Mixed-Type Multicentric Castleman's Disease Developing During a 17-Year Follow-Up of Sarcoidosis

□ CASE REPORT □

Mixed-type Multicentric Castleman’s Disease Developing during a 17-year Follow-up of Sarcoidosis

Nobuyasu Awano 1, Minoru Inomata 1, Keisuke Kondoh 1, Kohta Satake 1, Hiroyuki Kamiya 1, Atsuko Moriya 1, Tsunehiro Ando 1, Toshio Kumasaka 2, Tamiko Takemura 2, Kengo Takeuchi 3 and Soichiro Ikushima 1

Abstract

Multicentric Castleman’s Disease (MCD) is a systemic disease characterized by generalized lymphadenopathy and the proliferation of plasma cells. The development of MCD in a patient with preexisting sarcoidosis has not been previously reported. We herein describe a case of MCD developing in a 78-year-old woman with a 17-year history of sarcoidosis. The patient’s serum interleukin-6 (IL-6) levels were only slightly elevated; however, the IL-6 levels in the fluid of both pleural effusion and ascites were markedly elevated. The administration of steroid-pulse therapy and prednisolone was ineffective in treating the MCD, although treatment with tocilizumab proved highly effective.

Key words: sarcoidosis, Multicentric Castleman’s Disease (MCD), tocilizumab, IL-6

(Intern Med 51: 3061-3066, 2012) (DOI: 10.2169/internalmedicine.51.8120)

eases as well as treatment selection. Introduction Case Report Castleman’s Disease (CD) is a rare lymphoproliferative disease associated with human immunodeficiency virus A 60-year-old woman developed bilateral lower leg (HIV), human herpesvirus 8 (HHV-8), Kaposi’s sarcoma- erythema and a mass in the right breast in 1993. Skin and associated herpesvirus (KSHV), secondary amyloidosis and breast biopsies conducted elsewhere revealed non-caseating a number of malignancies, including malignant lymphoma, epithelioid cell granulomas (Fig. 1). The laboratory data polyneuropathy, organomegaly, endocrinopathy, M-protein showed elevations in the levels of serum angiotensin- and skin change syndrome (POEMS syndrome) (1, 2). Clini- converting enzyme (ACE) (23.6 IU/L) and lysozyme (10.8 cally, CD is divided into two variants: unicentric (UCD) and μg/mL), while a tuberculin test was negative. The patient multicentric (MCD) (3). Pathologically, it is divided into was diagnosed with sarcoidosis according to the criteria es- three variants: hyaline-vascular, plasma-cell and mixed (4). tablished in 1991 (6), and her case was followed by obser- Sarcoidosis is a multisystem granulomatous disorder of vation without the administration of any treatment, again unknown etiology. Although patients with sarcoidosis often satisfying criteria updated in 1999 (7). In 2003, she devel- develop lymphoproliferative or malignant diseases, the de- oped third-degree atrioventricular block as a result of car- velopment of MCD in a patient with preexisting sarcoidosis diac sarcoidosis. A pacemaker was implanted, and again no has not been previously reported, and only one report has follow-up treatment was administered. In December 2010, at described the coexistence of sarcoidosis with UCD (5). the age of 77, the patient came to our hospital with a slight We herein present the first case of sarcoidosis preceding fever and epigastric pain. Two weeks later, she developed MCD and discuss the possible relationship between the dis- dyspnea and systemic edema and was admitted to our hospi-

１Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan, ２Department of Pathology, Japanese Red Cross Medical Cen- ter, Japan and ３Department of Pathology, the Cancer Institute Hospital of JFCR, Japan Received for publication May 9, 2012; Accepted for publication August 1, 2012 Correspondence to Dr. Nobuyasu Awano, [email protected]

3061 Intern Med 51: 3061-3066, 2012 DOI: 10.2169/internalmedicine.51.8120

A B

Figure 1. A) A skin biopsy performed in 1993 revealed non-caseating epithelioid cell granulomas around a small blood vessel and hair follicle in the dermis (Hematoxylin and Eosin staining, ×20). B) A right breast biopsy performed in 1993 revealed non-caseating epthelioid cell granulomas with gi- ant cells. A lobule of a mammary gland in the right corner shows lymphocyte infiltration and granulomas (Hematoxylin and Eosin staining, ×15).

