from IPT-like IgG4-related lymphadenopathy .
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
International Journal of Rheumatology5
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
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
6International Journal of Rheumatology
Figure 5: IgG4-related lymphadenopathy (type V). This is a regional lymph node with IgG4-related cholangitis. (a) The majority of the
lymph node is replaced by hyalinized fibrous tissue. (b) Mature plasma cells infiltrate the hyalinized fibrous tissue. (c) The mature plasma
cells are IgG4+.
Figure 6: Multicentric Castleman’s disease with abundant IgG4+cells. (a) Atrophic germinal centers and interfollicular expansion are seen.
(b) Sheets of proliferating mature plasma cells are present in the interfollicular zone. (c) The majority of mature plasma cells are positive for
IgG4 (IgG4+/IgG+plasma cell ratio >70%).
synthesis . As such, hyper-IL-6 syndromes may also be
characterized by elevated serum IgE levels, rendering serum
IgE level less useful as a biomarker for a differential diagnosis
of the 2 diseases [8, 22].
Unlike IgG4-RD that involves other organs, IgG4-related
lymphadenopathy shows histological diversity, with 5 dis-
tinct subtypes. Moreover, recently, Takahashi et al. reported
a unique case of IgG4-related lymphadenopathy with epithe-
lioid granuloma . This histological diversity complicates
the diagnosis of IgG4-related lymphadenopathy, especially
considering the similarities of the different histological
subtypes to the histological characteristics of other organs
involved in IgG4-RD.
Indeed, hyper-IL-6 syndromes can often fulfill the
diagnostic criteria for IgG4-RD. Therefore, IgG4-RD, and
especially IgG4-related lymphadenopathy, cannot be differ-
entiated on the basis of histological findings alone. The
diagnosis of IgG4-RD needs to be based not only on
International Journal of Rheumatology7
(a) (b) (c)
Figure 7: Rheumatic lymphadenopathy with abundant IgG4+cells. (a), (b) The lymph node shows marked follicular hyperplasia and
interfollicular plasmacytosis with small lymphocytes; eosinophil infiltration is absent. (c) The majority of mature plasma cells are positive
for IgG4 (IgG4+/IgG+plasma cell ratio >60%).
pathological findings but also on clinical and laboratory
The authors thank Dr. Naomi Sasaki (Department of
the histology presented in Figure 5.
 Y. Sato, K. Notohara, M. Kojima, K. Takata, Y. Masaki,
and T. Yoshino, “IgG4-related disease: historical overview
and pathology of hematological disorders,” Pathology Interna-
tional, vol. 60, no. 4, pp. 247–258, 2010.
 W. Cheuk, H. K. L. Yuen, S. Y. Y. Chu, E. K. W. Chiu, L. K.
Lam, and J. K. C. Chan, “Lymphadenopathy of IgG4-related
32, no. 5, pp. 671–681, 2008.
 Y. Sato, M. Kojima, K. Takata et al., “Systemic IgG4-related
lymphadenopathy: a clinical and pathologic comparison to
multicentric Castleman’s disease,” Modern Pathology, vol. 22,
no. 4, pp. 589–599, 2009.
 H. Hamano, N. Arakura, T. Muraki, Y. Ozaki, K. Kiyosawa,
and S. Kawa, “Prevalence and distribution of extrapancreatic
lesions complicating autoimmune pancreatitis,” Journal of
Gastroenterology, vol. 41, no. 12, pp. 1197–1205, 2006.
 Y. Masaki, N. Kurose, and H. Umehara, “IgG4-related disease:
a novel lymphoproliferative disorder discovered and estab-
lished in Japan in the 21st century,” Journal of Clinical and
 Y. Sato, K. I. Ohshima, K. Ichimura et al., “Ocular adnexal
IgG4-related disease has uniform clinicopathology,” Pathology
International, vol. 58, no. 8, pp. 465–470, 2008.
 Y. Sato, K. Takata, K. Ichimura et al., “IgG4-producing
marginal zone B-cell lymphoma,” International Journal of
Hematology, vol. 88, no. 4, pp. 428–433, 2008.
 Y. Sato, M. Kojima, K. Takata et al., “Multicentric Castleman’s
disease with abundant IgG4-positive cells: a clinical and
vol. 63, no. 12, pp. 1084–1089, 2010.
 C. H. Koo, B. N. Nathwani, and C. D. Winberg, “Atypical lym-
phoplasmacytic and immunoblastic proliferation in lymph
nodes of patients with autoimmune disease (autoimmune-
disease-associated lymphadenopathy),” Medicine, vol. 63, no.
