Leukemia Research 34 (2010) e42–e45

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Letter to the Editor

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ulticentric Castleman disease complicated by tumor lysis syn-rome after systemic chemotherapy

. Introduction

Castleman disease (CD), also known as angiofollicular lymphode hyperplasia, was first described in 1954 by Dr. Benjaminastleman [1]. Although the etiology and pathogenesis is not fullynderstood, it has been associated with human immunodeficiencyirus (HIV) and human herpes virus-8; in addition, interleukin-6as been found to play a role in many cases of CD [2,3]. CD islassified by histological type and location of the disease [4,5]. Mul-icentric CD (MCD) is a plasma cell variant predominantly, withome cases with plasmablastic characteristics [6]. MCD has a vari-ble clinical course and may be progressive over months or episodicith recurrent exacerbations over years. The plasma cell type of CDas a poorer prognosis and more systemic manifestations. Clinicalndings such as fever, night sweats, weight loss, multiple lym-hadenopathy, and hepatosplenomegaly are common [7].

There are no standard guidelines for the treatment of CD. Uni-entric CD is usually responsive to surgery or radiation. By contrast,ymptomatic patients with MCD require systemic therapy suchs corticosteroids or chemotherapy regimens used to treat non-odgkin’s lymphoma [1,8]. The tumor lysis syndrome (TLS) inatients with CD is very rare [9]. Here, we report a patient with theumor lysis syndrome associated with MCD after treatment withhemotherapy.

. Case report

A 33-year-old man was admitted to the hospital with nightevers, chills, and enlarged neck lymph nodes for 1 month. The his-ory was positive for a tonsillar abscess 3 months prior to admissionhat was treated at a local otolaryngology clinic. The patient had10 kg weight loss. The blood pressure was 110/70 mmHg, tem-erature 38.8 ◦C, pulse rate 100/min, and respiration rate 20/minn admission. The physical examination was significant for theiver that was palpable 5 cm below the lower costal margin in theight mid-clavicular line and the spleen that was palpable 10 cmelow the lower costal margin in the left mid-clavicular line. Firm,ontender, fixed lymph nodes, 1.2 cm × 1 cm were detected in theubmandibular area, bilaterally.

The initial complete blood cell profile showed a hemoglobinHb) level of 9.9 g/dl, leukocyte count 1.9 × 109/l, and platelet

ount 65 × 103/l. Anti-HIV and anti-EBV antibodies were negative.he neck, chest and abdomen-pelvis computed tomography scanevealed enlargement of multiple lymph nodes. The bone marrowBM) biopsy showed markedly hypercellular marrow with ade-uate numbers of megakaryocytes and interstitial deposition of

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immature lymphocytes; the immunohistochemical (IHC) stainingshowed: CD3+, UCHL-1+, CD20+ with normal lymphoid follicles,and CD67+ (Fig. 1). The BM cytogenetics was normal. Excisionalbiopsy of a right submandibular lymph node revealed lymph nodeinvolvement of CD, the plasma cell variant. Small atrophic folli-cles and marked proliferation of histiocytes and plasma cells wereseen on the hematoxylin and eosin staining (H&E) (Fig. 2A and B).On the IHC staining, small atrophic follicles were: CD20+, UCHL-1+, CD30−, Bcl-6−, CD138+(Fig. 2C), and EMA+, compatible withthe plasma cell type of CD. Additional blood tests were performedto rule out autoimmune disease and associated infectious disease,e.g., anti-nuclear antibody, anti-double strand DNA, blood culturesand the quantiferon-tuberculosis gold test were all negative. Thepatient had relapsing fevers since the day of admission. The medianpeak temperature was 39.2 ◦C without any fever focus identified;the patient was treated empirically with antibiotics.

