Rheumatology

Rheumatol Int DOI 10.1007/s00296-015-3259-4

INTERNATIONAL

CASE BASED REVIEW - CASES WITH A MESSAGE

Immunoglobulin G4‑related disease mimicking lymphoma in a Chinese patient Yanhui Liu1 · Fei Xue2 · Jing Yang1 · Yin Zhang1 

Received: 19 January 2015 / Accepted: 16 March 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased IgG4 serum concentration, and responsiveness to steroid therapy. IgG4RD tends to form tumefactive lesions. As a result, patients are often suspected of having a malignancy such as lymphoma. In this article, a patient with IgG4-RD and the deep vein thrombosis who was initially suspected of lymphoma is reported. The 63-year-old man presented with painless salivary swelling and multi-lymphadenopathy, progressively swelling and pain in the left leg. Salivary biopsy showed IgG4+ plasma cells >50 per high-power field and IgG4+/IgG+ plasma cell ratio >40 %. The serum IgG4 level was 4.28 g/L (range 0.03–2.01 mg/dL). Ultrasonography showed that the inferior vena cava was partially occluded, and thrombosis in the left iliac vein. Computed tomography scan revealed plaque-like tissue surrounding the inferior vena cava and abdominal aortic, which is typical for the diagnosis of retroperitoneal fibrosis. The patient was effectively treated with corticosteroids, interventional therapy, and anticoagulant therapy which resulted in a reduction in the swelling of the lymph nodes and left leg. Patient with IgG4-RD and deep vein thrombosis is rare and could be misdiagnosed easily as malignant disease. Accurate diagnosis is critical for disease management. * Yanhui Liu [email protected] 1

Department of Hematology, Henan Provincial People’s Hospital, The People’s Hospital of Zhengzhou University, 7 Weiwu Street, Zhengzhou 450003, Henan Province, China

2

Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, The People’s Hospital of Zhengzhou University, 7 Weiwu Street, Zhengzhou 450003, Henan Province, China





Keywords  IgG4-related disease · Sialadenitis · Fibrosis · Retroperitoneal · Deep vein thrombosis · Treatment

Introduction Immunoglobulin G4-related disease (IgG4-RD) is a recently defined emerging clinical entity characterized by tissue infiltration by IgG4-positive (IgG4+) plasma cells, tissue fibrosclerosis, and elevated serum IgG4 concentration. This disease entity is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. Crucial to the identification of this disease were the observations by Japanese investigators in the research of autoimmune pancreatitis (AIP) [1]. Salivary gland and lymph nodes are the common sites for extra-pancreatic lesions, other involved organs including biliary tree, periorbital tissues, kidneys, lungs, meninges, aorta, breast, prostate, thyroid, pericardium, skin, and so on [2–4]. IgG4-RD tends to form tumefactive lesions. As a result, patients are often suspected of having a malignancy such as lymphoma. In this study, we report the clinical, laboratory, and histological characteristics of a rare Chinese patient with IgG4-RD and deep vein thrombosis who was initially suspected of lymphoma.

Case presentation A 63-year-old man presented a 3-month history of a painless mass in his left submandibular, enlargement of the neck and inguinal nodes, and progressively swelling and pain in the left leg. Upon physical examination, there was an approximately 3-cm hard mass in the left submandibular and several enlarged lymph nodes in the cervical, supraclavicular,

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Rheumatol Int

Fig.  1  a Computed tomography showing plaque-like tissue surrounding the abdominal aorta and inferior vena cava (arrow) without other organ involvement. b Histopathologic features of the salivary gland. The gland was very hard, and the cut surface is gray. HE staining of the excisional biopsy specimen revealed acinar atrophy, dense lym-

phoplasmacytic inflammation and fibrosis (×40 c, ×100 d). Immunohistochemical staining showed abundant IgG4-positive plasma cell (>50/high-power field) infiltration, with a ratio of IgG4/IgG-positive plasma cells of more than 40 % (×40 e, ×200 f)

submandibular, and inguinal area. Severe edema was seen in his left lower extremity. Blood tests revealed normal levels of blood cells and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Both antinuclear antibodies (ANA) and antiextractable nuclear antigen (ENA) antibodies were negative. Fibrin (-ogen) degradation products (FDP) 5.26 mg/L (0–5) and D-dimer 3.27 mg/L (0–0.5) were slightly or moderately elevated. Ultrasonography revealed left swollen submandibular gland (3.0 cm length × 3.5 cm width × 2.5 cm height), multi-lymphadenopathy in the cervical, supraclavicular,

