CASTLEMAN DISEASE, or angiofollicular

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1 CASE REPORT Renal Involvement in Multicentric Castleman Disease With Glomeruloid Hemangioma of Skin and Plasmacytoma Susan Uthup, DM, Krishna Balachandran, MD, Vimala Avadai Ammal, DM, Riyas Abdul Salam, MBBS, Jacob George, DM, Geetha M. Nair, DM, and Manju Leela, DM A 47-year-old man presented with fever of unknown origin, generalized weakness, edema, and renal failure. He had left-sided pleural effusion, generalized lymphadenopathy, multiple nontender cutaneous nodules, hepatomegaly, renal failure, and hypergammaglobulinemia. Axillary lymph node biopsy showed findings consistent with Castleman disease of the hyaline vascular type associated with interfollicular plasmacytosis. A renal biopsy performed in view of proteinuria and acute renal failure showed hypercellular glomeruli with capillary loop thickening and double contours consistent with membranoproliferative glomerulonephritis. Skin nodule biopsy showed a glomeruloid hemangioma characterized by dermal proliferation of capillary loops in a nodular manner resembling a glomerulus. He experienced clinical and biochemical remission with steroids. Discontinuation of steroid therapy was associated with recurrence of renal failure, reappearance of nodules, lymphadenopathy, and appearance of bony lytic lesions. Biopsy of bony lytic lesions showed plasmacytoma. The patient achieved complete remission on treatment with steroids and cyclophosphamide and is free of symptoms at the end of 40 months of follow-up. To our knowledge, this is the first case report of the occurrence of membranoproliferative glomerulonephritis, glomeruloid hemangioma of the skin, and plasmacytoma in a patient with multicentric Castleman disease without human immunodeficiency virus infection. Am J Kidney Dis 48:E17-E by the National Kidney Foundation, Inc. INDEX WORDS: Multicentric Castleman disease; membranoproliferative glomerulonephritis; glomeruloid hemangioma of skin; plasmacytoma; nephrotic syndrome; interleukin 6 (IL-6); vascular endothelial growth factor (VEGF). CASTLEMAN DISEASE, or angiofollicular lymph node hyperplasia, is a group of complex disorders causing nonmalignant proliferation of lymphoid tissue throughout the body. Clinically, Castleman disease may be unicentric or multicentric. Histologically, it is classified into the common hyaline vascular type seen in 90% of cases, the less common plasma cell type, and a mixed form. Localized disease can be divided into hyaline vascular type or plasma cell type. Multicentric Castleman disease (MCD) usually is associated with the plasma cell variant, but association with hyaline vascular and mixed types also are described. Most recently, an aggressive plasmablastic variant of MCD is described. 1 MCD commonly is seen in patients with human immunodeficiency virus (HIV) infection, older individuals with Kaposi sarcoma, and also in HIV-negative individuals. Independent of HIV infection, MCD occurs in the setting of immunoregulatory dysfunction. MCD is considered an aggressive disorder characterized by a waxing and waning course over long periods. 2 In patients with MCD, renal involvement is an uncommon secondary phenomenon related to immune dysregulation. Renal manifestations include nephrotic syndrome, acute renal failure, thrombotic microangiopathy, amyloidosis, and renal lymphoma. We present a case of multicentric Castleman disease of the hyaline vascular type with interfollicular plasmacytosis associated with membranoproliferative glomerulonephritis (MPGN). This patient also had plasmacytoma in the ribs and skin nodules, with histological examination showing glomeruloid hemangioma. In this context, we also discuss clinical manifestations, pathogenesis, and treatment of MCD, with special emphasis on renal involvement and glomeruloid hemangioma of the skin. CASE REPORT In July 2001, a 47-year-old man was admitted to our hospital with low-grade fever, generalized weakness, cough, dyspnea, edema, and macrohematuria. He had experienced weight loss of 10 kg during 6 months, small-joint arthritis, bilateral tender gynecomastia, and painless swellings over From the Departments of Nephrology and Pathology, Medical College Thiruvananthapuram, Kerala, India. Received November 10, 2005; accepted in revised form April 17, Originally published online as doi: /j.ajkd on July 3, Support: None. Potential conflicts of interest: None. Address reprint requests to Susan Uthup, DM, 58 Vikas Ln, Kunnukuzhi, Thiruvananthapuram, Kerala, India. susanuthup@yahoo.co.uk 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 48, No 2 (August), 2006: E17-E24 e17

