http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–4 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.985356
CASE REPORT
Multicentric Castleman disease mimicking IgG4-related disease: A case report
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Yasumori Izumi1, Hayato Takeshita1, Yuji Moriwaki2, Keiko Hisatomi3, Masakazu Matsuda1, Natsuki Yamashita1, Chieko Kawahara1, Yoshika Shigemitsu1, Nozomi Iwanaga1, Atsushi Kawakami4, Hirokazu Kurohama5, Daisuke Niino5, Masahiro Ito5, and Kiyoshi Migita1 1Departments of General Internal Medicine and Rheumatology, Nagasaki Medical Center, Omura City, Nagasaki, Japan, 2Departments of Hematology,
Nagasaki Medical Center, Omura City, Nagasaki, Japan, 3Departments of Respiratory Medicine, Nagasaki Medical Center, Omura City, Nagasaki, Japan, 4First Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, and 5Departments of Pathology,
Nagasaki Medical Center, Omura City, Nagasaki, Japan Abstract
Keywords
A 50-year-old woman was referred to our hospital for shoulder joint stiffness. She had a history of polyclonal hypergammaglobulinemia and an elevated C-reactive protein level. Her laboratory data revealed an elevated serum immunoglobulin G4 (IgG4) level, hypergammaglobulinemia, and rheumatoid factor positivity in the absence of anticyclic citrullinated peptide antibody. [18F]Fluorodeoxyglucose positron emission tomography showed significant [18F]-fluorodeoxyglucose uptake in multiple lymph nodes (axillary, hilar, para-aortic, and inguinal). Biopsy of the inguinal lymph node showed expansion of the interfollicular areas by heavily infiltrating plasma cells, consistent with multicentric Castleman disease (MCD). Immunohistochemical analysis revealed a 37.3% IgG4-positive:IgG-positive plasma cell ratio, indicating overlapping IgG4-related disease. However, serological cytokine analysis revealed elevated levels of interleukin-6 (9.3 pg/ml) and vascular endothelial growth factor (VEGF) (1210 pg/ml), which are compatible with MCD. Corticosteroid treatment resolved the serological and imaging abnormalities. IgG4-related disease can mimic MCD, and it is crucial to distinguish between these two diseases. Serum interleukin-6 and VEGF levels may help to discriminate MCD from IgG4-related disease.
IgG4-related disease, Interleukin-6, Multicentric Castleman disease
Introduction Multicentric Castleman disease (MCD) is a rare polyclonal lymphoproliferative disorder that manifests as lymphadenopathy and inflammatory symptoms [1,2]. IgG4-related disease (IgG4-RD) is clinically characterized by tumor-like enlargement of exocrine glands or extranodal tissues and a high serum IgG4 level [3]. IgG4-RD involves the regional and/or systemic lymph nodes and sometimes histologically mimics MCD [4]. Moreover, the lymph node abnormalities associated with IgG4-RD show histological findings similar to those associated with MCD [5]. Therefore, the clinical and histological features of IgG4-RD can be quite similar to and sometimes indistinguishable from those of MCD. The abnormal clinical findings seen in MCD, such as general fatigue, anemia, polyclonal hypergammaglobulinemia, and elevated C-reactive protein (CRP) levels, may be related to high interleukin-6 (IL-6) levels [6]. The diagnosis and treatment of MCD are challenging because patients with MCD require intensive therapies including corticosteroids, immunosuppressants, or tocilizumab, an IL-6 receptor antibody [7]. We herein report a case involving a patient with MCD with elevated serum IL-6 levels, mimicking the pathological
Correspondence to: Kiyoshi Migita, MD, Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan. Fax:⫹ 81-957-53-6675. Tel: ⫹ 81-957-52-3121. E-mail: migita@nmc. hosp.go.jp
History Received 5 August 2014 Accepted 4 November 2014 Published online 18 December 2014
findings of IgG4-RD with abundant infiltration of IgG4-positive plasma cells.