Table 1. Laboratory Data and the Examination Results of the Pleural Effusion and Ascites

WBC 8,600/ȝL Na: 136 mEq/L [pleural effusion] RBC 380×104ȝ/ K: 4.8 mEq/L Alb: 1.2g/dL Hb 10.3g/dL Cl: 106 mEq/L TG: 6mg/dL Plt 16.0×104ȝL Ca: 7.2 mg/dL protein: 2,400mg/dL PT%: 70% Fe: 7ȝg/dL glucose: 148mg/dL PT-INR: 1.17 Glucose: 10ȝg/dL LDH: 56 IU/L APTT: 46.2 sec ACE: 5.6 IU/L Hyaluronic acid 24,400ng/dL Fbg: 543 mg/dL BNP: 126.0 pg/mL CEA: 0.6ng/mL FDP: 51.3 ȝg/mL SCC: 0.6ng/mL CYFRA: 1.3ng/mL D-dimer 24.9 ȝg/mL CYFRA: 1.3ng/mL ADA: 6.7IU/L TP: 5.4g/dL NSE: 8.3ng/mL Cytology: Class II Alb: 2.5g/dL lysozyme: ȝg/mL [ascites] AST: 26 IU/L CRP: 15.94 mg/dL TG: 20mg/dL ALT: 19 IU/L IgG: 1,066 mg/dL protein: 2,700mg/dL LDH: 148 IU/L (polyclonal pattern) glucose: 15mg/dL ALP: 459IU/L sIL2R: 1,630 U/mL LDH: 65 IU/L Tcho: 95 mg/dL IL-6: 18pg/mL CEA: 0.5ng/mL BUN: 15 mg/dL IgG-4: 31mg/dL CA-19-9: 1U/mL Cre: 0.93 mg/dL VEGF: 69.4 pg/mL Cytology: Class II

Reference range: ACE: 8.3-21.4 IU/L, lysozyme: 5-10.2 μg/mL Measurement method: IL-6: chemiluminescent enzyme immunoassay, VEGF: enzyme immunoassay

tal. Her weight had increased from 48.0 to 57.1 kg in one the serum IL-6 level was found to have increased slightly to month. A physical examination revealed bilateral cervical 18 pg/mL. The serum level of vascular endothelial growth and axillary lymph node swelling and leg-pitting edema; factor (VEGF) increased to 69.4 pg/mL. HHV-8 deoxyribo- however, no dermatological, neurological or ophthalmologi- nucleic acid (DNA) was not found in the serum. Table 1 cal abnormalities were observed. The laboratory findings shows additional data. A serological test for HIV was nega- showed a white blood cell (WBC) count of 8,600/μL; how- tive, as were both quantiFERONⓇ-TB and tuberculin tests. ever, the C-reactive protein (CRP) level had increased to The arterial blood gas test was unremarkable, and cultures 15.94 mg/dL. The hemoglobin level was 10.3 g/dL, the of blood, sputum and the fluids of ascites and pleural effu- platelet count was 16.0×104/μL and a coagulation disorder sion were sterile. A closer inspection of the ascites and pleu- was evident with an fibrinogen degradation products (FDP) ral effusion revealed unremarkable results, except for a level of 51.3 μg/mL and a D-dimer level of 24.9 μg/mL. marked increase in the IL-6 levels. Chest radiography While the serum levels of calcium, ACE, lysozyme, immu- showed bilateral hilar lymphadenopathy and dull costo- noglobulin G (IgG) and IgG-4 were within normal limits, phrenic angles; however, no abnormal opacities were ob-

3062 Intern Med 51: 3061-3066, 2012 DOI: 10.2169/internalmedicine.51.8120

Figure 2. Computed tomography (CT) showed bilateral pleural effusion and ascites. Lymph nodes in the bilateral cervix, axilla, hilum, mediastinum and abdominal cavity showed swelling. There were no abnormal opacities in the lungs.