2 e18 the scalp, upper limbs, and left side of the chest. One month before admission, he had received antituberculous treatment in view of prolonged fever, night sweats, and left-sided pleural effusion. Because there was no improvement, he was admitted for further evaluation. Physical examination showed a well-built middle-aged man who was pale, with facial puffiness, bilateral pitting pedal edema, and bilateral tender gynecomastia. Blood pressure was 150/86 mm Hg. He had bilateral multiple firm rubbery nontender cervical, axillary, and inguinal lymph nodes and hepatomegaly. There were multiple nontender cutaneous nodules over the scalp and extensor surface of the upper limbs. A diffuse subcutaneous 6 4 cm swelling was present over the left sixth and seventh ribs in the midaxillary line, which was nontender, hard, and fixed to the bone. Cardiovascular and neurological examination showed no abnormalities. Laboratory evaluation showed a hemoglobin level of 10 g/dl (100 g/l) and white blood cell count of 9,800/ L, with 6,860 neutrophils/ L. Platelet count was 250,000/ L, and erythrocyte sedimentation rate was 110 mm/h. There was macrohematuria with red blood cell casts and proteinuria of 2 g/d. Results of biochemical investigations showed the following values: blood urea nitrogen, 26 mg/dl (9.28 mmol/l); serum creatinine, 3.5 mg/dl (309 mol/l); serum calcium, 8.6 mg/dl (2.15 mmol/l); phosphorus, 3.5 mg/dl (1.13 mmol/l); and uric acid, 16.1 mg/dl (958 mol/l). Results of liver function tests were as follows: alanine aminotransferase, 23 IU/L; aspartate aminotransferase, 20 IU/L; serum alkaline phosphatase, 273 IU/L; total protein, 6 g/dl (60 g/l); albumin, 2.7 g/dl (27 g/l); serum bilirubin, 0.8 mg/dl (14 mol/l); and serum cholesterol, 104 mg/dl (2.6 mmol/l). Serum protein electrophoresis showed hypergammaglobulinemia with no monoclonal band and hypoalbuminemia. Chest radiograph showed interstitial infiltrates and leftsided pleural effusion. Ultrasound scanning of the abdomen showed hepatomegaly; normal-sized echogenic kidneys, and UTHUP ET AL left pleural effusion. Pleural fluid studies showed 4 g/dl (40 g/l) of protein and 55 cells/ L: 46% polymorphs, 54% lymphocytes, numerous red blood cells, and scanty macrophages. There were no malignant cells. Bacterial cultures were sterile. Autoantibodies, including antinuclear and antineutrophil cytoplasmic antibodies, were negative. Hepatitis B, hepatitis C, syphilis, and HIV screening were negative. CD4 and CD8 counts were normal. Collagen vascular disease workup also was negative. Bone marrow examination, performed in view of anemia, hypergammaglobulinemia, and hyperuricemia, showed mild erythroid hyperplasia with normoblastic and micronormoblastic maturation. Myeloid series was mildly proliferative with predominant mature forms and 15% plasma cells. Megakaryocytes were normal. Histological examination of the axillary lymph node showed angiofollicular lymphoid hyperplasia with interfollicular plasmacytosis. Lymphoid aggregates contained varying degrees of hyalinization and were interspersed with capillaries suggestive of the hyaline vascular type of Castleman disease. However, the interfollicular plasmacytosis was a feature frequently seen in patients with the plasma cell type of Castleman disease (Fig 1). Biopsy of the cutaneous nodule from the hand showed glomeruloid hemangioma, a neoplasm composed of proliferating vascular channels. Ectatic vascular channels with intravascular growth of papillary tufts of capillaries were noted (Fig 2). Renal biopsy (light microscopy with hematoxylin and eosin) showed glomeruli with diffuse proliferation, fibrillary mesangial change, capillary loop thickening, and double contours. There were 3 to 4 glomeruli with segmental ectatic capillary loops and mesangiolysis. One artery showed focal mild intimal thickening. There was mild diffuse interstitial inflammation consisting of lymphocytes, plasma cells, and occasional neutrophils. Marked interstitial edema was present, separating the tubules. Mild interstitial fibrosis affecting less Fig 1. Light micrograph of lymph node biopsy specimen from the axilla (10 m) shows follicle-like lymphoid structures interspersed with capillaries showing hyalinization, interfollicular vascular proliferation, and sheets of plasma cells. (Hematoxylin and eosin stain.)

