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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, [email protected]
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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