Case report A 50-year-old Japanese woman had developed hypergammaglobulinemia and elevated CRP levels a couple of years back. She was referred to us because of bilateral shoulder joint stiffness. Upon admission to our hospital, she had widespread lymphadenopathy without joint swelling. Laboratory investigation (Table 1) showed a hemoglobin level of 10.7 g/dl, platelet count of 30.4 ⫻ 104/μl, erythrocyte sedimentation rate of 68 mm/h, IgG level of 4020 mg/ dl, IgA level of 202 mg/dl, IgM level of 370 mg/dl, and CRP level of 6.48 mg/dl. The patient’s biochemistry results were normal. She was also negative for human herpes virus-8 and hepatitis B and C viruses. However, her serum IgG4 level was high (231 mg/dl). [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed significant FDG uptake by multiple lymph nodes (axillary, hilar, para-aortal, and inguinal) (Figure 1). Computed tomography (CT) showed hepatomegaly and gross axillar and inguinal lymphadenopathy (Figure 2). The findings of FDG-PET and CT demonstrated no organ involvement of IgG4-RD, including salivary glands, lacrimal glands, pancreas, or retroperitoneum, except lymph nodes. Therefore, inguinal lymph node excision biopsy was performed. The biopsied specimens from the inguinal lymph nodes included germinal centers, which are normal to atrophic with expansion of the interfollicular
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Table 1. Laboratory Findings.
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Peripheral blood Red blood cells Hemoglobin White blood cells Neutrophil Monocyte Lymphocyte Eosinophil Basophil Platelet Blood chemistry Total protein Albumin Total bilirubin Glutamic-oxaloacetic transaminase Glutamic-pyruvic transaminase Lactate dehydrogenase Alkaline phosphatase Creatinine kinase Total cholesterol Blood urea nitrogen Creatinine Na K Cl Ca
334 ⫻ 104/μl 10.7g/dl 87.6 10300/μl 76.7% 3.2% 18.2% 1.5% 0.4% 30.4 ⫻ 104/μl 9.2g/dl 3.0g/dl 0.5mg/dl 12 IU/l (7–33) 10 IU/l (5–30) 134 IU/l (260–480) 412 IU/l (80–250) 21 IU/l (60–160) 189mg/dl 15.2mg/dl 0.6mg/dl 132mEq/l 4.1mEq/l 100mEq/l 8.7mg/dl
Serological tests C-reactive protein Erythrocyte sedimentation rate IgG IgA IgM IgG4 M protein C3 C4 Rheumatoid factor Antinuclear Ab PR-3-ANCA MPO-ANCA
6.48mg/dl (⬍ 0.30) 68mm/hr 4020mg/dl (900–2000) 202mg/dl 370mg/dl 231mg/dl (4.8–135) (⫺) 153mg/dl (86–160) 33mg/dl (17–45) 24(U/ml) (⬍ 17) ⫻ 80 (Speckled) ⬍ 1.0 U/ml (⬍ 3.5) ⬍ 1.0 U/ml (⬍ 3.5)
Anti-CCP Ab
⬍ 0.6U/ml (⬍ 4.5)
sIL-2R IL-6 VEGF Virological test HCV-Ab HBsAg HHV-8 DNA Urinalysis Protein Sugar Occult blood Sediment UP/Cr
1200U/ml (14–519) 9.3pg/ml (⬍ 6.0) 1210pg/ml (⬍ 115) (⫺) (⫺) (⫺) 2⫹ (⫺) (⫺) np 2.83g/gCr (⬍ 0.15)
HBsAg hepatitis B surface antigen, Anti-CCP Ab Anticyclic citrullinated peptide antibody, HCV hepatitic C virus, MMP-3 Matrix metalloproteinase-3, MPO-ANCA myeloperoxidase-antineutrophil cytoplasmic antibody, PR-3ANCA proteinase 3-antineutrophil cytoplasmic antibody, sIL-2R soluble interleukin-2 receptor, VEGF vascular endothelial growth factor; HHV-8, human herpes virus 8.