3 RENAL INVOLVEMENT IN MULTICENTRIC CASTLEMAN DISEASE e19 Fig 2. Light micrograph of skin biopsy specimen (20 m) shows typical glomerulus-like structures within ectatic vascular channels composed of papillary tufts lined by endothelial cells in the dermis: glomeruloid hemangioma. (Hematoxylin and eosin.) than 10% of the cortex was seen. Acute tubular injury with dilatation and attenuation of the tubules was present (Fig 3). Immunofluorescence showed mesangial blush for C3. Immunoglobulin G (IgG), IgA, IgM, C1q, and and light chains were negative. Focal casts stained equally bright for and light chains. Electron microscopy was not done. The clinical syndrome and histological findings were compatible with the diagnosis of MCD associated with MPGN and glomeruloid hemangioma of the skin in an HIV-negative patient. The patient was started on therapy with oral prednisolone, 40 mg/d, as a single dose. Over 1 month, the fever, edema, anemia, and lymphadenopathy regressed and renal function returned to normal. After 3 months of therapy, steroid dose was tapered and stopped. However, 1 month later, the patient was readmitted with renal failure, pallor, pedal edema, and generalized lymph node enlargement. There were multiple nontender purple nodules over the back of chest and extensor aspect of the Fig 3. Light microscopy of glomerulus (10 m) shows increased mesangial matrix, increased mesangial cellularity, and capillary loop thickening with double contours consistent with MPGN. (Hematoxylin and eosin.)

4 e20 UTHUP ET AL Fig 4. Computed tomographic scan of the thorax shows lytic lesion on the second rib. upper limbs. Also, he had a hard swelling of the left lateral chest wall fixed to the underlying sixth and seventh ribs. Investigation showed anemia with a hemoglobin level of 10.1 g/dl (101g/L), and erythrocyte sedimentation rate was 94 mm/h. White blood cell count was 11,500/ L, with 8,165 neutrophils/ L, and platelet count was 380,000/ L. There was microhematuria and proteinuria of 3 g/d of protein. Results of biochemical investigations showed the following values: blood urea nitrogen, 49.5 mg/dl (17.67 mmol/l); serum creatinine, 3.2 mg/dl (283 mol/l); uric acid, 8.4 mg/dl (500 mol/l); alanine aminotransferase, 15 IU/L; aspartate aminotransferase, 19 IU/L; serum alkaline phosphatase, 118 IU/L; total protein, 6.7 g/dl (67 g/l); albumin, 3.2 g/dl (32 g/l); serum bilirubin, 0.6 mg/dl (10 mol/l); and serum cholesterol, 68 mg/dl (1.76 mmol/l). Ultrasound scan of the abdomen showed hepatosplenomegaly and ascites. Computed tomography of the chest (Fig 4) showed an expansile lytic lesion with a soft tissue component at the angle of the eighth rib on the left side, with moderate contrast enhancement. A similar lesion was noted Fig 5. Light micrograph of lytic rib lesion (10 m) shows sheets of plasma cells dispersed in a fibrovascular stroma suggestive of plasmacytoma. (Hematoxylin and eosin.)

