Int J Clin Exp Pathol 2015;8(2):2090-2102 www.ijcep.com /ISSN:1936-2625/IJCEP0004209
Case Report Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature Yasunobu Sekiguchi1, Asami Shimada1,5, Kunimoto Ichikawa1,5, Mutsumi Wakabayashi1, Keiji Sugimoto1, Keigo Ikeda2, Iwao Sekikawa2, Shigeki Tomita3, Hiroshi Izumi3, Noriko Nakamura4, Tomohiro Sawada4, Yasunori Ohta5, Norio Komatsu6, Masaaki Noguchi1 Departments of 1Hematology, 2Collagen Diseases, 3Pathology, 4Clinical Laboratory, 6Hematology, Juntendo University Urayasu Hospital, Japan; 5Division of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Japan Received November 27, 2014; Accepted January 28, 2015; Epub February 1, 2015; Published February 15, 2015 Abstract: A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report. Keywords: Rheumatoid arthritis (RA), methotrexate (MTX), tacrolimus (FK506), multiple myeloma (MM), EpsteinBarr (EB) virus, other iatrogenic immunodeficiency associated lymphoproliferative disorders
Introduction Sporadic reports have documented the frequent concurrence of myeloma in patients with rheumatoid arthritis (RA) [1-7], but other reports have concluded that RA is unrelated to hematologic malignancies, including myeloma [8-10]. It has been suggested that RA is not the only risk factor for myeloma, but that other factors might also be involved, with the Epstein-Barr (EB) virus being one. Our extensive literature search revealed as few as 22 reported cases of EB virus-positive plasmacytoma [11-22]. The rarity of reported cases might be ascribed to the fact that plasma cells are devoid of cluster of differentiation (CD) 21, which is a receptor for EB virus. Whilst the background, pathophysiology, and molecular biologic characteristics of the
disorder remain unclear, reports of small-scale studies have suggested an unfavorable prognosis [13]. The median age of the affected patients was as young as 46 years, an extramedullary mass was demonstrable in about 60% of the patients, and the outcome was unfavorable, with a reported mean survival time of approximately 33 months (Tables 2, 3). These findings stress the need for the cautious monitoring of clinical progress. Case report The patient, a 61-year-old woman, with a chief complaint of M protein leukemia had been known to be affected with RA and indolent thyroiditis since the age of 55 years. Her family history was noncontributory. Figure 1 illustrates
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis gradually exacerbated, sought medical advice at the Department of Collagen Diseases of this hospital in July 2008. She was diagnosed as having RA and began receiving salazosulfapyridine (SASP) at a dosage of 1000 mg/day. As the drug regimen failed to afford a sufficient therapeutic response, concomitant methotrexate (MTX) therapy at a dosage of 6 mg/week was initiated in December of the same year, and SASP was discontinued in May 2009 on account of her favorable clinical progress. In March 2010, an RA relapse was noted and concurrent tacrolimus (TAC) medication was started. TAC was discontinued in April 2011 because the RA disease activity had diminished. There was a gradual increase of immunoglobulin G (IgG) (1171 mg/dL) in June 2012 and thereafter, and the IgG level exceeded the upper limit of the reference range in April 2013 (IgG: 1716 mg/dL). As a reelevation of the RA disease activity was also evident (rheumatoid factor [RF]: 55 IU/mL), concurrent prednisolone (PSL) Figure 1. Clinical course. The patient started treatment with SASP in July 2008. As the response was insufficient, concomitant MTX at a dosage of 6 mg/week was begun at a dosage of was started in December of the same year. The patient had a satisfactory clini2 mg/day. The RA disease cal progress, and SASP was discontinued in May 2009. Concomitant TAC was activity subsequently debegun in March 2010 and was discontinued in April 2011. The plasma IgG level creased while the IgG level began to increase from June 2012 onwards, and the concurrent administration continued to be elevated, of PSL at 2 mg/day was prescribed. MM was diagnosed in December 2013; reaching 3393 mg/dL in the MTX regimen was terminated, and the PSL dosage was raised to 5 mg/day in April 2014. BD therapy was performed after no improvement in the MM was December 2013. At this observed. A CR was attained after 2 cycles of therapy. An autologous peripheral time, the patient consulted blood stem cell transplantation was performed early in October. The patient has our department. An immubeen progressing favorably with respect to both MM and RA. HD-CY, high-dose noelectrophoretic analysis cyclophosphamide; HD-MEL, high-dose melphalan; Auto-PBSCT, autologous peof serum and urine samripheral blood stem cell transplantation. ples revealed the occurrence of IgG-κ paraprotein. the clinical course. Regarding the present illA bone marrow examination showed normoplaness, the patient began to experience right sia, with 10.8% anisocytotic immature plasma wrist joint pain in 2005 and, as the pain became cells with a slightly increased nuclear-cytoplas2091
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 2. Findings of bone marrow examination. A. (Smear, ×40): Normoplastic and 10.8% anisocytotic plasma cells with a slightly high N/C ratio were noted. B. (Smear, ×600): Slightly immature plasma cells were noted. C. (EBER, ×40): The tumor cells were positive. D. (EBER, ×600): The tumor cells were positive. E. (MIB-1, ×40): Low occurrence. F. (MIB-1, ×600): Low occurrence.
mic (N/C) ratio (Figure 2A, 2B). A bone marrow biopsy disclosed Epstein-Barr virus-encoded small RNA (EBER)-positive plasma cells (solid arrows, Figure 2C, 2D). The mindbomb E3 ubiquitin protein ligase 1 (MIB-1) index was low (Figure 2E, 2F). Using flow cytometry, the cells were found to be positive for CD138, mature
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plasma cell-1 (MPC-1), cytoplasmic κ, and CD54 (Figure 3A-C) and negative for CD20, CD45, CD49e, and cytoplasmic λ (Figure 3B-D). A chromosome analysis revealed G-banding to be of normal karyotype for females, and a fluorescent in situ hybridization (FISH) test demonstrated the presence of a 13q deletion and
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 3. Marrow blood flow cytometry. A. Positive for CD54 and CD138. B. Positive for MPC-1 and negative for CD45. C. Positive for cytoplasmic κ and negative for cytoplasmic λ. D. Negative for CD49e and CD20.