Treatment with prednisolone 1 mg/kg per day was started, andon day 2 after treatment, the pancytopenia improved and on treat-ment day 7, the patient was discharged without fever. However,18 days after treatment, the patient was admitted again withfever, the blood tests showed pancytopenia: Hb 9.3 g/dl, leukocytecount 0.9 × 109/l and platelet count 22 × 103/l. On admission day 4,CVP chemotherapy was started, consisting of cyclophosphamide800 mg/m2 and vincristine 1.4 mg/m2 on day 1 of chemother-apy, and prednisolone 1 mg/kg for 5 days. On chemotherapy day6, the patient developed a high fever without any fever focus,and the pancytopenia persisted; the CVP regimen appeared tohave no effect on the disease. On chemotherapy day 10, high-dose dexamethasone (40 mg) was started; 14 h after the infusion(chemotherapy day 11), he suddenly complained of dyspnea withan increase in the respiratory rate to 33/min, a blood pressure130/70 mmHg, temperature 36.5 ◦C, and pulse rate 116/min. Imme-diate arterial blood gas analysis showed severe acidosis (pH 6.9)and the serum creatinine, potassium, phosphorus, and uric acidrose to 2.4 mg/dl, 5.7 mmol/l, 9.0 mg/dl, and 9.4 mg/dl, respectively.Other chemistries: AST(SGOT), ALT(SGPT), total bilirubin, directbilirubin, and alkaline phosphatase increased to 1076 IU/l, 275 IU/l,8.6 mg/dl, 1.6 mg/dl, and 3517 IU/l, respectively. The blood culturesrevealed no growth of any microorganisms. Vigorous fluid ther-apy with continuous furosemide infusion and urine alkalinizationwas ineffective. Immediate continuous renal replacement therapywas started, but the oliguric renal failure did not improve (Table 1).The patient continued to have progressive multi-organ failure andfinally hypotension led to death on chemotherapy day 17.

3. Discussion

For patients with unicentric CD, surgery or radiation can becurative. For those with MCD, however, there are several effective

Letter to the Editor / Leukemia Research 34 (2010) e42–e45 e43

Fig. 1. (A) The BM shows marked increase of T lymphocytes (IHC for UCHL-1, ×200); (B) the BM shows only a small number of B lymphocytes (IHC for CD20, ×200); (C) theB

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reatment options; however, they are not well established. The usef prednisone or other glucocorticosteroids is one of the first linereatments, which has a temporary effect on the lymphadenopathy.hemotherapy, as a single agent or in combination, is currently thereatment of choice in patients with progressive or symptomatic

CD [8].TLS is a set of metabolic derangements that develops from treat-

ent of highly proliferative hematologic malignancies with a large

umor burden. TLS is characterized by the laboratory findings ofyperuricemia, hyperkalemia, hyperphosphatemia and hypocal-emia, and the clinical manifestations of renal failure, cardiacysrrhythmias, and seizures, which can be fatal. For prevention of

able 1mmediate continuous renal replacement therapy was started after detection of theumor lysis syndrome however the oliguric renal failure progressed.

Parameter Day 1 Day 10a Day 14b Day 19c

Blood urea nitrogen (8–26 mg/dl) 17 16 48 54Creatinine (0.6–1.2 mg/dl) 0.9 0.9 2.1 1.8Uric acid (2.4–7.0 mg/dl) 4.7 9.4Phosphorus (2.5–4.5 mg/dl) 4.6 9 3.4Calcium (8.0–10.0 mg/dl) 8.8 8Albumin (3.8–5.2 g/dl) 3.8 3.3 3.2 3.4Corrected calciumd 8.9 8.6Potassium (3.5–5.5 mmol/l) 4.2 3.2 5.7 4.8

a Chemotherapy day 7.b Chemotherapy day 11 (continuous renal replacement therapy started).c The day before expire.

TLS, aggressive hydration before and after chemotherapy is needed;once TLS occurs, massive hydration with urine alkalinization, useof uric acid lowering agents, like allopurinol or rasburicase (recom-binant form of urate oxidase), and as a final option, hemodialysisshould be performed [10,11].

CD has been reported to be strongly associated with HIV infec-tion, Kaposi’s sarcoma, non-Hodgkin’s lymphoma and Hodgkin’sdisease. At times, lymphoma and CD coexist or CD may progressto lymphoma [12–14]. In this case, however, the patient under-went surgical excisional biopsy of a submandibular lymph nodeand BM biopsy, which showed no monoclonality by IHC staining;these studies ruled out the possibility of a lymphoid malignancy.Biopsy of the liver or spleen was not performed because ofthe thrombocytopenia and risk of bleeding. Marked thrombocy-topenia, hepatosplenomegaly, and rapid disease progression areconsistent with the clinical features of hepatosplenic �� T-celllymphoma, diagnosed by clinical presentation and the histologyof the sinusal/sinusoidal tropism of neoplastic cells, and expres-sion of the �� T-cell receptor by tumor cells [15]. However, theBM findings of this patient had no monoclonality implicating aT-cell lymphoma. The marked histiocyte proliferation in the BMwas different from that of malignant histiocytosis [16], and thelaboratory findings did not reveal sarcoidosis or a tuberculosis

infection.