5 RENAL INVOLVEMENT IN MULTICENTRIC CASTLEMAN DISEASE e21 in the anterior end of the left second rib. There was no mediastinal or para-aortic lymph node enlargement. A biopsy of the second-rib lesion showed a neoplasm composed of sheets of round cells dispersed in a fibrovascular stroma. Cells were round or oval, with moderate cytoplasm and pleomorphic and hyperchromatic vesicular nuclei. Many cells were plasmacytoid; some cells show prominent nucleoli. Occasional cells were binucleated. Stroma showed thin-walled vascular channels (Fig 5). On immunohistochemical staining, cells were positive for plasma cell marker CD168 and chain. They were negative for leukocyte common antigen and light chain. The neoplasm was a -positive plasmacytoma. Serum anti human herpesvirus 8 (HHV-8) antibody test could not be performed. The patient was started on therapy with prednisolone and cyclophosphamide. He achieved complete remission within 3 months. Renal function normalized. He is free of symptoms at the end of 40 months and is on treatment with tapered doses of prednisolone. DISCUSSION Castleman disease, also called angiofollicular lymph node hyperplasia, is a rare atypical lymphoproliferative disorder first described by Benjamin Castleman in Castleman disease can be classified as: (1) unicentric versus multicentric, based on clinical and radiological findings; (2) hyaline vascular versus plasmacytic versus mixed cellularity variety, based on histopathologic examination; and (3) HIV negative versus HIV positive based on the HIV status of the patient. All 3 factors need to be taken into account in patient assessment. Unicentric or localized Castleman disease occurs in children and adults who present with large solitary masses of the mediastinum or markedly enlarged single peripheral or abdominal lymph nodes. Patients with MCD have lymphadenopathy, hepatosplenomegaly, and systemic manifestations. Many are severely ill, with malaise, fever, weight loss, night sweats, respiratory symptoms, peripheral edema, and skin rashes. Abnormal laboratory findings in these patients include anemia, thrombocytopenia, hypergammaglobulinemia, proteinuria, hypoalbuminemia, hypocholesterolemia, and increased levels of acutephase reactants. 4 The disease course may be rapidly progressive, chronic persistent, or episodic relapsing in patients with MCD. 1 Keller et al 5 divided Castleman disease histologically into 2 types: a hyaline vascular variant and plasma cell variant. The hyaline vascular variant shows prominent proliferation of small hyalinized follicles with marked interfollicular vascular proliferation. The plasma cell variant shows hyperplastic germinal centers, sheets of plasma cells in the interfollicular region, blood vessel proliferation, and persistent sinuses. A mixed-type variant of both hyaline vascular and plasma cell type also is described. 2 Our patient presented with lymphadenopathy, hepatosplenomegaly, and systemic manifestations. The lymph node biopsy showed features of the hyaline vascular type of Castleman disease with interfollicular plasmacytosis, suggesting a mixed type of the disorder. The current case also highlights the renal involvement in patients with MCD in the form of proteinuria and renal failure. Renal biopsy showed an MPGN-like lesion associated with mesangiolysis. Renal complications reported in patients with Castleman disease range from minimal change disease, 6 MPGN, 7-10 mesangioproliferative glomerulonephritis, 11 fibrillary glomerulonephritis, 7 thrombotic microangiopathy, 10 interstitial nephritis, amyloidosis, 12 and renal lymphoma. 13 Other less commonly reported associations include membranous nephropathy, 14 crescentic glomerulonephritis, 15 interstitial tubulitis, and renal interstitial cellular infiltration with plasma cells. 13 Various cytokines and growth factors are implicated in the pathogenesis of MCD and manifestations in patients with MCD including renal involvement. Interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) are the most important among them. Yoshizaki et al 16 noted elevated serum IL-6 concentrations in patients with Castleman disease that decreased to normal values after lymph node masses had been resected. IL-6 is a pleiotropic cytokine with a wide range of biological activities. It causes proliferation and differentiation of B cells into antibodyproducing cells, resulting in hyperplastic follicles. This causes the enlarged lymph nodes. IL-6 also increases VEGF secretion, causing angiogenesis, proliferation of vascular smooth muscle cells, and capillary proliferation with endothelial hyperplasia. IL-6 also is responsible for polarization of T lymphocytes to a type 2 cytokine profile leading to autoimmune phenomena, including autoimmune hemolytic anemia, antinuclear antibody positivity, and increased IgE levels. IL-6 induces synthesis of hepatic acute-phase reactants and increases the erythrocyte sedimentation rate and C-reactive protein, IgG, serum fibrinogen, and serum amyloid A