area. The interfollicular regions showed large numbers of mature plasma cells (Figure 3A, B). There was no immunoglobulin light chain restriction (data not shown). The number of IgG4-positive plasma cells was elevated, and the portion of IgG4-positive:IgGpositive plasma cells was 37.2% (Figure 3C). However, the patient’s blood test results (Table 1) showed high serum levels of IL-6 (9.3 pg/mL, ⬍ 6) and vascular endothelial growth factor (VEGF) (1210 pg/mL, ⬍ 115), which were inconsistent with the findings of IgG4-RD [5]. The pathological diagnosis of the affected lymph nodes was plasmacytic Castleman disease. Consequently, we concluded that all of the patient’s abnormalities, including the hypergammaglobulinemia, elevated levels of IgG4 and CRP, and systemic lymph node enlargement were manifestations of MCD. The final diagnosis was MCD with high levels of serum IgG4 secondary to hypergammaglobulinemia. Eight weeks after the lymph node biopsy, corticosteroid treatment was started (prednisolone, 50 mg/day), and resolution of the axillary and inguinal lymph node enlargement was confirmed by CT (data not shown). The serum IgG and IgG4 levels decreased to 2142 mg/dl and 97.8 mg/dl, respectively, 8 weeks after beginning the treatment.
Discussion We have herein described a patient with characteristic features of MCD, including polyclonal hypergammaglobulinema, multiple enlarged lymph nodes, and pulmonary interstitial infiltration. MCD is a lymphoproliferative disorder predominantly characterized by generalized lymphadenopathy and systemic proinflammatory manifestations [6]. MCD is considered to represent a systemic plasma cell proliferation, probably due to
an immunoregulatory deficit, and results in overgrowth of polyclonal B-cell populations [8]. Clinical features mainly involve lymphadenopathy, fever, and weight loss, all of which are consequences of IL-6 overproduction from activated plasma cells or B cells [9]. This condition is almost always symptomatic. However, the present patient was asymptomatic despite her elevated levels of acute-phase reactants and polyclonal hypergammaglobulinemia. IgG4-RD is pathologically characterized by lymphoplasmacytic infiltration and irregular fibrosis with infiltration of IgG4positive plasma cells into affected tissues [10]. Recent studies have indicated that IgG4-RD sometimes involves systemic lymph nodes. Systemic lymphadenopathy, which is characteristic of systemic MCD, is also seen in patients with IgG4-RD [11]. The present patient exhibited marked IgG4-positive plasma cell infiltration in the affected lymph nodes. The histological findings of IgG4-related lymphadenopathy can be categorized into five types: MCD-like, follicular hyperplasia, interfollicular expansion, progressive transformation of germinal centers, and inflammatory pseudotumor-like [12]. The morphological features of IgG4-RD differ from those of MCD because no sclerosis or phlebitis is typically present [13]. However, differentiation between Castleman disease-like IgG4-RD and MCD is quite difficult. There is practically a universal agreement that the threshold of the IgG4:IgG ratio should be set at ⬎ 40%; however, elevated IgG4:IgG ratios may also be observed in other diseases, including MCD [14]. Cheuk et al reviewed the diagnostic approach for lymphadenopathy of IgG4-RD. In this review, they proposed that lymphadenopathy of IgG4-RD can be over-diagnosed since the reactive lymphoid hyperplasia with increased IgG4⫹ cells can be accompanied with many other conditions, including MCD [15].
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DOI 10.3109/14397595.2014.985356
Castleman disease with abundant IgG4-positive cells
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Figure 2. Chest and abdomen CT scan on admission revealed bilateral axillary and inguinal lymphadenopathy.
Figure 1. FDG-PET/CT images (coronal PET slice). PET/CT imaging showed the presence increased FDG uptake in the bilabial axillary and inguinal lymph nodes.