t(4;14) (Table 1). F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) did not show any osseous lesions but disclosed an FDG accumulation in the upper region of the right lobe of the thyroid (SUVmax, 5.6) (Figure 4A, red arrow; Figure 4B, white arrow). This finding was thought to be ascribable to the patient’s history of indolent thyroiditis. The disorder was thus diagnosed as a multiple myeloma (MM), IgG-κ type, Durie & Salmon stage 1 and International Staging System (ISS) stage 1. The maturity of the tumor was considered to be intermediate, since marrow plasma cells were positive for MPC-1 and negative for CD45 and CD49e (Figure 3B, 3D). 2093
As the cells were found to be EBER-positive, MTX was discontinued and the dosage of PSL was increased to 5 mg/day in April 2014. However, the patient was admitted to this hospital in late May because of an increased IgG level (4694 mg/dL). The laboratory findings obtained on admission are summarized in Table 1. BD therapy (bortezomib at 1.3 mg/m2 subcutaneous injection on days 1, 4, 8, and 11, followed by a 7-day withdrawal, along with dexamethasone at 20 mg/day given orally on days 1, 2, 4, 5, 8, 9, 11, and 12; each cycle lasting 3 weeks) was initiated. The patient was disInt J Clin Exp Pathol 2015;8(2):2090-2102
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 4. A, B. FDG-PET-CT findings. FDG accumulation was confined solely to the upper part of the right lobe of the thyroid (SUVmax, 5.6) (a: red arrow; b: white arrow). This finding was thought to be due to indolent thyroiditis. No abnormal accumulation in the osseous tissues was seen.
charged after the completion of the first cycle of therapy in late June. She received the second cycle of BD therapy at the outpatient service of this hospital, during which a complete response (CR) was attained. In late August, she was re-admitted to this hospital for the collection of autologous peripheral blood stem cells preceded by high-dose cyclophosphamide therapy (2 g/m2). Early in October, an autologous peripheral blood stem cell transplantation was performed with pretreatment consisting of high-dose melphalan (200 mg/m2). As of November 2014, she has been progressing satis2094
factorily with a sustained CR in respect to the MM. She also remains asymptomatic for RA and negative for RF, with an uneventful course. Discussion In the case documented herein, EBER-positive (EB virus-positive) MM (plasmacytoma) developed following treatment with the immunosuppressants MTX and TAC for RA. Hence, the case falls in the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders.
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 1. Laboratory findings on admission Peripheral blood
Urinalysis
Biochemistry
Thyroid function test
Immunoserological findings
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WBC Neut Ly Mono Eo Ba RBC Hb Ht MCV MCH Plt Reti pH Specific gravity Protein Occult blood T.P Alb AST ALT LDH ALP g-GTP T-Bil BUN Cr Uric acid CRP TSH FT3 FT4 Thyroglobulin I-PTH IgG IgA IgM IgD Serum b2MG Immunoelectrophoresis (specific antiserum) Immunoelectrophoresis (urine) ANA Homogen Speckle Anti-DNA antibody RF MMP-3 Antithyroglobulin antibody TRACP-5b TSAB (RIA)
5300/μL 48.9% 39.0% 7.7% 1.6% 0.1% 422 × 104/μL 12.0 g/dL 38.3% ↓ 90.8 fl 28.6 pg 18.7 × 104/μL 1.3% 6.5 1.019 3+ 9.1 g/dL 2.9 g/dL ↓ 15 IU/L 16 IU/L 183 IU/L 295 IU/L 15 IU/L 0.5 mg/dL 15 mg/dL 0.57 mg/dL 4.4 mg/dL 0.3 mg/dL ≤ 0.010 μIU/mL↓ 7.46 pg/mL 2.83 ng/dL 18.1 ng/mL 50 pg/mL 4694 mg/dL 53 mg/dL ↓ 63 mg/dL 2.1 mg/dL 2.1 mg/dL IgG-κ positive IgG-κ positive 160 × 40 × 160 × ≤ 2.0 24 IU/mL 38.7 ng/mL 104 IU/mL 104 mU/dL ↓ 109%
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Findings in bone marrow smear examination
Marrow blood flow cytometry
Marrow blood chromosomes
Antibody to TSH receptor Anti-TPO antibody (ECLIA) Anti-HIV antibody EBV VCA IgG EBV VCA IgM EBV EBNA EBV DNA No. of nucleated cells Megakaryocyte count M:E ratio Plasma cell CD19 CD20 CD45 CD49e CD52 CD54
3.7 IU/L 122 IU/mL Negative 20 × < 10 × 10 × Negative 70.5 × 104/μL 72/mL 2.02 76.4% 1.3% 14.5% 4.2% 2.7% 6.9% 24.3%
CD56
97.3%
CD126
1.8%
CD138
59.7%
MPC-1
56.6%
κ
88.7%
λ G-banding FISH FISH
0.2% 46, XX 20/20 13q deletion, 27% t(4;14), 23%
Denotes above the upper limit of the reference range, and ↓ denotes below the lower limit of the reference range.
Regarding reports dealing with concurrent malignant tumors in RA patients, the American College of Rheumatology (ACR) Drug Safety Committee has reported high incidences of malignant lymphoma, lung cancer, skin cancer, and cancer death and low incidences of colorectal cancer and breast cancer, yet the report did not refer to myeloma [23]. However, there have been sporadic reports documenting the frequent concurrence of myeloma in patients with RA [1-7]. Monoclonal hypergammaglobulinemia [24] and a long-sustained disease activity of RA [6] are thought to constitute risk factors. These factors are considered to chronically affect the RA antibody production system, thereby stimulating cells of the reticuloendothelial and lymphoid systems and eventually giving rise to tumorous monoclonal proliferation [25, 26]. The average time from the onset of RA until that of MM is, in fact, reportedly as long as 34 and 13.6 years [26, 27]. The time in the present case was 5.4 years, which was relatively short.