submandibular, and inguinal area. Inferior vena cava below the liver segment was intermittent display, and hypoechoic was seen in the left iliac vein without blood flow signal, suggesting thrombosis in the left iliac vein. Intravenous contrast of inferior vena cava and vein in the left lower extremity confirmed thrombosis in the left iliac vein. Computed tomography (CT) scan showed plaque-like tissue surrounding the abdominal aortic and inferior vena cava without other organ involvement (Fig. 1a). Given the symptoms and laboratory findings described above, the patient was suspected of lymphoma with deep

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vein thrombosis. He received interventional therapy and stent implantation to relieve the obstruction, and an excisional biopsy examination of the cervical lymph nodes and the swollen submandibular gland to obtain definitive histological diagnosis. The biopsy of cervical lymph nodes showed reactive lymphoid hyperplasia, while in distinction from healthy individuals, the salivary gland was very hard and the cut surface is gray (Fig. 1b). Hematoxylin and eosin (HE) staining of the excisional biopsy specimen revealed acinar atrophy, abundant lymphocytoplasma cell infiltration, and marked fibrosis (Fig. 1c, d). Immunohistochemical staining showed abundant IgG4-positive plasma cells (>50/high-power field) in the excisional gland specimen of the patient, with a ratio of IgG4/IgG-positive plasma cells of more than 40 % (Fig. 1e, f). The plasma cells were CD138 + CD20 + CD3 + CD38 + CK + Kappa + Lam bda  + with Ki67 expression (approximately 20 %) (figure not shown), suggesting a polyclonal expansion rather than malignant lymphoma. The serum IgG and IgG4 levels were postoperatively found to be 23.1 g/L (6.3–15.2) and 4.28 g/L (0.03–2.01). Accordingly, an ultimate diagnosis of IgG4-RD with deep vein thrombosis was made. Although no biopsy or surgical resection of the soft tissue stranding and thickening surrounding the abdominal aortic and inferior vena cava was performed, the periaortic tissue was suspected to be clinically due to IgG4-related sclerosing disease. Thus, steroid (30 mg/day) and anticoagulant therapy was administered, which immediately reduced the swelling of the lymph nodes and left leg. Follow-up CT revealed that the periaortic tissue was no longer observed.

Discussion The concept of IgG4-RD as a novel clinical entity emerged over the first 10 years of the twenty-first century. As a newly recognized disease, the epidemiology of IgG4-RD remains poorly described. The only data of AIP in Japan are 0.2–1/100,000 [1]. The typical patient with IgG4-RD is a middle-aged to elderly male. The overall male-to-female ratio in IgG4-RD in most organ systems is of 3.5–1. In China, only several case reports have been published in the last 10 years. The first serial report of IgG4-RD from China described 28 cases [5], in which the mean age at onset of disease was of 51.5 years and male-to-female ratio is 1.8:1, suggesting that IgG4-RD in China was generally similar to that reported from other countries. The diagnosis of IgG4-RD relies primarily on the documentation of certain characteristic histopathologic features. The four major pathological hallmarks of IgG4-RD are a dense lymphoplasmacytic infiltrate with a high percentage of IgG4+ plasma cells, storiform fibrosis, obliterative

