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□ CASE REPORT □

Plasmablastic Extramedullary Plasmacytoma Associatedwith Epstein-Barr Virus Arising in an Immunocompetent

Patient with Multiple Myeloma

Shugo Sasaki 1, Koji Hashimoto 1, Shin-ichi Nakatsuka 2, Masataka Hasegawa 1,

Tomoaki Nakano 1, Seiki Nagata 1, Yuzuru Kanakura 3 and Norio Hayashi 1

Abstract

We encountered a case of plasmablastic extramedullary plasmacytoma with multiple myeloma. Histological

findings revealed that the extramedullary plasmacytoma of this patient was of the plasmablastic type, which

was positive for λ-stain and EBV-encoded RNA. In contrast, bone marrow aspiration demonstrated a

common-type multiple myeloma, which was positive for λ-stain and negative for EBV-encoded RNA. This

was a rare case of plasmablastic extramedullary plasmacytoma associated with Epstein-Barr virus arising in

an immunocompetent patient with multiple myeloma.

Key words: multiple myeloma, plasmablastic lymphoma, extramedullary plasmacytoma

(Intern Med 50: 2615-2620, 2011)(DOI: 10.2169/internalmedicine.50.4892)

Introduction

Extramedullary involvement of multiple myeloma (MM)

has been reported in 15-20% of patients at the time of diag-

nosis and in an additional 15% during the course of

MM (1, 2). When MM is terminated owing to uncontrolled

disease or chemotherapy resistance, cytological transforma-

tion into a high-grade lymphoma-like disorder has been rec-

ognized in association with prominent extramedullary in-

volvement (3-5). In the present case, the tumor cells simul-

taneously showed two distinct morphologic appearances,

typical myeloma cells in the bone marrow and plasmablastic

cells in the extramedullary location. The histological charac-

teristics of plasmablastic extramedullary plasmacytoma (EP)

are similar to those of plasmablastic lymphoma (PBL).

PBL has recently been listed in the World Health Organi-

zation (WHO) classification as a subtype of diffuse large B-

cell lymphoma and has a high incidence in Epstein-Barr vi-

rus (EBV)-positive, human immunodeficiency virus (HIV)-

positive patients (6). It is difficult to distinguish between

PBL and plasmablastic EP (7, 8), and therefore it is impor-

tant to pay careful attention when making the differential di-

agnosis of PBL and EP. The presence of EBV infection is

much more strongly associated with PBL than MM (7-10).

However, EPs in the head and neck region and gastrointesti-

nal tract have been occasionally associated with EBV in im-

munocompetent patients (10-12). These findings prompted

us to study the effects of EBV on plasmablastic EP and

MM. We describe here plasmablastic EP associated with

EBV arising in an immunocompetent patient with MM.

Case Report

A 62-year-old Japanese man was referred to our hospital

in September 2010 owing to a one-month history of left

cheek discomfort. On physical examination, his left upper

cheek was partially swollen. No abnormalities were found in

the physical examination except the cheek lesion. Magnetic

resonance imaging (MRI) showed a subcutaneous tumor that

infiltrated the left maxillary sinus (Fig. 1A). 18F-

fluorodeoxyglucose-positron-emission tomography (FDG-

PET) demonstrated intense uptake in the left cheek, ster-

num, bilateral scapulas, left humerus, right forearm bone,

１Department of Internal Medicine, Kansai Rosai Hospital, Japan, ２Department of Pathology, Kansai Rosai Hospital, Japan and ３Department of

Hematology and Oncology, Osaka University Graduate School of Medicine, Japan

Received for publication November 24, 2010; Accepted for publication August 2, 2011

Correspondence to Dr. Shugo Sasaki, shugosasaki@yahoo.co.jp

Intern Med 50: 2615-2620, 2011 DOI: 10.2169/internalmedicine.50.4892

2616

Figure　1.　A. Magnetic resonance imaging showed a subcutaneous tumor that infiltrated the left maxillary sinus. The arrow indicates the subcutaneous tumor (→). B. The subcutaneous tumor was not detected after chemotherapy. C. 18F-fluorodeoxyglucose-positron-emission tomography demon-strated intense uptake in the left cheek, sternum, bilateral scapulas, left humerus, right forearm bone, left rib and right ilium.