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On the other hand, there have also been reports purporting that RA is unrelated to hematologic malignancies, including myeloma [8-10]; therefore, RA might not be the only risk factor, and other factors such as EB virus or multifactorial involvement are likely. Many reports have implied the irrelevance of drugs, including MTX, to the development of concurrent MM in RA patients [3, 28-30]. Further long-term pursuit of a large-scale study is needed. In the present case, we noted the EB virus-positive plasmacytoma because the tumor cells were positive for EBER. The development of EB virus-positive plasmacytoma has been reported, including the present case, in 22 cases according to our extensive literature search (Table 2). The rarity of pertinent cases may be ascribed to the fact that plasma cells are devoid of CD21, which is a receptor for the EB virus. The characteristics of the reported cases are
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 2. Twenty-three reported cases of EB virus-positive plasma cell tumors Case
Age (y)/ gender
Underlying disease
Treatment of underlying disease
Clinical findings
Type of myeloma
Time from onset of underlying disease to onset of myeloma (y)
Treatment of myeloma
Therapeutic response
Outcome
Reference
1
11/F
None
None
Osteolytic lesion
IgA/κ/MM
-
Systemic steroid/ RT/DEXA/Thal
Remission
Alive Elective for HSCT
[11]
2
78/M
None
None
Left submaxillary gland mass/ osteolytic lesion
Plasmacytoma
-
Ex
Unknown
Unknown
[12]
3
40/M
Unknown
Unknown
Plasmacytoma/no osteolytic lesion
Plasmacytoma Bone marrow invasion plasmablastic
Unknown
Ex/RT
Remission maintained for 75 m
Alive 75 m
[13]
4
27/M
Unknown
Unknown
Osteolytic lesion
IgG/MM nonplasmablastic
Unknown
CT
Remission maintained for 30 m
DOMM 74 m
[13]
5
60/M
Unknown
Unknown
Osteolytic lesion
IgG/MM plasmablastic
Unknown
CT/RT
Remission maintained for 67 m
DOMM 97 m
[13]
6
51/M
Unknown
Unknown
Osteolytic lesion
IgG/MM plasmablastic
Unknown
CT
Not improved
DOMM 5 m
[13]
7
Unknown/ Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
[14]
8
Unknown/ Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
[14]
9
47/M
Chronic renal failure
Renal transplantation, CsA/AZA/PSL
Extramedullary mass/ no osteolytic lesion
IgG-κ type plasmacytoma high-grade anaplastic plasmacytoma
12
Immunosup pressants discont’d/ CY/PSL/RT
CR maintained
Died of respiratory tract infection 2 m later
[15]
10
49/F
None
None
Ileum ulcer
Plasmacytoma λ
-
Unknown
Unknown
Unknown
[16]
11
46/M
None
None
Stomach nodular
Plasmacytoma κ
-
Unknown
Unknown
Unknown
[16]
12
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
13
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
14
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
15
52/M
Hepatic failure and renal failure
Hepato-renal transplantation CsA/PSL/ ALG/AZA/mPSL
Multiple pelvic soft tissue tumor
IgG-κ type plasmacytoma
1.4
CsA discont’d/RT
Complete remission maintained for 24 m
Alive 24 m
[18]
16
30/M
HIV
None
Gingival mass/ maxillary soft tissue mass & destructive bone lesion/skin nodules
Anaplastic plasmacytoma κ
4
RT
Improved
Died 4 m later
[19]
17
34/M
HIV
None
Short breath Abdominal pain Ascites Dementia
Immature plasma cell λ
3
RT
Improved
Died 5 days later
[19]
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis 18
41/M
Hodgkin’s lympho-ma
Curative therapy
Plasmacytoma involving skin and testis
Plasmacytoma κ
7
Unknown
Unknown
Unknown
[20]
19
51/Unknown
Unknown
Liver transplantationCsA
Periumbilical plasmacy-toma
Plasmacytoma κ
Unknown
Unknown
Unknown
Unknown
[20]
20
31/M
HIV
Unknown
Fever/confusion/slurred speech/progres sive lethargy/polyuria polydypsia/left tonsillar mass/lung mass
IgG/κ IgM/λ Plasmablast Leukemic visceral and meningeal involvement
Unknown
Unknown
Unknown
Died of aspiration pneumonia
[21]
21
1.2/M
Unknown
Organ transplantation/CsA/PSL/AZA
Purulent rhinorrhea/ difficulty breathing/ recurrent otitis media/ nasopharyngeal mass
Nasopharyngeal mass focal infiltration of plasmacells
0.9
Ex/immuno suppressant dose reduction
Improved
Unknown
[22]
22
61/F
RA
SASP/MTX/TAC/PSL
None
IgG/κ/MM
5.4
MTX discont’d/BD/ Auto-PBSCT
CR
Surviving with CR, 12 m
Subject case
y, year; F, female; RT, radiation therapy; DEXA, dexamethasone; Thal, thalidomide; HSCT, hematopoietic stem cell transplantation; M, male; Ex, excision; m, month; CT, chemotherapy; DOMM, dead of multiple myeloma; CsA, cyclosporine; AZA, azathioprine; CY, cyclophosphamide; ALG, antilymphocyte globulin; mPSL, methylprednisolone; Auto-PBSCT, autologous peripheral blood stem cell transplantation.