5, pp. 274–290, 1984.
 K. Lennert and H. K. M¨ uller–Hermelink, “Lymphocyten
and ihre funktionsformen morphologie, organization und
immunologische bedeutung,” Verhandlungen der Anatomis-
chen Gesellschaft, vol. 69, pp. 19–62, 1975.
 B. M. Osborne and J. J. Butler, “Clinical implications of
progressive transformation of germinal centers,” American
Journal of Surgical Pathology, vol. 8, no. 10, pp. 725–733, 1984.
 Y. Sato, D. Inoue, N. Asano, K. Takata, H. Asaoku, Y.
Maeda et al., “Association between IgG4-related disease and
progressively transformed germinal centers of lymph nodes,”
Modern Pathology. In press.
 Y. Sato, M. Kojima, K. Takata, H. Huang, E. Hayashi, and
A. Manabe, “Immunoglobulin G4-related lymphadenopa-
thy with inflammatory pseudotumor-like features,” Medical
Molecular Morphology, vol. 44, no. 3, pp. 179–182, 2011.
 C. A. Moran, S. Suster, and S. L. Abbondanzo, “Inflammatory
pseudotumor of lymph nodes: a study of 25 cases with
emphasis onmorphological heterogeneity,” Human Pathology,
vol. 28, no. 3, pp. 332–338, 1997.
 M. Kojima, S. Nakamura, K. Shimizu et al., “Inflamma-
tory pseudotumor of lymph nodes: clinicopathologic and
immunohistological study of 11 Japanese cases,” International
Journal of Surgical Pathology, vol. 9, no. 3, pp. 207–214, 2001.
 G. Frizzera, “Atypical lymphoproliferative disorders,” in Neo-
plastic Hematopathology, D. M. Knowles, Ed., pp. 569–622,
Lippincott Williams & Wilkins, Baltimore, Md, USA, 2nd
 N. Nishimoto, K. Terao, T. Mima, H. Nakahara, N. Takagi,
and T. Kakehi, “Mechanisms and pathologic significances
8International Journal of Rheumatology
in increase in serum interleukin-6 (IL-6) and soluble IL-
6 receptor after administration of an anti-IL-6 receptor
antibody, tocilizumab, in patients with rheumatoid arthritis
 J. N. Bertolini and E. M. Benson, “The role of human
Interleukin-6 in B-cell isotype regulation and differentiation,”
Cellular Immunology, vol. 125, no. 1, pp. 197–209, 1990.
 Y. Kawano, T. Noma, K. Kou, I. Yoshizawa, and J. Yata,
“Regulation of human IgG subclass production by cytokines:
human IgG subclass production enhanced differentially by
interleukin-6,” Immunology, vol. 84, no. 2, pp. 278–284, 1995.
 M. Kojima, N. Nakamura, N. Tsukamoto et al., “Atypi-
cal lymphoplasmacytic and immunoblastic proliferation of
autoimmune disease : clinicopathologic and immunohisto-
Hematopathology, vol. 50, no. 2, pp. 113–119, 2010.
 J. D. Strehl, A. Hartmann, and A. Agaimy, “Numerous IgG4-
positive plasma cells are ubiquitous in diverse localised non-
specific chronic inflammatory conditions and need to be
distinguished from IgG4-related systemic disorders,” Journal
of Clinical Pathology, vol. 64, no. 3, pp. 237–243, 2011.
 N. Asano and Y. Sato, “Rheumatoid lymphadenopathy with
abundant IgG4+plasma cells: a case mimicking IgG4-related
disease,” Journal of Clinical and Experimental Hematopathol-
ogy. In press.
 M. Yamamoto, T. Tabeya, Y. Naishiro, H. Yajima, K. Ishigami,
Y. Shimizu et al., “Value of serum IgG4 in the diagnosis of
IgG4-related disease and in differentiation from rheumatic
diseases and other diseases,” Modern Rheumatology. In press.
 H. H. Jabara, D. J. Ahern, D. Vercelli, and R. S. Geha,
“Hydrocortisone and IL-4 induce IgE isotype switching in
human B cells,” Journal of Immunology, vol. 147, no. 5, pp.
K. Hara et al., “Primary IgG4-related lymphadenopathy with
prominent granulomatous inflammation and reactivation of
Epstein-Barr virus,” Virchows Archiv, vol. 460, no. 2, pp. 225–