A diagnosis of IgG4-related lymphadenopathy should be made with great caution in the absence of well-documented IgG4related disease (organ involvement). Therefore, patients’ clinical and laboratory findings must be taken into consideration to reach a final diagnosis of IgG4-RD or MCD. Sato et al. investigated the clinical and pathological features of IgG4-related lymphadenopathy in comparison to MCD [16]. Histologically, the interfollicular plasmacytosis in IgG4-related lymphadenopathy mimicked Castleman disease-like features. Eosinophilic infiltrations in the affected lymph nodes are features of IgG4-related lymphadenopathy [16]. These findings were not demonstrated in the present case. Additionally, laboratory examinations revealed that the levels of IL-6 or CRP were within the normal limit in IgG4-related lymphadenopathy [16]. IL-6 and CRP may become considerably important as differential diagnostic markers between systemic IgG4-related lymphadenopathy and MCD. Sato et al. reported that IgG4-related disease is not associated with an elevated serum IL-6 level [16]. Increased expressions of VEGF were demonstrated in the tissues of MCD [17]. Although the elevated plasma levels of VEGF was demonstrated in a case report of IgG4-related arthropathy [18], the present patient had significantly elevated levels of IL-6, in addition to VEGF, suggesting that clinical findings are compatible with those of MCD. In general, the clinical course of IgG4-RD is responsive to steroid therapy [3]. However, the prognosis of MCD is generally poor. The use of high-dose steroid therapy alone is
reportedly associated with incomplete responses in most cases [9]. Treatment using tocilizumab has shown promising results [19]. Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor and a cytokine that plays a crucial role in MCD [19]. In our patient, corticosteroid therapy alone seemed to be effective for MCD-related symptoms, including systemic lymphadenopathy. Our patient showed a relatively low serum IL-6 level with respect to her high CRP level. The potential correlation between serum IL-6 levels during pretreatment and clinical responses to corticosteroid therapy in patients with MCD is worth investigation. Kojima et al. investigated the clinical and pathological findings of 28 Japanese patients with idiopathic MCD and showed that Japanese patients are delineated into two distinct groups: idiopathic plasmacytic lymphadenopathy (IPL) type and non-IPL type [20]. IPL type is defined by prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node; non-IPL type is characterized by female predominance, higher age group, high incidence of pleural effusion or ascites, and frequent association with autoimmune diseases [20]. It was demonstrated that the clinical remission can be achieved more frequently in IPL type compared with that in non-IPL type [21]. These phenotypic variations in MCD may contribute to the good response to corticosteroids seen in our patient. In summary, we have reported a case involving a patient with MCD with high levels of serum IgG4 and IgG4-positive plasma cell infiltrations in the affected lymph nodes. MCD and IgG4-RD exhibit overlapping but somewhat distinct findings; histological and serum data (CRP and IL-6 levels) are useful for differentiating these two conditions. Because MCD and IgG4-RD are rare, investigation of a larger series of patients is necessary to learn more about both conditions. Little is known about the lymphomagenesis of IgG4-RD, and MCD and IgG4-RD cannot be completely distinguished based on clinical and serological findings. Identification of pathogenic factors involved in the development of MCD and IgG4-RD is needed.
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Figure 3. (A) Lymph nodes showed a normal germinal center with expansion of the interfollicular area. The interfollicular zone was expanded and densely populated by mature plasma cells accompanied by endothelial venules. (Hematoxylin and eosin staining) (B) Interfollicular area showed heavy infiltration of mature plasma cells. (Hematoxylin and eosin staining) (C) Interfollicular IgG4 staining demonstrated a large number of IgG4-positive cells infiltrating the lymph node, and the IgG4-positive:IgG-positive cell ratio was 37.2%.
Conflict of interest None.
References 1. Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasmacell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer. 1972;29(3):670–83. 2. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer. 1956;9(4): 822–30. 3. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68(8):1310–5. 4. Takenaka K, Takada K, Kobayashi D, Moriguchi M, Harigai M, Miyasaka N. A case of IgG4-related disease with features of Mikulicz’s disease, and retroperitoneal fibrosis and lymphadenopathy mimicking Castleman’s disease. Mod Rheumatol. 2011;21(4):410–4. 5. Sato Y, Kojima M, Takata K, Morito T, Asaoku H, Takeuchi T, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman’s disease. Mod Pathol. 2009;22(4): 589–99. 6. Shahidi H, Myers JL, Kvale PA. Castleman’s disease. Mayo Clin Proc. 1995;70(10):969–77. 7. Dispenzieri A, Gertz MA. Treatment of Castleman’s disease. Curr Treat Options Oncol. 2005;6(3):255–66. 8. Bowne WB, Lewis JJ, Filippa DA, Niesvizky R, Brooks AD, Burt ME, Brennan MF. The management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literature. Cancer. 1999;1;85(3):706–17. 9. Palestro G, Turrini F, Pagano M, Chiusa L. Castleman’s disease. Adv Clin Path. 1999;3(1–2):11–22. 10. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181–92.
11. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4related disease: historical overview and pathology of hematological disorders. Pathol Int. 2010;60(4):247–58. 12. Sato Y, Yoshino T. IgG4-Related Lymphadenopathy. Int J Rheumatol. 2012;2012:572539. 13. Stone JH, Khosroshahi A, Deshpande V, Chan JK, Heathcote JG, Aalberse R, et al. Recommendations for the nomenclature of IgG4related disease and its individual organ system manifestations. Arthritis Rheum. 2012;64(10):3061–7. 14. Grimm KE, Barry TS, Chizhevsky V, Hii A, Weiss LM, Siddiqi IN, et al. Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol. 2012;25(3):480–91. 15. Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 2012;29(4):226–34. 16. Sato Y, Kojima M, Takata K, Morito T, Asaoku H, Takeuchi T, et al. Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman’s disease. Mod Pathol. 2009; 22(4):589–99. 17. Nishi J, Maruyama I. Increased expression of vascular endothelial growth factor (VEGF) in Castleman’s disease: proposed pathomechanism of vascular proliferation in the affected lymph node. Leuk Lymphoma. 2000;38(3–4):387–94. 18. Umekita K, Kaneko Y, Yorita K, Hashiba Y, Matsuda M, Miyauchi S, et al. Arthropathy with infiltrate IgG4-positive plasma cells in synovium. Rheumatology (Oxford). 2012;51(3):580–2. 19. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106(8):2627–32. 20. Kojima M, Nakamura S, Shimizu K, Itoh H, Yamane Y, Murayama K, et al. Clinical implication of idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia: a report of 16 cases. Int J Surg Pathol. 2004;12(1):25–30. 21. Kojima M, Nakamura N, Tsukamoto N, Otuski Y, Shimizu K, Itoh H, et al. Clinical implications of idiopathic multicentric castleman disease among Japanese: a report of 28 cases. Int J Surg Pathol. 2008;16(4):391–8.
CASE REPORT
Multicentric Castleman disease mimicking IgG4-related disease: A case report
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Yasumori Izumi1, Hayato Takeshita1, Yuji Moriwaki2, Keiko Hisatomi3, Masakazu Matsuda1, Natsuki Yamashita1, Chieko Kawahara1, Yoshika Shigemitsu1, Nozomi Iwanaga1, Atsushi Kawakami4, Hirokazu Kurohama5, Daisuke Niino5, Masahiro Ito5, and Kiyoshi Migita1 1Departments of General Internal Medicine and Rheumatology, Nagasaki Medical Center, Omura City, Nagasaki, Japan, 2Departments of Hematology,
Nagasaki Medical Center, Omura City, Nagasaki, Japan, 3Departments of Respiratory Medicine, Nagasaki Medical Center, Omura City, Nagasaki, Japan, 4First Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, and 5Departments of Pathology,
Nagasaki Medical Center, Omura City, Nagasaki, Japan Abstract
Keywords
A 50-year-old woman was referred to our hospital for shoulder joint stiffness. She had a history of polyclonal hypergammaglobulinemia and an elevated C-reactive protein level. Her laboratory data revealed an elevated serum immunoglobulin G4 (IgG4) level, hypergammaglobulinemia, and rheumatoid factor positivity in the absence of anticyclic citrullinated peptide antibody. [18F]Fluorodeoxyglucose positron emission tomography showed significant [18F]-fluorodeoxyglucose uptake in multiple lymph nodes (axillary, hilar, para-aortic, and inguinal). Biopsy of the inguinal lymph node showed expansion of the interfollicular areas by heavily infiltrating plasma cells, consistent with multicentric Castleman disease (MCD). Immunohistochemical analysis revealed a 37.3% IgG4-positive:IgG-positive plasma cell ratio, indicating overlapping IgG4-related disease. However, serological cytokine analysis revealed elevated levels of interleukin-6 (9.3 pg/ml) and vascular endothelial growth factor (VEGF) (1210 pg/ml), which are compatible with MCD. Corticosteroid treatment resolved the serological and imaging abnormalities. IgG4-related disease can mimic MCD, and it is crucial to distinguish between these two diseases. Serum interleukin-6 and VEGF levels may help to discriminate MCD from IgG4-related disease.