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 3. Summary of 23 reported cases of EB virus-positive plasma cell tumors Patients Age (y)/gender
Underlying disease
Treatment
Clinical findings
Type of myeloma
n = 22 n = 17 1.2-78 (46) Unknown: 5 n = 16 M:F = 13:3 Unknown: 6 n = 11 None: 4 Chronic renal failure: 2 Hepatic failure: 1 HIV: 3 Hodgkin’s lymphoma: 1 RA: 1 Unknown: 11 n = 12 None: 6 Organ transplantation: 4 CsA: 4 AZA: 3 PSL: 5 ALG: 1 SASP: 1 MTX: 1 TAC: 1 Unknown: 10 n = 20 Extramedullary mass: 12 Bone lesion: 5 Ileum ulcer: 1 Shortness of breath: 1 Abdominal pain: 1 Ascites: 1 Dementia: 1 Fever: 1 Clouding of consciousness: 1 Lethargy: 1 Polyuria: 1 Polydysplasia: 1 Slurred speech: 1 Purulent rhinorrhea: 1 Dyspnea: 1 Otitis media: 1 None: 1 Unknown: 2 n = 17 IgA: 1 IgG: 7
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis IgM: 1 κ: 9 λ: 3 Plasmacytoma: 11 Plasmablastic: 4 Non-plasmablastic: 1 Time from onset of underlying disease to that of myeloma (yr)
Treatment of myeloma
Therapeutic response
Outcome
summarized in Table 3. The median age of the patients was relatively young, at 46 years (1.2 to 78 years), and the disease was more common in men (male:female = 13:3), and the underlying disease was RA in only the present case, whereas cases with immunodeficiency in their clinical background, such as human immunodeficiency virus (HIV), chronic renal failure, hepatic insufficiency, and Hodgkin’s lymphoma, accounted for about 1/3 (7 cases) of all the cases. As for the treatment of underlying diseases, organ transplantation was involved in as many as 4 cases, and the administration of various immunosuppressants was relatively common (16 cases). It would be reasonable to assume that an immunodeficiency state following organ transplantation or that is associated with immunosuppressant therapy exists in the 2100
n=7 0.9-12 (median: 4) No underlying disease: 4 Unknown: 11 n = 12 Corticosteroids (incl. PSL): 2 DEXA: 2 RT: 7 Ex: 3 CT: 4 Thal: 1 BD: 1 Auto-PBSCT: 1 Immunosuppressants discont’d or dose reduced: 4 Unknown: 10 n = 11 Remission (improved): 10 Not improved: 1 Unknown: 11 n = 11 Surviving: 4 DOMM: 3 Died of infection: 2 Died, cause unknown: 2 Unknown: 11
background. The involvement of other factors seemed likely, nevertheless, inasmuch as there was no treatment or unknown treatment of the underlying disease in as many as 70% (15 cases) of patients. A variety of symptoms were noted as to the clinical findings, and about 60% (12 cases) of the patients had an extramedullary mass, which is a poor prognostic factor. The most frequent type of MM was IgG type (7 cases). The median time from the onset of the underlying disease to that of MM was relatively short, at 4 years (0.9-12 years), and coincided with that in the present case. Regarding the treatment for MM, there were no cases in which a clinical improvement was attained with immunosuppressant discontinuance or dosage reduction alone [15, 18, 22], and the same held true for the present case as well. Various treatInt J Clin Exp Pathol 2015;8(2):2090-2102
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis ments were provided, producing an improvement in the MM in 10 of the 11 cases, but only 4 patients survived, and the mean survival time for the 11 cases was about 33 months; hence, the outcome was not considered favorable. In fact, according to a report with only 4 cases, the possibility of a poor prognosis was suggested given the plasmablastic cytomorphologic features with high labeling indices and the high MIB-1 index that were observed [13]. To date, there has been no report of a case of plasmacytoma occurring with an underlying disease of RA or after TAC or MTX therapy and falling under the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) [31]; thus, the present case is the first to be reported. The present case was considered to be MTXLPD, as the patient was maintained on MTX. MTX-LPD usually results in lymphoma, and its disappearance after the discontinuation of MTX therapy is not uncommon, although many reported cases were EBV-related LPD [31]. In the present EBV-related LPD case, however, spontaneous remission did not occur following the discontinuation of MTX medication. No cases have been reported in which a clinical improvement followed dose reduction or the discontinuation of immunosuppressant medication [15, 18, 22]. Further studies of accumulated cases of post-immunosuppressant therapy for EB virus-positive plasmacytoma are needed. The RA disease activity increased despite MTX therapy, and an elevation of the IgG level occurred about 1 year later (estimated to be the onset phase of MM) in the present case. The likelihood that MM developed as a result of the increased RA disease activity as well as the immunosuppression (EBER-positive status) was considered. Such a situation might account for the shorter period from the onset of RA until that of the plasmacytoma (5.4 years) in this case, compared with previously reported averages of 34 and 13.6 years [26, 27].
047-381-5054; E-mail: [email protected]
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Disclosure of conflict of interest None. Address correspondence to: Dr. Yasunobu Sekiguchi, Department of Hematology, Juntendo University Urayasu Hospital, 1-1, Tomioka 2-chome, Urayasu, Chiba Prefecture. Tel: 047-353-3111; Fax:
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logical disorders. Zhonghua Yi Xue Za Zhi (Taipei) 2002; 65: 119-123. Papadaki HA, Stefanaki K, Kanavaros P, Katonis P, Papastathi H, Valatas W, Stylianoy K and Eliopoulos GD. Epstein-Barr virus-associated high-grade anaplastic plasmacytoma in a renal transplant patient. Leuk Lymphoma 2000; 36: 411-415. Tomita Y, Ohsawa M, Hashimoto M, Qiu K, Yang WI, Park CI and Aozasa K. Plasmacytoma of the gastrointestinal tract in Korea: higher incidence than in Japan and Epstein-Barr virus association. Oncology 1998; 55: 27-32. Aguilera NS, Kapadia SB, Nalesnik MA and Swerdlow SH. Extramedullary plasmacytoma of the head and neck: use of paraffin sections to assess clonality with in situ hybridization, growth fraction, and the presence of EpsteinBarr virus. Mod Pathol 1995; 8: 503-508. Joseph G, Barker RL, Yuan B, Martin A, Medeiros J and Peiper SC. Posttransplantation plasma cell dyscrasias. Cancer 1994; 74: 1959-1964. Kumar S, Kumar D, Schnadig VJ, Selvanayagam P and Slaughter DP. Plasma cell myeloma in patients who are HIV-positive. Am J Clin Pathol 1994; 102: 633-639. Medeiros LJ, Kingma DW, Martin AW, Barker RL, Jaffe ES and Peiper SC. Epstein-Barr virus (EBV)-induced lymphoproliferative disorder (LPD) manifesting as plasmacytomas. In: United States and Canadian Academy of Pathology. Meeting, United States and Canadian Academy of Pathology, editors. Abstracts: 1993 Annual Meeting, United States and Canadian Academy of Pathology. New Orleans: United States and Canadian Academy of Pathology; 1993. Voelkerding KV, Sandhaus LM, Kim HC, Wilson J, Chittenden T, Levine AJ and Raska K Jr. Plasma cell malignancy in the acquired immune deficiency syndrome. Association with Epstein-Barr virus. Am J Clin Pathol 1989; 92: 222-228. Ho M, Jaffe R, Miller G, Breinig MK, Dummer JS, Makowka L, Atchison RW, Karrer F, Nalesnik MA and Starzl TE. The frequency of EpsteinBarr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 1988; 45: 719-727.
