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□ CASE REPORT □

CD3- and CD4-Positive Plasmablastic Lymphoma:A Literature Review of Japanese Plasmablastic

Lymphoma Cases

Yuhko Suzuki 1,2, Tsutomu Yoshida 3, Naoya Nakamura 6, Hirotoshi Kamata 1, Shouko Kotani 4,

Manabu Ohsaka 1, Sabine Kajita 3, Koji Miyazaki 1, Shinichi Ohtani 2, Meijin Nakayama 5,

Ryouichi Horie 1, Kazushige Hayakawa 4, Nozomi Niitsu 7 and Masaaki Higashihara 1

Abstract

Plasmablastic lymphoma (PBL) is a very rare and recently-described subtype of diffuse large B-cell lym-

phoma. A maxillary tumor in an 84-year-old HIV-negative Japanese-man was referred. The biopsied speci-

men showed a diffuse proliferation of mature plasma cells, expressing CD3 (+), CD4 (+), CD20 (-), CD138

(+) and EBER (+) by immunohistochemistry. He was diagnosed as a plasmablastic lymphoma; radiation ther-

apy (RT) was started, but the response to the RT was only a partial response. To our knowledge, this is the

first report of a patient with PBL expressing CD3 and CD4.

Key words: plasmablastic lymphoma, Japanese, CD3

(Inter Med 49: 1801-1805, 2010)(DOI: 10.2169/internalmedicine.49.3164)

Introduction

Plasmablastic lymphoma (PBL) is a recently-described

subtype of diffuse large B-cell lymphoma. It has its highest

incidence in HIV-positive individuals, predominantly males.

PBL may also be associated with other immunodeficiency

states, including advanced age and post-transplant lym-

phoproliferative disorders (1-6).

PBL is characterized by diffuse growth of large tumor

cells with a high MIB-1 proliferation index, the presence of

immunoglobulin heavy (IgH)-chain gene rearrangement, and

expression of the plasma cell-associated antigens CD38 and

CD138. Typically, PBL lacks expression of leukocyte com-

mon antigen, CD19, and CD20. Positivity for Epstein-Barr

virus (EBV)-encoded RNA (EBER) is frequently ob-

served (1).

We describe the case of PBL, which interestingly ex-

pressed CD3 and CD4, and review the literature of Japanese

cases.

Case Report

An 84-year-old Japanese man was referred to our hospital

in 2008 due to a two-month history of left face pain and

inadaptation of a denture. On physical examination, the left

paranasal area of his face was swollen and his left upper

gingiva was partially swollen with a tumor. His peripheral

blood count was within normal range. Biochemical analysis

revealed the following: C-reactive protein 2.70 mg/dL, lac-

tate dehydrogenase 167 IU/L, BUN 41 mg/dL, and cre-

atinine 2.33 mg/dL. Hypergammopathy and monoclonal

gammopathy were detected neither in urine nor in serum.

The patient was HIV negative. Even though the tumor cells

１Department of Hematology, Kitasato University School of Medicine, Sagamihara, ２Department of Transfusion and Cell Transplantation, Ki-

tasato University School of Medicine, Sagamihara, ３Department of Pathology, Kitasato University School of Medicine, Sagamihara, ４Department

of Radiology, Kitasato University School of Medicine, Sagamihara, ５Department of Otolaryngology, Kitasato University School of Medicine,

Sagamihara, ６Department of Pathology, Tokai University School of Medicine, Isehara and ７Department of Hematology, Comprehensive Cancer

Center, International Medical Center, Saitama Medical University, Hidaka

Received for publication November 19, 2009; Accepted for publication April 26, 2010

Correspondence to Dr. Yuhko Suzuki, ysuzuki-hki@umin.ac.jp

Inter Med 49: 1801-1805, 2010 DOI: 10.2169/internalmedicine.49.3164

1802

Figure 1. a. Head non-contrast-enhanced CT scan showed that the left paranasal sinus was occu-pied by a tumor and the tumor infiltrated the oral cavity. b. The tumor infiltrated the nasal cavity.

a b

expressed the T cell markers, CD3 and CD4 by IHC, results

of IgH rearrangement indicated B cell lymphoma, and the

diagnosis of PBL was established.