A B

C D

Figure 3. A right axillary lymph node biopsy showed two characteristic features: A) onion skin- like small vessels in the germinal center (Hematoxylin and Eosin staining) and B) CD21-positive dendric cell proliferation in the germinal center (immunohistochemical staining). C) and D) Marked interfolicular plasma cell infiltration (Hematoxylin and Eosin staining). E) CD138-positive cell proliferation around the lymphoid follicle (immunohistochemical staining). served in the lung lesion. Computed tomography (CT) fusion (Fig. 2). Both electrocardiogram and transthoracic ul- showed multiple lymphadenopathies, ascites and pleural ef- trasonic cardiograph were normal, and Gallium scintigraphy

3063 Intern Med 51: 3061-3066, 2012 DOI: 10.2169/internalmedicine.51.8120

D-dimer (ug/mL) Plt (×10~4/uL) 1,000 3days 1,000 3days PSL CRP (mg/dL) (mg)

CRP Plt D-dimer CTRX CEZ 60 60 50 40 (×10ǹ4/uL) 18 70 400mg 400mg 400mg Tocilizumab 16 60 14 10 1015 10 10 50 Plt transfusion (U) 12 40 10 D-dimer 8 30 Plt 6 20 4

10 2 CRP 0 0 st 1 day 5 10 15 20 25 30 35 4045 50 55 60 65 70 75 80 unit S 18 8 181 71 27 pg/mL IL-6 P 768 802 pg/mL I L- 6 A 2375 1986 pg/mL IL-6 BW 57 57 61 64 64 65 60 58 53 47 46 44 43 kg AC 85 88 90 102 101 97 96 91 83 78 77 77 cm

Figure 4. The patient’s clinical course. Plt: platelet, PSL: prednisolone, CTRX: ceftriaxone, CEZ: cefazolin, S IL-6: serum IL-6, P IL-6: pleural effusion IL-6, A IL-6: ascites IL-6, BW: body weight, AC: abdominal circumference showed no abnormal uptake in the lymph nodes or systemic has continued to be administered every two weeks. Her con- organs. Histology of a right axillary lymph node biopsy dition is presently stable with no recurrence of MCD as of showed two abnormal features: 1) onion skin-like small ves- May 2012. sels and CD21-positive follicular dendric cell proliferation in the germinal center, a characteristic of hyaline-vascular type Discussion CD (Fig. 3A and B); and 2) marked interfollicular plasma cell infiltration and CD138-positive cell proliferation around CD is a lymphoproliferative disorder characterized by en- the lymphoid follicle, a characteristic of plasma-cell type larged hyperplastic lymph nodes and striking vascular and CD. The dominant cell type was lambda rather than kappa plasma cell proliferation (3). While the etiology of CD is without monoclonality (Fig. 3C, D and E). The patient was unknown, the proposed pathogenic mechanisms include diagnosed with mixed-type MCD, and there was no evi- chronic inflammation, infection (particularly with HHV-8), dence of sarcoidosis or any other lymphoproliferative disor- autoimmunity and immunodeficiency (3, 8). Although the ders. exact etiology and pathogenesis of sarcoidosis also remain After admission, the platelet count decreased gradually unknown, one cause is thought to be an immune response in while the patient’s weight and ascites increased and she susceptible patients to one or more environmental agents, in- thereafter developed disseminated intravascular coagulation cluding Propionibacterium acnes (9, 10). An association be- (DIC). Neither heparin with antithrombin and gabexate me- tween sarcoidosis and lymphoproliferative diseases such as silate, thrombomodulin, prednisolone nor steroid pulse ther- malignant lymphoma (also known as sarcoid-lymphoma syn- apy (methylprednisolone sodium succinate 1,000 mg/d for drome) has been described (11), although the simultaneous three days) could control the DIC, ascites or pleural effu- appearance of sarcoidosis and lymphoma is infrequent, with sion. Although the serum IL-6 level was only slightly ele- one occasionally preceding the other (11-13). In contrast, no vated, the markedly high levels in the ascites and pleural ef- reports show a clear association between sarcoidosis and fusion induced us to administer tocilizumab (400 mg/body) CD. The occurrence of lymphoproliferative disorders after with dramatic results. After the administration of tocilizu- sarcoidosis may be attributable to immunological abnormali- mab every two weeks, the DIC improved (Fig. 4) and CT ties (14), and in the case of CD, this particularly includes showed a complete resolution of the ascites and pleural effu- the development of an abnormal B cell function. sion, as well as the significant shrinking of the lymph To our knowledge, only three cases (including the present nodes. The patient was discharged and tocilizumab treatment case) of sarcoidosis that subsequently developed or coex-