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[23] Cush JJ, Kay J and Dao KH, editors. Does Rheumatoid Arthritis or Biologic Therapy Increase Cancer Risk? Drug Safety Quarterly Vol.4(2) August 2012 [Internet]. Atlanta: American College of Rheumatology; 2012. [24] Kelly C, Baird G, Foster H, Hosker H and Griffiths I. Prognostic significance of paraproteinaemia in rheumatoid arthritis. Ann Rheum Dis 1991; 50: 290-294. [25] Wegelius O, Skrifvars B and Andersson L. Rheumatoid arthritis terminating in plasmocytoma. Acta Med Scand 1970; 187: 133-138. [26] Zawadzki ZA and Benedek TG. Rheumatoid arthritis, dysproteinemic arthropathy, and paraproteinemia. Arthritis Rheum 1969; 12: 555568. [27] Inoue F, Ohno T and Furukawa H. [A case of rheumatoid arthritis associated with multiple myeloma]. Nihon Rinsho Meneki Gakkai Kaishi 1996; 19: 94-99. [28] Grardel B, Fauquert P and Hardouin P. Malignancy in patients with rheumatoid arthritis treated with methotrexate. J Rheumatol 1997; 24: 805-806. [29] Moder KG, Tefferi A, Cohen MD, Menke DM and Luthra HS. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med 1995; 99: 276-281. [30] Flipo RM, Deprez X, Fardellone P, Duquesnoy B and Delcambre B. [Rheumatoid arthritis and multiple myeloma. Apropos of 22 cases. Results of a multicenter national survey]. Rev Rhum Ed Fr 1993; 60: 269-273. [31] In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Geneva: WHO press; 2008. pp. 350351.
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Case Report Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature Yasunobu Sekiguchi1, Asami Shimada1,5, Kunimoto Ichikawa1,5, Mutsumi Wakabayashi1, Keiji Sugimoto1, Keigo Ikeda2, Iwao Sekikawa2, Shigeki Tomita3, Hiroshi Izumi3, Noriko Nakamura4, Tomohiro Sawada4, Yasunori Ohta5, Norio Komatsu6, Masaaki Noguchi1 Departments of 1Hematology, 2Collagen Diseases, 3Pathology, 4Clinical Laboratory, 6Hematology, Juntendo University Urayasu Hospital, Japan; 5Division of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Japan Received November 27, 2014; Accepted January 28, 2015; Epub February 1, 2015; Published February 15, 2015 Abstract: A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report. Keywords: Rheumatoid arthritis (RA), methotrexate (MTX), tacrolimus (FK506), multiple myeloma (MM), EpsteinBarr (EB) virus, other iatrogenic immunodeficiency associated lymphoproliferative disorders
Introduction Sporadic reports have documented the frequent concurrence of myeloma in patients with rheumatoid arthritis (RA) [1-7], but other reports have concluded that RA is unrelated to hematologic malignancies, including myeloma [8-10]. It has been suggested that RA is not the only risk factor for myeloma, but that other factors might also be involved, with the Epstein-Barr (EB) virus being one. Our extensive literature search revealed as few as 22 reported cases of EB virus-positive plasmacytoma [11-22]. The rarity of reported cases might be ascribed to the fact that plasma cells are devoid of cluster of differentiation (CD) 21, which is a receptor for EB virus. Whilst the background, pathophysiology, and molecular biologic characteristics of the
disorder remain unclear, reports of small-scale studies have suggested an unfavorable prognosis [13]. The median age of the affected patients was as young as 46 years, an extramedullary mass was demonstrable in about 60% of the patients, and the outcome was unfavorable, with a reported mean survival time of approximately 33 months (Tables 2, 3). These findings stress the need for the cautious monitoring of clinical progress. Case report The patient, a 61-year-old woman, with a chief complaint of M protein leukemia had been known to be affected with RA and indolent thyroiditis since the age of 55 years. Her family history was noncontributory. Figure 1 illustrates
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis gradually exacerbated, sought medical advice at the Department of Collagen Diseases of this hospital in July 2008. She was diagnosed as having RA and began receiving salazosulfapyridine (SASP) at a dosage of 1000 mg/day. As the drug regimen failed to afford a sufficient therapeutic response, concomitant methotrexate (MTX) therapy at a dosage of 6 mg/week was initiated in December of the same year, and SASP was discontinued in May 2009 on account of her favorable clinical progress. In March 2010, an RA relapse was noted and concurrent tacrolimus (TAC) medication was started. TAC was discontinued in April 2011 because the RA disease activity had diminished. There was a gradual increase of immunoglobulin G (IgG) (1171 mg/dL) in June 2012 and thereafter, and the IgG level exceeded the upper limit of the reference range in April 2013 (IgG: 1716 mg/dL). As a reelevation of the RA disease activity was also evident (rheumatoid factor [RF]: 55 IU/mL), concurrent prednisolone (PSL) Figure 1. Clinical course. The patient started treatment with SASP in July 2008. As the response was insufficient, concomitant MTX at a dosage of 6 mg/week was begun at a dosage of was started in December of the same year. The patient had a satisfactory clini2 mg/day. The RA disease cal progress, and SASP was discontinued in May 2009. Concomitant TAC was activity subsequently debegun in March 2010 and was discontinued in April 2011. The plasma IgG level creased while the IgG level began to increase from June 2012 onwards, and the concurrent administration continued to be elevated, of PSL at 2 mg/day was prescribed. MM was diagnosed in December 2013; reaching 3393 mg/dL in the MTX regimen was terminated, and the PSL dosage was raised to 5 mg/day in April 2014. BD therapy was performed after no improvement in the MM was December 2013. At this observed. A CR was attained after 2 cycles of therapy. An autologous peripheral time, the patient consulted blood stem cell transplantation was performed early in October. The patient has our department. An immubeen progressing favorably with respect to both MM and RA. HD-CY, high-dose noelectrophoretic analysis cyclophosphamide; HD-MEL, high-dose melphalan; Auto-PBSCT, autologous peof serum and urine samripheral blood stem cell transplantation. ples revealed the occurrence of IgG-κ paraprotein. the clinical course. Regarding the present illA bone marrow examination showed normoplaness, the patient began to experience right sia, with 10.8% anisocytotic immature plasma wrist joint pain in 2005 and, as the pain became cells with a slightly increased nuclear-cytoplas2091
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 2. Findings of bone marrow examination. A. (Smear, ×40): Normoplastic and 10.8% anisocytotic plasma cells with a slightly high N/C ratio were noted. B. (Smear, ×600): Slightly immature plasma cells were noted. C. (EBER, ×40): The tumor cells were positive. D. (EBER, ×600): The tumor cells were positive. E. (MIB-1, ×40): Low occurrence. F. (MIB-1, ×600): Low occurrence.