IgG4-related disease, Interleukin-6, Multicentric Castleman disease
Introduction Multicentric Castleman disease (MCD) is a rare polyclonal lymphoproliferative disorder that manifests as lymphadenopathy and inflammatory symptoms [1,2]. IgG4-related disease (IgG4-RD) is clinically characterized by tumor-like enlargement of exocrine glands or extranodal tissues and a high serum IgG4 level [3]. IgG4-RD involves the regional and/or systemic lymph nodes and sometimes histologically mimics MCD [4]. Moreover, the lymph node abnormalities associated with IgG4-RD show histological findings similar to those associated with MCD [5]. Therefore, the clinical and histological features of IgG4-RD can be quite similar to and sometimes indistinguishable from those of MCD. The abnormal clinical findings seen in MCD, such as general fatigue, anemia, polyclonal hypergammaglobulinemia, and elevated C-reactive protein (CRP) levels, may be related to high interleukin-6 (IL-6) levels [6]. The diagnosis and treatment of MCD are challenging because patients with MCD require intensive therapies including corticosteroids, immunosuppressants, or tocilizumab, an IL-6 receptor antibody [7]. We herein report a case involving a patient with MCD with elevated serum IL-6 levels, mimicking the pathological
Correspondence to: Kiyoshi Migita, MD, Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan. Fax:⫹ 81-957-53-6675. Tel: ⫹ 81-957-52-3121. E-mail: migita@nmc. hosp.go.jp
History Received 5 August 2014 Accepted 4 November 2014 Published online 18 December 2014
findings of IgG4-RD with abundant infiltration of IgG4-positive plasma cells.
Case report A 50-year-old Japanese woman had developed hypergammaglobulinemia and elevated CRP levels a couple of years back. She was referred to us because of bilateral shoulder joint stiffness. Upon admission to our hospital, she had widespread lymphadenopathy without joint swelling. Laboratory investigation (Table 1) showed a hemoglobin level of 10.7 g/dl, platelet count of 30.4 ⫻ 104/μl, erythrocyte sedimentation rate of 68 mm/h, IgG level of 4020 mg/ dl, IgA level of 202 mg/dl, IgM level of 370 mg/dl, and CRP level of 6.48 mg/dl. The patient’s biochemistry results were normal. She was also negative for human herpes virus-8 and hepatitis B and C viruses. However, her serum IgG4 level was high (231 mg/dl). [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed significant FDG uptake by multiple lymph nodes (axillary, hilar, para-aortal, and inguinal) (Figure 1). Computed tomography (CT) showed hepatomegaly and gross axillar and inguinal lymphadenopathy (Figure 2). The findings of FDG-PET and CT demonstrated no organ involvement of IgG4-RD, including salivary glands, lacrimal glands, pancreas, or retroperitoneum, except lymph nodes. Therefore, inguinal lymph node excision biopsy was performed. The biopsied specimens from the inguinal lymph nodes included germinal centers, which are normal to atrophic with expansion of the interfollicular
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Table 1. Laboratory Findings.
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Peripheral blood Red blood cells Hemoglobin White blood cells Neutrophil Monocyte Lymphocyte Eosinophil Basophil Platelet Blood chemistry Total protein Albumin Total bilirubin Glutamic-oxaloacetic transaminase Glutamic-pyruvic transaminase Lactate dehydrogenase Alkaline phosphatase Creatinine kinase Total cholesterol Blood urea nitrogen Creatinine Na K Cl Ca
334 ⫻ 104/μl 10.7g/dl 87.6 10300/μl 76.7% 3.2% 18.2% 1.5% 0.4% 30.4 ⫻ 104/μl 9.2g/dl 3.0g/dl 0.5mg/dl 12 IU/l (7–33) 10 IU/l (5–30) 134 IU/l (260–480) 412 IU/l (80–250) 21 IU/l (60–160) 189mg/dl 15.2mg/dl 0.6mg/dl 132mEq/l 4.1mEq/l 100mEq/l 8.7mg/dl
Serological tests C-reactive protein Erythrocyte sedimentation rate IgG IgA IgM IgG4 M protein C3 C4 Rheumatoid factor Antinuclear Ab PR-3-ANCA MPO-ANCA
6.48mg/dl (⬍ 0.30) 68mm/hr 4020mg/dl (900–2000) 202mg/dl 370mg/dl 231mg/dl (4.8–135) (⫺) 153mg/dl (86–160) 33mg/dl (17–45) 24(U/ml) (⬍ 17) ⫻ 80 (Speckled) ⬍ 1.0 U/ml (⬍ 3.5) ⬍ 1.0 U/ml (⬍ 3.5)
Anti-CCP Ab
⬍ 0.6U/ml (⬍ 4.5)
sIL-2R IL-6 VEGF Virological test HCV-Ab HBsAg HHV-8 DNA Urinalysis Protein Sugar Occult blood Sediment UP/Cr
1200U/ml (14–519) 9.3pg/ml (⬍ 6.0) 1210pg/ml (⬍ 115) (⫺) (⫺) (⫺) 2⫹ (⫺) (⫺) np 2.83g/gCr (⬍ 0.15)
HBsAg hepatitis B surface antigen, Anti-CCP Ab Anticyclic citrullinated peptide antibody, HCV hepatitic C virus, MMP-3 Matrix metalloproteinase-3, MPO-ANCA myeloperoxidase-antineutrophil cytoplasmic antibody, PR-3ANCA proteinase 3-antineutrophil cytoplasmic antibody, sIL-2R soluble interleukin-2 receptor, VEGF vascular endothelial growth factor; HHV-8, human herpes virus 8.