A

B

C

left rib and right ilium (Fig. 1C). As shown in Fig. 2A-G,

histologic section with Hematoxylin and Eosin (H&E) stain-

ing of the subcutaneous tumor revealed diffuse proliferation

composed of large tumor cells showing irregular nuclear

contours with a few prominent nucleoli in the middle of the

nuclei and a small-medium amount of amphophilic cyto-

plasm. Immunohistological study revealed that these tumor

cells were positive for CD45 and CD56, and MIB1 labeling

index was about 90%, and negative for CD3 and CD20. The

result of in situ hybridization for EBV-encoded RNA

(EBER) was positive in most of the tumor cells. At first, a

diagnosis of non-Hodgkin’s lymphoma, extranodal NK/T

cell lymphoma, nasal type, was made on the basis of these

findings. However, bone marrow aspiration revealed that

myeloma cells were detected for 30% of nuclear cells. The

cytoplasm of the myeloma cells was well developed and the

nucleus eccentrically placed with a prominent hof (Fig. 3A).

Flow cytometry (FCM) analysis of the myeloma cells using

the CD38 gating method revealed that they were positive for

CD138 (84.3%), MPC-1 (83.2%) and CD56 (97.6%), and

negative for CD20 (1.2%), CD45 (2.0%) and CD49e (1.3%)

(Fig. 3B). CD38 gating two-color FCM analysis of cytoplas-

mic light chains showed that the proportion of cytoplasmic

kappa (κ)-positive/lambda (λ)-negative cells was 0% and

that of κ-negative/λ-positive cells was 89.4%. Immunohis-

tological study revealed that the MIB1 labeling index of

these plasma cells was about 10%. Bone marrow cells re-

vealed a normal karyotype. Neither t (8 ; 14), add (14) (q

32), t (14 ; 18), nor t (4,14) was detected by fluorescent insitu hybridization of chromosomal analysis of bone marrow.

The result of in situ hybridization for EBER was negative.

Laboratory evaluation revealed a serum IgA level of 3,825

mg/dL, while IgG and IgM levels were suppressed. Mono-

clonal gammopathy was detected in both serum and urine,

and serum immunoelectrophoretic pattern was IgA-λ. No

Bence Jones protein was detected. Hemoglobin concentra-

tion was 12.2 g/dL. Biochemical analysis revealed the fol-

lowing: lactate dehydrogenase level 134 U/L, blood urea ni-

trogen 13.9 mg/dL, creatinine 0.97 mg/dL, uric acid 6.8 mg/

dL, calcium 9.2 mg/dL and albumin 3.8 g/dL. In a periph-

eral blood smear, abnormal lymphoid cells were not ob-

served. HIV antibody result was negative. IgG antibody to

the viral capsid antigen (VCA-IgG) result was ×320, VCA-

IgM result was <×10 and EBV antibody to nuclear antigen

Intern Med 50: 2615-2620, 2011 DOI: 10.2169/internalmedicine.50.4892

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Figure　2.　Histological and immunohistochemical photographs of the subcutaneous tumor (original magnification×400 without Fig. 2B×1000). A, B. Hematoxylin and Eosin staining. C. Anti-CD56. D. Anti-CD138. E. Anti-CD20. F. MIB1. G. in situ hybridization for Epstein-Barr virus-encoded RNA. H. λ-stain. I. κ-stain. Photographs show diffuse proliferation composed of large tumor cells that are positive for CD56, CD138 and negative for CD20. MIB1 labeling index is about 90%. Epstein-Barr virus in situ hybridization result was positive in most of the tumor cells. Tumor cells of plasmablas-tic EP were predominantly positive for λ-stain but entirely negative for κ-stain.

A B C

D E F

G H I

Figure　3.　A. Morphological findings with May-Giemsa staining of the bone marrow confirmed that myeloma cells were detected for 30% of nuclear cells. The cytoplasm of the myeloma cells was well developed and the nucleus eccentrically placed with a prominent hof. B. Flow cytometry analy-sis of the myeloma cells using the CD38 gating method revealed that they were positive for CD138 (84.3%), MPC-1 (83.2%) and CD56 (97.6%), and negative for CD20 (1.2%), CD45 (2.0%) and CD49e (1.3%).

A B

result was ×20, indicating past history of EBV infection.

EBV DNA quantitative polymerase chain reaction was <

2.0×10 copies in 1×106 white blood cells both before and

after treatment. Bone X-ray survey revealed no osteolytic le-

sion. Therefore, the patient was diagnosed with multiple

myeloma (IgA-λ, Durie-Salmon stage IIA).