mic (N/C) ratio (Figure 2A, 2B). A bone marrow biopsy disclosed Epstein-Barr virus-encoded small RNA (EBER)-positive plasma cells (solid arrows, Figure 2C, 2D). The mindbomb E3 ubiquitin protein ligase 1 (MIB-1) index was low (Figure 2E, 2F). Using flow cytometry, the cells were found to be positive for CD138, mature
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plasma cell-1 (MPC-1), cytoplasmic κ, and CD54 (Figure 3A-C) and negative for CD20, CD45, CD49e, and cytoplasmic λ (Figure 3B-D). A chromosome analysis revealed G-banding to be of normal karyotype for females, and a fluorescent in situ hybridization (FISH) test demonstrated the presence of a 13q deletion and
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 3. Marrow blood flow cytometry. A. Positive for CD54 and CD138. B. Positive for MPC-1 and negative for CD45. C. Positive for cytoplasmic κ and negative for cytoplasmic λ. D. Negative for CD49e and CD20.
t(4;14) (Table 1). F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) did not show any osseous lesions but disclosed an FDG accumulation in the upper region of the right lobe of the thyroid (SUVmax, 5.6) (Figure 4A, red arrow; Figure 4B, white arrow). This finding was thought to be ascribable to the patient’s history of indolent thyroiditis. The disorder was thus diagnosed as a multiple myeloma (MM), IgG-κ type, Durie & Salmon stage 1 and International Staging System (ISS) stage 1. The maturity of the tumor was considered to be intermediate, since marrow plasma cells were positive for MPC-1 and negative for CD45 and CD49e (Figure 3B, 3D). 2093
As the cells were found to be EBER-positive, MTX was discontinued and the dosage of PSL was increased to 5 mg/day in April 2014. However, the patient was admitted to this hospital in late May because of an increased IgG level (4694 mg/dL). The laboratory findings obtained on admission are summarized in Table 1. BD therapy (bortezomib at 1.3 mg/m2 subcutaneous injection on days 1, 4, 8, and 11, followed by a 7-day withdrawal, along with dexamethasone at 20 mg/day given orally on days 1, 2, 4, 5, 8, 9, 11, and 12; each cycle lasting 3 weeks) was initiated. The patient was disInt J Clin Exp Pathol 2015;8(2):2090-2102
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Figure 4. A, B. FDG-PET-CT findings. FDG accumulation was confined solely to the upper part of the right lobe of the thyroid (SUVmax, 5.6) (a: red arrow; b: white arrow). This finding was thought to be due to indolent thyroiditis. No abnormal accumulation in the osseous tissues was seen.
charged after the completion of the first cycle of therapy in late June. She received the second cycle of BD therapy at the outpatient service of this hospital, during which a complete response (CR) was attained. In late August, she was re-admitted to this hospital for the collection of autologous peripheral blood stem cells preceded by high-dose cyclophosphamide therapy (2 g/m2). Early in October, an autologous peripheral blood stem cell transplantation was performed with pretreatment consisting of high-dose melphalan (200 mg/m2). As of November 2014, she has been progressing satis2094
factorily with a sustained CR in respect to the MM. She also remains asymptomatic for RA and negative for RF, with an uneventful course. Discussion In the case documented herein, EBER-positive (EB virus-positive) MM (plasmacytoma) developed following treatment with the immunosuppressants MTX and TAC for RA. Hence, the case falls in the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders.
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 1. Laboratory findings on admission Peripheral blood
Urinalysis
Biochemistry
Thyroid function test
Immunoserological findings
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WBC Neut Ly Mono Eo Ba RBC Hb Ht MCV MCH Plt Reti pH Specific gravity Protein Occult blood T.P Alb AST ALT LDH ALP g-GTP T-Bil BUN Cr Uric acid CRP TSH FT3 FT4 Thyroglobulin I-PTH IgG IgA IgM IgD Serum b2MG Immunoelectrophoresis (specific antiserum) Immunoelectrophoresis (urine) ANA Homogen Speckle Anti-DNA antibody RF MMP-3 Antithyroglobulin antibody TRACP-5b TSAB (RIA)
5300/μL 48.9% 39.0% 7.7% 1.6% 0.1% 422 × 104/μL 12.0 g/dL 38.3% ↓ 90.8 fl 28.6 pg 18.7 × 104/μL 1.3% 6.5 1.019 3+ 9.1 g/dL 2.9 g/dL ↓ 15 IU/L 16 IU/L 183 IU/L 295 IU/L 15 IU/L 0.5 mg/dL 15 mg/dL 0.57 mg/dL 4.4 mg/dL 0.3 mg/dL ≤ 0.010 μIU/mL↓ 7.46 pg/mL 2.83 ng/dL 18.1 ng/mL 50 pg/mL 4694 mg/dL 53 mg/dL ↓ 63 mg/dL 2.1 mg/dL 2.1 mg/dL IgG-κ positive IgG-κ positive 160 × 40 × 160 × ≤ 2.0 24 IU/mL 38.7 ng/mL 104 IU/mL 104 mU/dL ↓ 109%
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis
Findings in bone marrow smear examination
Marrow blood flow cytometry
Marrow blood chromosomes
Antibody to TSH receptor Anti-TPO antibody (ECLIA) Anti-HIV antibody EBV VCA IgG EBV VCA IgM EBV EBNA EBV DNA No. of nucleated cells Megakaryocyte count M:E ratio Plasma cell CD19 CD20 CD45 CD49e CD52 CD54
3.7 IU/L 122 IU/mL Negative 20 × < 10 × 10 × Negative 70.5 × 104/μL 72/mL 2.02 76.4% 1.3% 14.5% 4.2% 2.7% 6.9% 24.3%
CD56
97.3%
CD126
1.8%
CD138
59.7%
MPC-1
56.6%
κ
88.7%
λ G-banding FISH FISH
0.2% 46, XX 20/20 13q deletion, 27% t(4;14), 23%
Denotes above the upper limit of the reference range, and ↓ denotes below the lower limit of the reference range.