area. The interfollicular regions showed large numbers of mature plasma cells (Figure 3A, B). There was no immunoglobulin light chain restriction (data not shown). The number of IgG4-positive plasma cells was elevated, and the portion of IgG4-positive:IgGpositive plasma cells was 37.2% (Figure 3C). However, the patient’s blood test results (Table 1) showed high serum levels of IL-6 (9.3 pg/mL, ⬍ 6) and vascular endothelial growth factor (VEGF) (1210 pg/mL, ⬍ 115), which were inconsistent with the findings of IgG4-RD [5]. The pathological diagnosis of the affected lymph nodes was plasmacytic Castleman disease. Consequently, we concluded that all of the patient’s abnormalities, including the hypergammaglobulinemia, elevated levels of IgG4 and CRP, and systemic lymph node enlargement were manifestations of MCD. The final diagnosis was MCD with high levels of serum IgG4 secondary to hypergammaglobulinemia. Eight weeks after the lymph node biopsy, corticosteroid treatment was started (prednisolone, 50 mg/day), and resolution of the axillary and inguinal lymph node enlargement was confirmed by CT (data not shown). The serum IgG and IgG4 levels decreased to 2142 mg/dl and 97.8 mg/dl, respectively, 8 weeks after beginning the treatment.
Discussion We have herein described a patient with characteristic features of MCD, including polyclonal hypergammaglobulinema, multiple enlarged lymph nodes, and pulmonary interstitial infiltration. MCD is a lymphoproliferative disorder predominantly characterized by generalized lymphadenopathy and systemic proinflammatory manifestations [6]. MCD is considered to represent a systemic plasma cell proliferation, probably due to
an immunoregulatory deficit, and results in overgrowth of polyclonal B-cell populations [8]. Clinical features mainly involve lymphadenopathy, fever, and weight loss, all of which are consequences of IL-6 overproduction from activated plasma cells or B cells [9]. This condition is almost always symptomatic. However, the present patient was asymptomatic despite her elevated levels of acute-phase reactants and polyclonal hypergammaglobulinemia. IgG4-RD is pathologically characterized by lymphoplasmacytic infiltration and irregular fibrosis with infiltration of IgG4positive plasma cells into affected tissues [10]. Recent studies have indicated that IgG4-RD sometimes involves systemic lymph nodes. Systemic lymphadenopathy, which is characteristic of systemic MCD, is also seen in patients with IgG4-RD [11]. The present patient exhibited marked IgG4-positive plasma cell infiltration in the affected lymph nodes. The histological findings of IgG4-related lymphadenopathy can be categorized into five types: MCD-like, follicular hyperplasia, interfollicular expansion, progressive transformation of germinal centers, and inflammatory pseudotumor-like [12]. The morphological features of IgG4-RD differ from those of MCD because no sclerosis or phlebitis is typically present [13]. However, differentiation between Castleman disease-like IgG4-RD and MCD is quite difficult. There is practically a universal agreement that the threshold of the IgG4:IgG ratio should be set at ⬎ 40%; however, elevated IgG4:IgG ratios may also be observed in other diseases, including MCD [14]. Cheuk et al reviewed the diagnostic approach for lymphadenopathy of IgG4-RD. In this review, they proposed that lymphadenopathy of IgG4-RD can be over-diagnosed since the reactive lymphoid hyperplasia with increased IgG4⫹ cells can be accompanied with many other conditions, including MCD [15].