phlebitis, and mild-to-moderate tissue eosinophilia [1]. The international consensus statement on the histological diagnostic criteria for IgG4-RD confirmed the importance of morphological appearance on biopsy. Tissue IgG4 counts and IgG4/IgG ratios are secondary in importance [6]. IgG4-RD can involve almost any organ. The salivary glands are among the more common sites for involvement in IgG4-RD [7]. In the series report of 28 patients of China, 17 patients have salivary glands involved [5]. In almost all the cases, the affected salivary gland is the submandibular gland, usually bilaterally, whereas in only rare cases, the affected gland is parotid and sublingual gland [7]. The main manifestation is enlargement of salivary glands usually bilaterally and synchronous, without significant weight loss, fevers, or other manifestations of systemic inflammation. Salivary functions in this disease are either unremarkable or only slightly decreased. Histological sections show preservation of lobular architecture, marked lymphoplasmacytic inflammation, acinar atrophy, obliterative phlebitis, and characteristically the presence of prominent cellular interlobular fibrosis, which is similar to that observed in other organs involved by IgG4-RD. Our patient presented unilateral sublingual gland involved without remarkable xerostomia. Although typical obliterative phlebitis and tissue eosinophilia were not seen in this patient, the remaining typical features which are significantly different from other forms of sialadenitis were observed. Therefore, an ultimate diagnosis of IgG4-related sialadenitis was made with consideration of the elevated serum IgG4 (4.28 g/L). Besides unilateral sublingual gland enlargement, multilymphadenopathy and deep vein thrombosis were the main clinical features in our patient. Lymphadenopathy is often a prominent clinical feature of IgG4-RD. The biopsy of cervical lymph nodes in this patient showed reactive lymphoid hyperplasia without characteristic histopathologic features of IgG4-RD such as storiform fibrosis and obliterative phlebitis. The same phenomenon has also been reported previously [1, 8], suggesting that establishing the diagnosis through lymph node biopsy is generally difficult because it is unusual for lymph nodes to undergo the degree of fibrosis observed in other organs. Retroperitoneal fibrosis (RPF) is another common manifestation of IgG4-RD, which is marked by the development of a periaortic fibroinflammatory mass [9]. The fibroinflammatory infiltration can encase the abdominal aorta, inferior vena cava, ureters, and other abdominal organs. The clinical presentation often includes constitutional symptoms, abdominal pain, and signs of renal insufficiency or renal failure related to ureteral obstruction. Less frequently, RPF may present with vascular complications, such as venous thrombosis or claudication [10]. The term of “idiopathic retroperitoneal fibrosis,” known for decades as Ormond’s disease, is referred to as IgG4-related chronic periaortitis [11].

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Table 1  Main differences and similarities between IgG4-RD and lymphoma IgG4-RD

Lymphoma

Clinical features Age and sex Multifocal and systemic involvement Lymphadenopathy Painless mass Compression Dysfunction of affected organs Vascular thrombosis Systemic symptoms Fever Weight loss Major pathological hallmarks

Mainly middle-aged to elderly men + + + + + Less common + Less common Less common Polyclonal Lymphoplasmacytic infiltrate

Any age and sex + + + + + Common + Frequent Frequent Monoclonal Lymphoma cells expansion

Treatment

Immunosuppressive therapy

Chemotherapy

A streaky densification of soft tissue surrounding retroperitoneal vessels and other organs revealed by modern imaging tools such as ultrasound, CT, and magnetic resonance imaging (MRI) is typical for the diagnosis of retroperitoneal fibrosis. In the present case, although no histopathologic analysis of the abdominal aortic or inferior vena cava was performed, the periaortic lesion was suspected clinically to be IgG4-related chronic periaortitis, and the thrombosis in the left iliac vein was secondary to a compression of inferior vena cava by inflamed connective tissue. IgG4-RD tends to form tumefactive lesions. As a result, patients are often suspected of having a malignancy, especially when with deep vein thrombosis as it is common in malignant disease. The main differential features of IgG4RD and lymphoma are listed in Table 1 [2, 4, 5]. The patient described here who presented mass in the submandibular, multi-lymphadenopathy, and deep vein thrombosis was initially suspected of lymphoma. The diagnosis of IgG4-RD was finally made according to the patient’s history and multiple laboratory findings. We treat the patient with corticosteroid therapy according to the comments from Japanese investigators [12], and the clinical course showed a good response to the therapy. In summary, we report a rare case of IgG4-RD involved salivary gland, lymph nodes, and retroperitoneal fibrosis with deep vein thrombosis which mimics lymphoma. Since the differential diagnosis of IgG4-RD and lymphoma is very difficult and their treatment and prognosis are quite different, we suggest that IgG4-RD should always be considered in case of malignancy, especially when with deep vein thrombosis concomitantly. Acknowledgments  This work was supported by the Nature Science Foundation Committee (NO. 81273260) and the Project of science and technology of Zhengzhou City (131PPTGG379-1).

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Conflict of interest  The authors declare that they have no competing interests.

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Immunoglobulin G4-related disease mimicking lymphoma in a Chinese patient.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by multiorgan fibrosis with IgG4-producing plasma cells, increased Ig...
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