3064 Intern Med 51: 3061-3066, 2012 DOI: 10.2169/internalmedicine.51.8120

Table 2. Cases of Sarcoidosis That Subsequently Developed or Coexisted with CD

CASE 1 CASE 2 CASE 3 (U.S.A.) (Our hospital) (This report) Age·Sex 37y·F 41y· M 60y· F Diagnosis X (37y) 2000 (41y) 1993 (60y) lung, LNs (Lt cervix, Skin (bilateral leg), Rt Sarcoid Involved bilateral hilum and lung, eye (uveitis) Organ breast,heart -osis mediastinum)

Treatment PSL, MTX nothing nothing

Diagnossis X (37y) 2003 (44y) 2010 (77y) Lung, LNs (bilateral LNs (bilateral cervix, axilla, hilum, Involved Lt cervical LNs hilum and Organ mediastinum and CD mediastinum) abdominal cavity) Pathologica UCD MCD MCD l type hyaline vascular type plasma cell type mixed type Treatment PSL, MTX PSL PSL, Tocilizumab Course remission remission remission

Lt: left, Rt: right, LNs: lymph nodes, PSL: prednisolone, MTX: methotrexate, X: not available

isted with either type of CD have been reported (Table 2). ered. First, vascular hyperpermeability may have resulted in Case 1 is the only case in which the two diseases developed the transfer of serum IL-6 to the ascites and pleural effu- simultaneously (type UCD) (5). This is the first case report sion. Second, IL-6 synthesis may have increased in the as- of sarcoidosis concomitant with MCD. Our hospital has also cites and pleural effusion, for example in the involved experienced two additional cases, and in both instances, sar- lymph nodes. Third, the clearance of IL-6 from the ascites coidosis preceded MCD, although the second case at our and pleural effusion may have been disrupted. IL-6 signal- hospital has yet to be reported. All cases were successfully ing is mediated by binding to IL-6 receptors, which thus treated with prednisolone, methotrexate or tocilizumab. contributes to its clearance (16). Based on these findings, The present patient showed a retention of ascites and the increased IL-6 levels observed in our patient may have pleural effusion. We initially considered POEMS syndrome been due to a lack or dysfunction of IL-6 receptors in the in the differential diagnosis because the serum level of tissues related to the ascites and pleural effusion. VEGF was 69.4 pg/mL, which is characteristic of POEMS Although many treatments for MCD are available, includ- syndrome. However, the patient did not exhibit polyneuropa- ing steroids, chemotherapy, antiviral agents, rituximab and thy, monoclonal hypergammaglobulinemia, endocrine abnor- tocilizumab (8, 17), no standard therapy has yet been estab- malities, skin changes or bone lesions, and thus did not lished. MCD is often refractory to steroids and chemother- meet the current Mayo Clinic criteria for POEMS syn- apy. In fact, steroid-pulse therapy and prednisolone were in- drome (15). Some patients with MCD have complications effective in this case. Recently, several reports have revealed with other malignancies, including Kaposi’s sarcoma and that tocilizumab is effective for treating MCD (18, 19). In- malignant lymphoma (2). The present patient did not display deed, we administered tocilizumab and observed a dramatic these complications; however, she did develop DIC. Since improvement as the DIC was eliminated and the retention of there was no evidence of infection, trauma, collagen disease pleural effusion and ascites was controlled. In our present or malignancy, the exact cause of DIC was unknown. Nev- patient, the serum IL-6 level increased to 181 pg/mL after ertheless, we assume that MCD contributed to the develop- the administration of tocilizumab. One explanation for this ment of DIC. is that tocilizumab might stimulate the production of IL-6 if The serum IL-6 level often increases in patients with its blockade of IL-6 signaling inhibits the negative feedback MCD (16). IL-6 is a cytokine that participates in a wide effect of IL-6 on IL-6 production. Another explanation is range of activities with links to a variety of abnormal symp- that tocilizumab might inhibit the clearance of IL-6 from the toms and laboratory data, including fever, pyrexia, general- serum (16). The IL-6 level observed during the inhibition of ized fatigue, loss of appetite, anemia, hypergammaglobuline- IL-6 receptors by tocilizumab may thus represent the actual mia, hypoalbuminemia, hypocholesterolemia and hyper- endogenous production of IL-6 and the true disease activity thrombocytemia (4). In this case, the IL-6 level in the serum in patients much more accurately than the serum IL-6 level, was dissociated from that in the ascites and pleural effusion. which is measured before the administration of tocilizumab To account for this, the following mechanisms were consid- treatment (16). As a result, the true disease activity in our