Since the bone marrow and laboratory evaluation results

did not disagree with the histological findings of the subcu-

taneous tumor, we further examined the subcutaneous tumor

by immunohistological analysis. The tumor cells were

Intern Med 50: 2615-2620, 2011 DOI: 10.2169/internalmedicine.50.4892

2618

strongly positive for CD138 and negative for T-cell re-

stricted intracellular antigen-1 (TIA-1) (Fig. 2D). Tumor

cells of plasmablastic EP were predominantly positive for λ-

stain but entirely negative for κ-stain (Fig. 2H, I). As a re-

sult, a final diagnosis of MM with EP composed of plas-

mablastic cells was made. In the present case, since we ex-

pected a poor response with conventional chemotherapy for

MM owing to the plasmablastic phenotype and since the pa-

tient’s performance status was good, he was treated with in-

tensive chemotherapy consisting of dexamethasone,

etoposide, ifosfamide and carboplatin (DeVIC chemother-

apy). After the first course of chemotherapy, the subcutane-

ous tumor was not detected on MRI (Fig. 1B) and the se-

rum IgA level had markedly decreased from 3,850 mg/dL to

655 mg/dL. Bone marrow aspiration revealed that plasma

cells decreased to 1% of nuclear cells. He is now scheduled

to receive the second course of chemotherapy.

Discussion

MM is a plasma cell neoplasm commonly found in the

middle-aged and elderly. The median survival is approxi-

mately 3 years from diagnosis. Extramedullary involvement

of MM has been reported in 15-20% of patients at the time

of diagnosis and in an additional 15% during the course of

MM (1, 2). In general, MM terminating as an uncontrolled

disease or chemotherapy resistance frequently develops as a

form of plasma cell leukemia. Furthermore, cytological

transformation into a high-grade lymphoma-like disorder has

been recognized in association with prominent extramedul-

lary involvement (3-5). Although the present case was diag-

nosed as having both MM and plasmablastic EP simultane-

ously, there are several interesting points concerning the di-

agnosis.

Myeloma cells of bone marrow in the present case exhib-

ited cytoplasm that was well developed and nucleus that was

eccentrically placed with a prominent hof and MPC1+

CD49e- CD45-. Plasmablastic cytomorphologic features in

aspirated smears were not observed. In aspirate smears, plas-

mablastic features were defined for equal to or greater than

2% of blasts in accordance with the criteria of Greipp et

al (13). These findings indicate mature MM in accordance

with previous reports (10, 13-15). In contrast, the extrame-

dullary tumor revealed diffuse proliferation composed of

monomorphic large tumor cells showing irregular nuclear

contours with a few prominent nucleoli in the middle of the

nuclei and a small-medium amount of amphophilic cyto-

plasm. The proliferative rate with MIB1 labeling index was

extremely high, suggesting morphologic features of PBL

rather than those of plasmablastic EP because Vega et al (8)

reported that PBL was characterized by a monotonous pro-

liferation of plasmablasts and/or immunoblasts, with rare or

no obvious plasmacytic cells. However, in H&E-stained sec-

tions, plasmablastic features were defined as equal to or

greater than 30% of blasts (16). In fact, plasmacytic cells

were frequently seen in plasmablastic MM (8). However,

there are some subtle differences in the morphology between

PBL and plasmablastic MM (8). Thus, evidence of mor-

phologic features is insufficient to differentiate between PBL

and plasmablastic EP, which is a progression from underly-

ing MM. Moreover, cytogenetic/molecular studies such as insitu hybridization for EBER and clonality are needed to

make the distinction.

PBL was first described as an aggressive lymphoma pre-

senting in the oral cavity of patients with HIV (17). PBL is

currently listed by WHO as a rare subgroup of diffuse large

B-cell lymphoma. PBL was also characterized by diffuse

growth of large tumor cells with a high MIB1 labeling in-

dex, as well as positivity for CD38 and CD138 and negativ-

ity for CD19 and CD20. The test result for EBER is fre-

quently positive (6). These findings share many morphologi-

cal and immunophenotypic features with the present case.