Regarding reports dealing with concurrent malignant tumors in RA patients, the American College of Rheumatology (ACR) Drug Safety Committee has reported high incidences of malignant lymphoma, lung cancer, skin cancer, and cancer death and low incidences of colorectal cancer and breast cancer, yet the report did not refer to myeloma [23]. However, there have been sporadic reports documenting the frequent concurrence of myeloma in patients with RA [1-7]. Monoclonal hypergammaglobulinemia [24] and a long-sustained disease activity of RA [6] are thought to constitute risk factors. These factors are considered to chronically affect the RA antibody production system, thereby stimulating cells of the reticuloendothelial and lymphoid systems and eventually giving rise to tumorous monoclonal proliferation [25, 26]. The average time from the onset of RA until that of MM is, in fact, reportedly as long as 34 and 13.6 years [26, 27]. The time in the present case was 5.4 years, which was relatively short.
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On the other hand, there have also been reports purporting that RA is unrelated to hematologic malignancies, including myeloma [8-10]; therefore, RA might not be the only risk factor, and other factors such as EB virus or multifactorial involvement are likely. Many reports have implied the irrelevance of drugs, including MTX, to the development of concurrent MM in RA patients [3, 28-30]. Further long-term pursuit of a large-scale study is needed. In the present case, we noted the EB virus-positive plasmacytoma because the tumor cells were positive for EBER. The development of EB virus-positive plasmacytoma has been reported, including the present case, in 22 cases according to our extensive literature search (Table 2). The rarity of pertinent cases may be ascribed to the fact that plasma cells are devoid of CD21, which is a receptor for the EB virus. The characteristics of the reported cases are
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 2. Twenty-three reported cases of EB virus-positive plasma cell tumors Case
Age (y)/ gender
Underlying disease
Treatment of underlying disease
Clinical findings
Type of myeloma
Time from onset of underlying disease to onset of myeloma (y)
Treatment of myeloma
Therapeutic response
Outcome
Reference
1
11/F
None
None
Osteolytic lesion
IgA/κ/MM
-
Systemic steroid/ RT/DEXA/Thal
Remission
Alive Elective for HSCT
[11]
2
78/M
None
None
Left submaxillary gland mass/ osteolytic lesion
Plasmacytoma
-
Ex
Unknown
Unknown
[12]
3
40/M
Unknown
Unknown
Plasmacytoma/no osteolytic lesion
Plasmacytoma Bone marrow invasion plasmablastic
Unknown
Ex/RT
Remission maintained for 75 m
Alive 75 m
[13]
4
27/M
Unknown
Unknown
Osteolytic lesion
IgG/MM nonplasmablastic
Unknown
CT
Remission maintained for 30 m
DOMM 74 m
[13]
5
60/M
Unknown
Unknown
Osteolytic lesion
IgG/MM plasmablastic
Unknown
CT/RT
Remission maintained for 67 m
DOMM 97 m
[13]
6
51/M
Unknown
Unknown
Osteolytic lesion
IgG/MM plasmablastic
Unknown
CT
Not improved
DOMM 5 m
[13]
7
Unknown/ Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
[14]
8
Unknown/ Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
[14]
9
47/M
Chronic renal failure
Renal transplantation, CsA/AZA/PSL
Extramedullary mass/ no osteolytic lesion
IgG-κ type plasmacytoma high-grade anaplastic plasmacytoma
12
Immunosup pressants discont’d/ CY/PSL/RT
CR maintained
Died of respiratory tract infection 2 m later
[15]
10
49/F
None
None
Ileum ulcer
Plasmacytoma λ
-
Unknown
Unknown
Unknown
[16]
11
46/M
None
None
Stomach nodular
Plasmacytoma κ
-
Unknown
Unknown
Unknown
[16]
12
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
13
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
14
Unknown/ Unknown
Unknown
Unknown
Head and neck extramedullary mass
Unknown
Unknown
Unknown
Unknown
Unknown
[17]
15
52/M
Hepatic failure and renal failure
Hepato-renal transplantation CsA/PSL/ ALG/AZA/mPSL
Multiple pelvic soft tissue tumor
IgG-κ type plasmacytoma
1.4
CsA discont’d/RT
Complete remission maintained for 24 m
Alive 24 m
[18]
16
30/M
HIV
None
Gingival mass/ maxillary soft tissue mass & destructive bone lesion/skin nodules
Anaplastic plasmacytoma κ
4
RT
Improved
Died 4 m later
[19]
17
34/M
HIV
None
Short breath Abdominal pain Ascites Dementia
Immature plasma cell λ
3
RT
Improved
Died 5 days later
[19]
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis 18
41/M
Hodgkin’s lympho-ma
Curative therapy
Plasmacytoma involving skin and testis
Plasmacytoma κ
7
Unknown
Unknown
Unknown
[20]
19
51/Unknown
Unknown
Liver transplantationCsA
Periumbilical plasmacy-toma
Plasmacytoma κ
Unknown
Unknown
Unknown
Unknown
[20]
20
31/M
HIV
Unknown
Fever/confusion/slurred speech/progres sive lethargy/polyuria polydypsia/left tonsillar mass/lung mass
IgG/κ IgM/λ Plasmablast Leukemic visceral and meningeal involvement
Unknown
Unknown
Unknown
Died of aspiration pneumonia
[21]
21
1.2/M
Unknown
Organ transplantation/CsA/PSL/AZA
Purulent rhinorrhea/ difficulty breathing/ recurrent otitis media/ nasopharyngeal mass
Nasopharyngeal mass focal infiltration of plasmacells
0.9
Ex/immuno suppressant dose reduction
Improved
Unknown
[22]
22
61/F
RA
SASP/MTX/TAC/PSL
None
IgG/κ/MM
5.4
MTX discont’d/BD/ Auto-PBSCT
CR
Surviving with CR, 12 m
Subject case
y, year; F, female; RT, radiation therapy; DEXA, dexamethasone; Thal, thalidomide; HSCT, hematopoietic stem cell transplantation; M, male; Ex, excision; m, month; CT, chemotherapy; DOMM, dead of multiple myeloma; CsA, cyclosporine; AZA, azathioprine; CY, cyclophosphamide; ALG, antilymphocyte globulin; mPSL, methylprednisolone; Auto-PBSCT, autologous peripheral blood stem cell transplantation.