6 e22 UTHUP ET AL protein levels. Increased serum amyloid A protein levels may result in AA amyloidosis, whereas hyperfibrinogenemia may have a role in venous thrombosis. Finally, systemic manifestations virtually are always associated with increased IL-6 levels. 1,16 Kaposi sarcoma associated herpes virus (KSHV), also called HHV-8 (KSHV/HHV-8), is reported to be an etiologic agent in Castleman disease, especially in patients infected with HIV and also in non-hiv infected patients A viral homologue of IL-6 encoded by KSHV/ HHV-8 shares functional properties with human IL-6. Both human and viral IL-6 can induce VEGF production in such experimental animals as mice. In patients with MCD, increased IL-6 and VEGF levels have been noted. MCD exacerbations correlated with levels of human IL-6, IL-10, serum C-reactive protein, and viral load of KSHV DNA in peripheral-blood cells. IL-6 also causes mesangial cell proliferation, mesangiolysis, and inflammatory cell infiltration in the kidney. 10,16 VEGF is expressed strongly in plasma cells in the interfollicular region of the lymph node. It can influence and modify the activity of MCD and renal involvement. Autocrine action of VEGF from plasma cells may be responsible for pleural effusion, ascites, edema, and proteinuria. It acts by enhancing vascular permeability, inducing mesangiolysis and widening of the subendothelial space. VEGF also was reported to protect and accelerate renal recovery in antiglomerular endothelial antibody induced thrombotic microangiopathy in rats. Thus, the role of VEGF, whether protective or causative, in renal injury is not precisely known. 10 In the present case, serum IL-6 and VEGF levels were not studied. Histological examination of the cutaneous nodule in our patient showed glomeruloid hemangioma, a benign vascular tumor. This term was coined by Chan et al 20 in Although it is considered a cutaneous marker for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome, glomeruloid hemangioma associated with MCD without POEMS syndrome was reported. 21 This lesion usually occurs as multiple red papules over the trunk and extremities. Microscopically ectatic dermal vascular spaces are filled with aggregates of capillaries, resulting in structures reminiscent of renal glomeruli. Several cases of vascular neoplasia were described in patients with Castleman disease, and it is viewed as a pathological manifestation of the intimate functional relationship that exists between the immune and vascular systems. Other vascular neoplasms reported in patients with MCD are Kaposi sarcoma, especially in association with HIV; histiocytoid hemangioma; and angiomatoid malignant histiocytoma. All these lesions may be caused by angiogenic factors produced by activated lymphoid cells. 22 This patient also had lytic lesions in the ribs. Histological examination showed plasmacytoma. A solitary plasmacytoma occurring in patients with MCD was reported previously in the literature. The plasma cell proliferation may be related to pleotropic cytokines. 22 Another clinical observation is the association of MCD with POEMS syndrome. 20 Our patient had hepatomegaly, gynecomastia, and skin changes (glomeruloid hemangioma); however, polyneuropathy and monoclonal protein were not seen. Although glomeruloid hemangioma is a cutaneous marker for POEMS syndrome, this patient did not fulfill criteria for POEMS syndrome. The constellation of relevant clinical signs and symptoms, such as extensive lymphadenopathy, hepatomegaly, hypergammaglobulinemia, renal involvement, and histopathologic evaluation, confirmed the diagnosis of MCD in this patient. At present, there is no consensus about the optimal management strategy for patients with MCD. Successful treatment of patients with MCD, regardless of whether associated with HHV-8, has been achieved by using combination chemotherapy with or without prednisone, administered at the time of the initial diagnosis. Localized Castleman disease not associated with HHV-8 infection generally is curable with surgical resection, with or without radiotherapy. Chemotherapeutic agents used include doxorubicin, vincristine, cyclophosphamide, melphalan, and chlorambucil. These have been used as single agents, together with steroids, or in combination (eg, cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]). Azathioprine and bone marrow transplantation also have been attempted, especially after failure of CHOP therapy, but yielded mixed results. 3 Vinca alkaloids and other cytotoxic agents, with or without