Vega et al found that the only significant difference between

MM and PBL was the presence of EBER, which was posi-

tive in all PBL cases and negative in all MM cases (8). In

contrast with Vega et al (8), although the presence of EBV

infection is much more strongly associated with PBL than

MM (7-10), Chang et al reported that EBER+ plasmablastic

MMs and plasmacytomas, although rare, existed in immuno-

competent patients (10). For diagnostic purposes in im-

munocompetent patients, EBER+ transcripts in tumor cells

seemed to be of little value when the differential diagnoses

were between PBL and plasmablastic MM (10). Thus, in

cases of immunocompetent patients such as the present case,

the presence of EBER does not enable differentiation be-

tween plasmablastic EP and PBL. In addition, since Suzuki

et al reported that only one patient (10%) was HIV-positive

among 9 Japanese cases with PBL (18), the presence or ab-

sence of HIV infection is also insufficient to differentiate

between these neoplasms. In practice, the distinction be-

tween PBL and plasmablastic MM frequently depends on

the clinical correlation (19). Since the two distinct lesions of

extramedulary and bone marrow simultaneously occurred in

the present case, to make the distinction between plasmab-

lastic EP and PBL, it is very important to determine the re-

lationship of plasmablastic EP and MM in terms of their

clonal origin. Tumor cells of plasmablastic EP were signifi-

cantly positive for λ-stain compared to κ-stain although they

were not strongly stained. And these cells were positive for

CD45 and CD56 although the neoplastic cells of PBL usu-

ally express negativity for CD45 and CD56 (6, 20). These

findings were consistent with the FCM analysis of cytoplas-

mic light chains of MM. Therefore, we established the diag-

nosis of plasmablastic EP arising from MM against coexis-

tence of PBL and MM. Moreover, to confirm the clonality,

heavy chain gene rearrangement including CDR3 analysis

should be employed; however, we could not perform the

analysis owing to a lack of specimens.

EPs in the head and neck region and gastrointestinal tract

were found to be occasionally associated with EBV in im-

munocompetent patients (10-12). Aguilera et al reported that

EP of the head and neck in patients not known to be im-

Intern Med 50: 2615-2620, 2011 DOI: 10.2169/internalmedicine.50.4892

2619

munosuppressed showed a small number of EBV-positive

cases (11), and Tomita et al also reported a close association

of EBV and Korean gastrointestinal tract plasmacytoma in

patients without findings suggestive of the presence of im-

munodeficiency (12), suggesting that the possibilities of a

relationship of EP from these anatomic regions and the ef-

fects of EBV should be considered even in immunocompe-

tent patients. In the present case, given that in situ hybridi-

zation for EBER of bone marrow was negative and EBV

DNA level was <2.0×10 copies in 1×106 white blood cells,

we postulated that reactivation of EBV might have been im-

portant for the development to plasmablastic EP, which re-

sulted in two distinct morphologic appearances in MM and

EP at diagnosis. Interestingly, EP may have been driven by

EBV to obtain the plasmablastic features irrespective of

MM, even if the present case was immunocompetent.

EBV-positive lymphoma is frequently resistant to combi-

nation chemotherapy, and EBV association results in poorer

clinical outcome (21, 22). In particular, the effects of EBV

association on the prognosis of MM have not been well

clarified. One of the mechanisms of chemoresistance is the

overexpression of the multidrug resistance gene products,

which cause both drug efflux from cells and decreased intra-

cellular accumulation of drugs such as adriamycin and vinca

alkaloids. Nakazato et al reported that there was no response

to VAD (adriamycin, vinca alkaloids and dexamethasone) in

a case of plasmablastic-type myeloma with multiple

EPs (23). Thus, we expected a poor response with conven-

tional chemotherapy as VAD chemotherapy for MM and

therefore chose DeVIC chemotherapy, which is an intensive

chemotherapy not only including high-dose dexamethasone

but also without adriamycin and vinca alkaloids, and for

which adverse effects are mild compared with those of vari-

ous intensive regimens for aggressive lymphomas (24). After

informed consent was obtained, we planed to use Borte-

zomib immediately if DeVIC chemotherapy was not effec-

tive, the patient was treated with DeVIC chemotherapy and

had a significant response. The clinical course was good. In

such cases, following the course, autologous peripheral

blood stem cell transplantation should also be a concern.

However, the effects of EBV association on the prognosis of

plasma cell neoplasms should be analyzed and the most

suitable chemotherapy for plasma cell neoplasms composed

of plasmablastic cells should be determined in a larger se-

ries.

In summary, plasmablastic EP associated with EBV aris-

ing in an immunocompetent patient with MM is reported to

be extremely rare. The present case indicates that the occa-

sional development of plasmablastic features associated with

EBV from extramedullary locations is possible, even in im-

munocompetent patients.

The authors state that they have no Conflict of Interest (COI).

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