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DOI 10.3109/14397595.2014.985356
Castleman disease with abundant IgG4-positive cells
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Figure 2. Chest and abdomen CT scan on admission revealed bilateral axillary and inguinal lymphadenopathy.
Figure 1. FDG-PET/CT images (coronal PET slice). PET/CT imaging showed the presence increased FDG uptake in the bilabial axillary and inguinal lymph nodes.
A diagnosis of IgG4-related lymphadenopathy should be made with great caution in the absence of well-documented IgG4related disease (organ involvement). Therefore, patients’ clinical and laboratory findings must be taken into consideration to reach a final diagnosis of IgG4-RD or MCD. Sato et al. investigated the clinical and pathological features of IgG4-related lymphadenopathy in comparison to MCD [16]. Histologically, the interfollicular plasmacytosis in IgG4-related lymphadenopathy mimicked Castleman disease-like features. Eosinophilic infiltrations in the affected lymph nodes are features of IgG4-related lymphadenopathy [16]. These findings were not demonstrated in the present case. Additionally, laboratory examinations revealed that the levels of IL-6 or CRP were within the normal limit in IgG4-related lymphadenopathy [16]. IL-6 and CRP may become considerably important as differential diagnostic markers between systemic IgG4-related lymphadenopathy and MCD. Sato et al. reported that IgG4-related disease is not associated with an elevated serum IL-6 level [16]. Increased expressions of VEGF were demonstrated in the tissues of MCD [17]. Although the elevated plasma levels of VEGF was demonstrated in a case report of IgG4-related arthropathy [18], the present patient had significantly elevated levels of IL-6, in addition to VEGF, suggesting that clinical findings are compatible with those of MCD. In general, the clinical course of IgG4-RD is responsive to steroid therapy [3]. However, the prognosis of MCD is generally poor. The use of high-dose steroid therapy alone is
reportedly associated with incomplete responses in most cases [9]. Treatment using tocilizumab has shown promising results [19]. Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor and a cytokine that plays a crucial role in MCD [19]. In our patient, corticosteroid therapy alone seemed to be effective for MCD-related symptoms, including systemic lymphadenopathy. Our patient showed a relatively low serum IL-6 level with respect to her high CRP level. The potential correlation between serum IL-6 levels during pretreatment and clinical responses to corticosteroid therapy in patients with MCD is worth investigation. Kojima et al. investigated the clinical and pathological findings of 28 Japanese patients with idiopathic MCD and showed that Japanese patients are delineated into two distinct groups: idiopathic plasmacytic lymphadenopathy (IPL) type and non-IPL type [20]. IPL type is defined by prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node; non-IPL type is characterized by female predominance, higher age group, high incidence of pleural effusion or ascites, and frequent association with autoimmune diseases [20]. It was demonstrated that the clinical remission can be achieved more frequently in IPL type compared with that in non-IPL type [21]. These phenotypic variations in MCD may contribute to the good response to corticosteroids seen in our patient. In summary, we have reported a case involving a patient with MCD with high levels of serum IgG4 and IgG4-positive plasma cell infiltrations in the affected lymph nodes. MCD and IgG4-RD exhibit overlapping but somewhat distinct findings; histological and serum data (CRP and IL-6 levels) are useful for differentiating these two conditions. Because MCD and IgG4-RD are rare, investigation of a larger series of patients is necessary to learn more about both conditions. Little is known about the lymphomagenesis of IgG4-RD, and MCD and IgG4-RD cannot be completely distinguished based on clinical and serological findings. Identification of pathogenic factors involved in the development of MCD and IgG4-RD is needed.
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Figure 3. (A) Lymph nodes showed a normal germinal center with expansion of the interfollicular area. The interfollicular zone was expanded and densely populated by mature plasma cells accompanied by endothelial venules. (Hematoxylin and eosin staining) (B) Interfollicular area showed heavy infiltration of mature plasma cells. (Hematoxylin and eosin staining) (C) Interfollicular IgG4 staining demonstrated a large number of IgG4-positive cells infiltrating the lymph node, and the IgG4-positive:IgG-positive cell ratio was 37.2%.
Conflict of interest None.
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