CD is generally known to have a benign course. However, in thiscase, the patient had MCD with the plasma cell variant and progres-sive multi-organ failure as a result of TLS after chemotherapy. Thiscase illustrates that the management of MCD, with the plasma cell

e44 Letter to the Editor / Leukemia Research 34 (2010) e42–e45

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ig. 2. (A) An enlarged lymph node shows hyperplastic changes with small lymphoiH&E, ×400); (C) IHC for CD138 reveals infiltrated plasma cells in interfollicular reg

ariant, which has a large tumor burden, should include cautiousreventive measures for complications such as TLS.

onflict of interest statement

None.

cknowledgements

None.

eferences

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[3] Yoshizaki K, Matsuda T, Nishimoto H, et al. Pathogenic significance ofinterleukin-6 (IL-5/BSF-2) in Castleman’s disease. Blood 1989;74:1360–7.

[4] Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types ofgiant lymph node hyperplasia of the mediastinum and other locations. Cancer1972;29:670–83.

[5] McCarthy M, Vukelja S, Banks P, et al. Angiofollicular lymph node hyperplasia(Castleman’s disease). Cancer Treat Rev 1995;21:291–310.

[6] Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablasticvariant of Castleman disease that is linked to HHV-positive plasmablastic lym-

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[7] Frizzera G, Peterson BA, Bayrd ED, et al. A systemic lymphoproliferative dis-order with morphologic features of Castleman’s disease: clinical findings andclinicopathologic correlations in 15 patients. J Clin Oncol 1985;3:1202–16.

[8] Chronowski GM, Ha CS, Wilder RB, et al. Treatment of unicentric and multicen-tric Castleman disease and the role of radiotherapy. Cancer 2001;92:670–6.

cles (H&E, ×100); (B) interfollicular region shows multifocal plasma cell infiltrationC, ×200) (right submandibular lymph node biopsy).

[9] Lee KD, Lee KW, Choi IS, et al. Multicentric Castleman’s disease complicated bytumor lysis syndrome. Ann Hematol 2004;83:722–5.

10] Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies andclassification. Br J Haematol 2004;127:3–11.

11] Del Toro G, Morris E, Cairo MS. Tumor lysis syndrome: pathophysiology,definition, and alternative treatment approaches. Clin Adv Hematol Oncol2005;3:54–61.

12] Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcoma-associated herpes virus-related non-Hodgkin lymphoma in patients with HIVinfection and multicentric Castleman disease. Blood 2002;99:2331–6.

13] Peterson BA, Frizzera G. Multicentric Castleman’s disease. Semin Oncol1993;20:636–47.

14] Larroche C, Cacoub P, Soulier J, et al. Castleman’s disease and lymphoma: reportof eight cases in HIV-negative patients and literature review. Am J Hematol2002;69:119–26.

15] Belhadj K, Reyes F, Farcet JP, et al. Hepatosplenic �-� T-cell lymphoma is a rareclinicopathologic entity with poor outcome: report on a series of 21 patients.Blood 2003;102:4261–9.

16] Gaulard P, Jaffe E, Krenacs L, et al. Hepatosplenic T-cell lymphoma. In:Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification oftumours of haematopoietic and lymphoid tissues. 4th edition Lyon: IARC; 2008.p. 292–3.

Ji Hyun Lee a

Kyung A. Kwon a

Suee Lee a

Sung Yong Oh a

Hyuk-Chan Kwon a

Jin Yeong Han b

Sook Hee Hong c

Sung-Hyun Kim a,∗a Department of Internal Medicine, Dong-A University

College of Medicine, Busan, South Korea

ia Re

Letter to the Editor / Leukem

b Department of Laboratory Medicine, Dong-AUniversity College of Medicine, Busan, South Korea

c Department of Pathology, Dong-A University Collegeof Medicine, Busan, South Korea

∗ Corresponding author at: Department of InternalMedicine, Dong-A University College of Medicine,

search 34 (2010) e42–e45 e45

3-1 Dongdaeshin-dong, Seo-gu, Busan, 602-715,South Korea. Tel.: +82 51 240 2608;

fax: +82 51 240 2088.E-mail address: kshmoon@dau.ac.kr (S.-H. Kim)

28 June 2009Available online 10 September 2009