Kimura’s disease presenting with a giant suspensory tumor and associated with membranoproliferative glomerulonephritis

ARTICLE

Auteur(s) : Rieko Kabashima¹, Kenji Kabashima¹, Shoko Mukumoto¹, Ryosuke Hino¹, Yumi Huruno², Naritoshi Kabashima², Yoshiki Tokura¹

¹Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan
²Second Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan

accepté le 22 Juin 2009

Kimura’s disease is a chronic, lymphoproliferative and inflammatory disease that develops in the dermis, soft tissues and lymph nodes. This intriguing condition was first described from China in 1937 [1], and named Kimura’s disease after similar cases were reported by Kimura et al. in 1948 [2]. It is characterized clinically by subcutaneous masses or indurations occurring predominantly on the head and neck region [2] and histologically by the formation of lymphoid follicles and marked infiltration of eosinophils. The other predilection sites are the orbit, lacrimal gland, arm, and lymph nodes of the axilla and inguinal regions [3, 4]. The associated laboratory findings include blood eosinophilia and elevated serum immunoglobulin E (IgE) [3-5]. It has been shown that mRNA expression of interleukin (IL)-4, IL-5, and IL-13 is elevated in peripheral blood mononuclear cells in patients with Kimura’s disease, suggesting that these Th2 cytokines play an essential role in the dysregulation of eosinophilia and serum IgE level [6].

Kimura’s disease occasionally involves the kidney, usually manifesting as proteinuria and nephrotic syndrome [7-9]. Membranous glomerulonephritis and minimal change nephropathy, known as T helper 2 (Th2) type disease [10], may be the histological types associated with Kimura’s disease. Here we report a Japanese woman with Kimura’s disease, who presented with a large tumor on the inguinal region, and nephrotic syndrome showing the histological changes of membranoproliferative glomerulonephritis (MPGN).

Case report

We initially suspected inguinal herniation or ectopic endometriosis, which was excluded by gynecological and radiological examinations. A magnetic resonance imaging exhibited an iso-high intensitive mass by T1 intensity (figure 2B, left), and high intensive irregular nodules existing in the mass by T2 intensity (figure 2B, right). The tumor and enlarged lymph nodes were reinforced uniformly in contrast media. A computed tomography scan showed a protruded tumor in the right genitocrural region (figure 2C, left). Multiple swollen lymph nodes were seen in both groin areas, and the lymphadenopathy was more conspicuous in the right area (figure 2C, right).

A skin biopsy specimen from the mass revealed multiple lymphoid follicles with distinct germinal centers (figiure 2A) and a dense diffuse infiltrate of eosinophils and lymphocytes (figure 2B). Vascular proliferation consisting of blood vessels lined by enlarged endothelial cells was also seen. There was at least no substantial number of mast cells by toluidine blue staining. Immunohistochemically, centrocytes in the germinal center were positive for CD20+ B cells, and lymphocytes surrounding the follicles were CD3+ T cells, consisting of both CD4+ and CD8+ populations. The tumor was histologically diagnosed as Kimura’s disease.

Hematology revealed an elevated count of leukocytes (12,500/μL) with 49.0% (6,125/μL) eosinophils. Serum IgE was markedly elevated (110,000 U/mL; normal, 0-170 U/mL), with increased levels of particular cytokines: IL-4, 9.6 pg/mL (normal, < 6.0); IL-5, 19.4 pg/mL (normal, < 10); and IL-6, 1.6 pg/mL (normal, < 4.0). She had hypoalbuminemia (1.9 g/dL; normal, 4.0-5.0 g/dL) and hypercholesterolemia (365 mg/dL; normal, 128-256 mg/dL). Her serum creatinine was 1.6 mg/dL (normal, 0.4-0.7 mg/dL), and her urine contained erythrocytes 20-29/HPF, and her mean systolic and diastolic blood pressure were 146/86 mmHg, respectively. Furthermore, the amount of protein in the 24 hour urine sample was 10.12 g/day. Therefore, she was diagnosed as having nephrotic syndrome and referred for a kidney biopsy. A biopsy specimen demonstrated remarkable increments of mesangial cells and matrix with thickened glomerular basement membrane and an infiltrate of eosinophils (figure 2C). An immunofluorescence study showed deposition of IgE (figure 2D). Thus, the renal condition was diagnosed as MPGN.

The patient was treated with half-pulse methylprednisolone (500 mg daily for 3 days), followed by oral prednisolone (30 mg daily). The tumor shrank and was reduced in size. Laboratory data were improved as follows: eosinophils, 0.8% (90/μL); IgE, 24,000 U/mL; and urinary protein, 7.16 g/day in the 24 hour sample. After the mass size reduction by the steroids, total surgical removal of the tumor was performed. Histologically, the tumor was encapsulated with scar tissue, and a reminiscence of lymphocytic infiltrates was present. She was additionally given 150 mg daily of mizoribine, and the combination of prednisolone and mizoribine continued for 7 months. Currently, 11 months after cessation of the therapy, she is free of relapse with normalized laboratory data (eosinophils, 0.2% or 264/μL; creatinine, 1.2 mg/dL; hematuria, 1-4/HPF; blood pressure, 135/72 mmHg), except for moderately elevated urinary protein (1.22 g/day) and serum IgE level (1,787 U/mL).

Discussion

Proteinuria was reported in 12-16% of patients with Kimura’s disease, and 59-78% of those cases had nephrotic syndrome [16-18]. Renal diseases may precede, follow, or coincide with Kimura’s disease. In accordance with the finding that Th2 cytokines promote the permeability of the glomerular basement membrane [6, 19], Th2 type renal diseases, such as membranous glomerulonephritis and minimal change nephropathy, are occasionally associated with Kimura’s disease [10, 20, 21]. Although some authors have suggested that MPGN is a Th1 immune response according to the histological patterns [20, 21], few studies are available to allow assessment of the polarization of Th responses in MPGN. In glomeruli, IgG3 (Th1 type) is a predominant subclass, and IgG4 and IgE (Th2 type) are recessive ones. Given that the activation of C1q is restricted to IgG3, our observation of IgE presence, and C1q absence in the kidney specimen suggests that the patient’s MPGN represents Th2 type renal disease.

A number of treatment modalities have been reported for Kimura’s disease [6-10, 15, 18], including intralesional corticosteroids, cyclosporine, electrodessication, curettage, cryotherapy, radiotherapy, interferon-α, and chemotherapy [10, 22-26]. Systemic treatment with corticosteroids is effective in reducing the size of lesions, but they can recur when steroids are ceased [27]. Surgical resection of the lesions is recommended by some authors [28]. Our patient was successfully treated with systemic steroids with a following excision of the mass.

It seems that Kimura’s disease and MPGN are both related to a Th2 dominant immune response. Our patient may represent an extreme case of Kimura’s disease, as she had the large skin lesion and the coexistence of important renal disorders.

Acknowledgements

References

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