7 RENAL INVOLVEMENT IN MULTICENTRIC CASTLEMAN DISEASE e23 high-dose corticosteroids, produced frequent, but short-lived, responses. MCD sometimes is refractory to treatment with corticosteroids and chemotherapy. 2 A number of therapies have been used for multicentric disease: intravenous immunoglobulin; antiherpes drugs, eg, acyclovir, (Val) ganciclovir in HIV-positive and HHV-8 positive patients; and, in intractable cases, even autologous stem cell transplantation. 23 Surgery also may be useful in debulking disease. 24 The antiangiogenesis factor thalidomide has been used successfully in the treatment of patients with glomerular diseases like steroid-dependent nephrotic syndrome secondary to proliferative mesangial glomerulonephritis in Castleman disease. 6 Treatment with interferon alfa or the anti-cd20 monoclonal antibody rituximab resulted in durable clinical remission of the disease. Rituximab targets B cells, a KSHV reservoir and probably a major source of the IL-6 and other soluble mediators of MCD. 25,26 Because dysregulated overproduction of IL-6 is responsible for clinical manifestations of MCD, anti IL-6 therapies include suramin; anti IL-6 antibody or anti IL-6 receptor antibody may be beneficial. Suramin is a polysulfonated urea compound originally used for trypanosomiasis. Suramin inhibits viral reverse transcriptase and has a number of biological effects, which include inhibition of growth factor and cytokine binding to their respective receptors, eg, IL-6, platelet derived growth factor, and fibroblast growth factor. Suramin also modulates cytokine secretion. 23,24 Anti IL-6 antibody is particularly effective in controlling IL-6 related symptoms, but also can induce disease regression with durable remissions. 27,28 Atlizumab, the monoclonal anti IL-6 receptor antibody, dramatically alleviates symptoms and biochemical abnormalities in patients with MCD; but not its underlying pathophysiological process. The disease may relapse on cessation of therapy. 26,29,30 Although MCD is non-neoplastic, without treatment, the prognosis is poor. Infections, multiorgan failure, renal failure, and development of such malignancies as lymphoma (Hodgkin and non-hodgkin) or Kaposi sarcoma are common causes of death in these patients. HHV-8 positive MCD is more aggressive and has a poor prognosis, with a median survival of less than 30 months. 1,2,4,17,18,24 Our patient responded to treatment with cyclophosphamide and prednisolone. The 40- month follow-up after diagnosis and treatment documented an excellent response to the chemotherapy regimen and no evidence of active disease. He remains under active surveillance because he is considered to be at high risk for the development of non-hodgkin lymphoma and Kaposi sarcoma. 31 ACKNOWLEDGMENT The authors thank Dr Anjali Kale, Department of Pathology, Amritha Institute of Medical Sciences and Technology Cochin, Kerala; Dr Philip W. Allen, Flinder s Medical Center, Adelaide, Australia; Dr Pradeep, Department of Dermatology; and Dr Jayakumar, Department of Radiotherapy, Medical College Thiruvananthapuram, Kerala, India, for their help. REFERENCES 1. McClain KL, Natkunam Y, Swerdlow SH: Atypical cellular disorders. Hematology: , Peterson BA, Frizzera G: Multicentric Castleman s disease. Semin Oncol 20: , Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 9: , Herrada J, Cabanillas F, Rice L, Manning J, Pugh W: Clinical behavior of localized and multicentric Castleman s disease. Ann Intern Med 128: , Keller AR, Hocholzer L, Castleman B: Hyalinevascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 29: , Menegato MA, Canelles MF, Tonutti E, Pizzolitto S: Remission of nephrotic syndrome after thalidomide therapy in a patient with Castleman s disease. Clin Nephrol 61: , Akimoto H, Shirai M, Usutani S, et al: Membranoproliferative glomerulonephritis-like lesion with fibrillary deposition associated with multicentric Castleman s disease. Nippon Jinzo Gakkai Shi 40: , Said R, Tarawneh M: Membranoproliferative glomerulonephritis associated with multicentric angiofollicular lymph node hyperplasia. Case report and review of the literature. Am J Nephrol 12: , Chan TM, Cheng IK, Wong KL, Chan KW: Resolution of membranoproliferative glomerulonephritis complicating angiofollicular lymph node hyperplasia (Castleman s disease). Nephron 65: , Seida A, Wada J, Morita Y, et al: Multicentric Castleman s disease associated with glomerular microangiopathy and MPGN-like lesion: Does vascular endothelial cell derived growth factor play causative or protective roles in renal injury? Am J Kidney Dis 43(1):E3-E9, 2004(available

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