3065 Intern Med 51: 3061-3066, 2012 DOI: 10.2169/internalmedicine.51.8120 patient was high, which in turn suggests the basis for the ef- matol 129: 3-17, 2005. fectiveness of tocilizumab, even though the serum IL-6 level 9. Ishige I, Usui Y, Takemura T, et al. Quantitative PCR of mycobac- terial and propionibacterial DNA in lymph nodes of Japanese pa- was not abnormally high. These clinical results show that tients with sarcoidosis. Lancet 354: 120-123, 1999. tocilizumab will thus play an important role in the treatment 10. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobac- of intractable MCD. terial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 40: 198-204, The authors state that they have no Conflict of Interest (COI). 2002. 11. Elisabet GC, Lourdes MS, Emma GM, et al. Sarcoidosis- lymphoma syndrome. Reumatol Clin 5: 31-33, 2009. References 12. Nada S, Branislava M, Maja P, et al. Two cases of sarcoidosis- lymphoma syndrome. Med Oncol 24: 469-471, 2007. 1. Castleman B, Iverson L, Menendez VP. Localized mediastinal 13. Maayan H, Ashkenazi Y, Nagler A. Sarcoidosis and lymphoma: lymph node hyperplasia resembling thymoma. Cancer 9: 822-830, case series and literature review. Sarcoidosis vasculitis and diffuse 1956. lung disease 28: 146-152, 2011. 2. Oksenhendier E, Duarte M, Soulier J. Multicentric Castleman’s 14. Brincker H, Wilbek E. The incidence of malignant tumors in pa- Disease in HIV infection: a clinical and pathological study of 20 tients with respiratory sarcoidosis. Br J Cancer 29: 247-251, 1974. patients. AIDS 10: 61-67, 1996. 15. Dispenzieri A. POEMS syndrome. Blood reviews 21: 285-299, 3. Herrada J, Cabanillas F, Rice L, et al. The clinical behavior of lo- 2007. calized and multicentric Castleman’s Disease. Ann Intern Med 16. Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic 128: 657-662, 1998. significances in increase in serum interleukin-6 (IL-6) and soluble 4. Peterson BA, Frizzera G. Multicentric Castleman’s Disease. Semin IL-6 receptor after administration of an anti-IL-6 receptor anti- Oncol 20: 636-647, 1993. body, tocilizumab, in patients with rheumatoid arthritis and Castle- 5. Rice BL, Farver CF, Pohlman B, et al. Concomitant Castleman’s man disease. Blood 112: 3959-3964, 2008. Disease and Sarcoidosis. The Am J Medical Sciences 341: 257- 17. Dispenzieri A, Gertz MA. Treatment of Castleman’s Disease. Curr 259, 2011. Treat Options Oncol 6: 255-266, 2005. 6. Yamamoto M, Sharma Om P, Hosoda Y, et al. Special report: the 18. Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 re- 1991 descriptive definition of sarcoidosis. Sarcoidosis 9: 33-34, ceptor antibody (Tocilizumab) treatment of multicentric Castle- 1992. man’s Disease. Internal Medicine 46: 771-774, 2007. 7. Statement on sarcoidosis. Am J Respir Crit Care Med 160: 736- 19. Nishimoto N, Kanakura Y, Aozawa K, et al. Humanized anti- 755, 1999. interleukin-6 receptor antibody treatment of Multicentric Castle- 8. Casper C. The etiology and management of Castleman’s Disease man’s Disease. Blood 106: 2627-2632, 2005. at 50 years: translating pathophysiology to patient care. Br J Hae-

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