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis Table 3. Summary of 23 reported cases of EB virus-positive plasma cell tumors Patients Age (y)/gender
Underlying disease
Treatment
Clinical findings
Type of myeloma
n = 22 n = 17 1.2-78 (46) Unknown: 5 n = 16 M:F = 13:3 Unknown: 6 n = 11 None: 4 Chronic renal failure: 2 Hepatic failure: 1 HIV: 3 Hodgkin’s lymphoma: 1 RA: 1 Unknown: 11 n = 12 None: 6 Organ transplantation: 4 CsA: 4 AZA: 3 PSL: 5 ALG: 1 SASP: 1 MTX: 1 TAC: 1 Unknown: 10 n = 20 Extramedullary mass: 12 Bone lesion: 5 Ileum ulcer: 1 Shortness of breath: 1 Abdominal pain: 1 Ascites: 1 Dementia: 1 Fever: 1 Clouding of consciousness: 1 Lethargy: 1 Polyuria: 1 Polydysplasia: 1 Slurred speech: 1 Purulent rhinorrhea: 1 Dyspnea: 1 Otitis media: 1 None: 1 Unknown: 2 n = 17 IgA: 1 IgG: 7
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Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis IgM: 1 κ: 9 λ: 3 Plasmacytoma: 11 Plasmablastic: 4 Non-plasmablastic: 1 Time from onset of underlying disease to that of myeloma (yr)
Treatment of myeloma
Therapeutic response
Outcome
summarized in Table 3. The median age of the patients was relatively young, at 46 years (1.2 to 78 years), and the disease was more common in men (male:female = 13:3), and the underlying disease was RA in only the present case, whereas cases with immunodeficiency in their clinical background, such as human immunodeficiency virus (HIV), chronic renal failure, hepatic insufficiency, and Hodgkin’s lymphoma, accounted for about 1/3 (7 cases) of all the cases. As for the treatment of underlying diseases, organ transplantation was involved in as many as 4 cases, and the administration of various immunosuppressants was relatively common (16 cases). It would be reasonable to assume that an immunodeficiency state following organ transplantation or that is associated with immunosuppressant therapy exists in the 2100
n=7 0.9-12 (median: 4) No underlying disease: 4 Unknown: 11 n = 12 Corticosteroids (incl. PSL): 2 DEXA: 2 RT: 7 Ex: 3 CT: 4 Thal: 1 BD: 1 Auto-PBSCT: 1 Immunosuppressants discont’d or dose reduced: 4 Unknown: 10 n = 11 Remission (improved): 10 Not improved: 1 Unknown: 11 n = 11 Surviving: 4 DOMM: 3 Died of infection: 2 Died, cause unknown: 2 Unknown: 11
background. The involvement of other factors seemed likely, nevertheless, inasmuch as there was no treatment or unknown treatment of the underlying disease in as many as 70% (15 cases) of patients. A variety of symptoms were noted as to the clinical findings, and about 60% (12 cases) of the patients had an extramedullary mass, which is a poor prognostic factor. The most frequent type of MM was IgG type (7 cases). The median time from the onset of the underlying disease to that of MM was relatively short, at 4 years (0.9-12 years), and coincided with that in the present case. Regarding the treatment for MM, there were no cases in which a clinical improvement was attained with immunosuppressant discontinuance or dosage reduction alone [15, 18, 22], and the same held true for the present case as well. Various treatInt J Clin Exp Pathol 2015;8(2):2090-2102
Epstein-barr virus-positive multiple myeloma with rheumatoid arthritis ments were provided, producing an improvement in the MM in 10 of the 11 cases, but only 4 patients survived, and the mean survival time for the 11 cases was about 33 months; hence, the outcome was not considered favorable. In fact, according to a report with only 4 cases, the possibility of a poor prognosis was suggested given the plasmablastic cytomorphologic features with high labeling indices and the high MIB-1 index that were observed [13]. To date, there has been no report of a case of plasmacytoma occurring with an underlying disease of RA or after TAC or MTX therapy and falling under the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) [31]; thus, the present case is the first to be reported. The present case was considered to be MTXLPD, as the patient was maintained on MTX. MTX-LPD usually results in lymphoma, and its disappearance after the discontinuation of MTX therapy is not uncommon, although many reported cases were EBV-related LPD [31]. In the present EBV-related LPD case, however, spontaneous remission did not occur following the discontinuation of MTX medication. No cases have been reported in which a clinical improvement followed dose reduction or the discontinuation of immunosuppressant medication [15, 18, 22]. Further studies of accumulated cases of post-immunosuppressant therapy for EB virus-positive plasmacytoma are needed. The RA disease activity increased despite MTX therapy, and an elevation of the IgG level occurred about 1 year later (estimated to be the onset phase of MM) in the present case. The likelihood that MM developed as a result of the increased RA disease activity as well as the immunosuppression (EBER-positive status) was considered. Such a situation might account for the shorter period from the onset of RA until that of the plasmacytoma (5.4 years) in this case, compared with previously reported averages of 34 and 13.6 years [26, 27].
047-381-5054; E-mail: [email protected]
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Disclosure of conflict of interest None. Address correspondence to: Dr. Yasunobu Sekiguchi, Department of Hematology, Juntendo University Urayasu Hospital, 1-1, Tomioka 2-chome, Urayasu, Chiba Prefecture. Tel: 047-353-3111; Fax:
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