Computed tomography (CT) showed a soft tissue mass

that infiltrated the left nasal cavity and upper oral cavity

(Fig. 1). Bone marrow aspiration and biopsy were negative

for infiltration of lymphoma cells by light microscopy and

flow cytometry. He was Stage IIA and the international

prognostic index was low-intermediate. After informed con-

sent, the patient chose to receive involved-field radiation

therapy (RT) of 30 Gy/20 fractions and limited local field

RT of 20 Gy/10 fractions (total 50 Gy) and had a partial re-

sponse to the RT. Three months after the completion of RT,

a right chest wall tumor was newly found, suggesting lym-

phoma infiltration.

Histopathology, immunohistology, in situ hybridiza-

tion, and flow cytometry

Histopathological analysis revealed diffuse proliferation of

mature plasma cells having a round nucleus, intermingled

with large-sized cells with higher nuclear to cytoplasmic (N/

C) ratio were intermingled (Fig. 2a, b). On immunohisto-

chemistry (IHC), the tumor cells were negative for B cell

markers including CD10, CD20 (Fig. 2e), CD38, CD79a,

and PAX-5, but were positive for the T cell markers, CD3

(Fig. 2c) and CD4 (Fig. 2d). They were also positive for

plasma cell markers, CD138 (Fig. 2f) and MUM-1. As other

markers that are often used for IHC to diagnose lymphoma,

Bcl-2, CD56, and TdT were negative, but Bcl-6 was posi-

tive. The MIB-1 labeling index was high, and the tumor

cells were strongly positive on in situ hybridization with an

EBER probe (Fig. 2g). The flow cytometric study of the bi-

opsied specimen did not reflect the actual lymphoma cells.

PCR

At first, clonality analysis of IgH chain was performed

with primer recognizing not only FR2 but also FR3 region;

semi-nested PCR using FR3A and LJH for the first PCR

and FR3A and VLJH for the second PCR, as described pre-

viously (7, 8). To analyze clonality of T cell receptor βchain, multiplex PCR assays were performed, as described

previously (9).

PCR of the IgH chain showed a discrete band, indicating

IgH rearrangement (Fig. 3), but PCR of T cell receptor

(TCR) beta (V beta/J beta 1, 2, V beta/J beta 2, D beta/J

beta) showed no amplification, indicating no rearrangement.

Discussion

We reported the first Japanese patient with PBL, and it

expressed CD3 and CD4, and it arose in an 84-year-old,

HIV-negative Japanese patient. Interestingly, this case het-

erotropically expressed CD3 and CD4. The pathological

findings of the present case seemed to resemble pyothorax-

associated lymphoma (PAL), which usually arises from

chronic inflammation (10, 11). PAL is often associated with

EBV infection, and it also frequently expresses T-cell anti-

gen. However, the present patient did not have a medical

history of chronic inflammation of sinusoids. Heterotropic

expression of T-cell antigen in B-cell lymphoma is fre-

quently associated with EBV infection with or without

chronic inflammation.

Our case was interesting and difficult to diagnose because

it expressed pan-T cell antigens, CD3 and CD4, as detected

by IHC. And this case is the first report of CD3 and CD4

positive PBL. CD3 positivity by IHC is used as a pan-

T (12) and pan-thymic marker, namely, CD3-positive lym-

phoma generally means T-cell lymphoma. The monoclonal

antibody for CD3, clone F7.2.38 (DAKO), which we use,

recognizes the cytoplasmic domain of the epsilon chain, and

stained at least membrane and cytoplasm of lymphoma cells

in this case.

Several studies on aggressive CD3-positive B-cell lym-

phoma were reported (11, 13-18). PAL has peculiar clinico-

pathological features, and some cases express CD3 and

other T cell antigens (11). Aggressive CD3-positive B cell

lymphoma cases are often EBER-positive (11, 16, 17) as in

the present case. EBV may interfere with the PAX-5 gene,

Inter Med 49: 1801-1805, 2010 DOI: 10.2169/internalmedicine.49.3164

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Figure 2. Histological and immunohistochemical photographs of the biopsied tumor. a. Hematox-ylin and Eosin staining, original magnification×100. b. Hematoxylin and Eosin staining, original magnification×400. c. Anti-CD3 (original magnification×400). d. Anti-CD4 (original magnifica-tion×400). e. Anti-CD20 (original magnification×400). f. Anti-CD138 (original magnification×400). g. EBER (original magnification×400). Photographs show diffuse proliferation of large cells that are positive for CD3, CD4 (weak), CD138, and EBER and negative for CD20, which indicates a plasmablastic lymphoma. In figure 1-c, d, arrows indicate epithelial cells( → ) and normal T cells( ⇒ ). CD3 and CD4 are stained in the serial section, and CD3 and CD4 coexist on the same lymphoma cells. Compared to the normal T cells, positivities for CD3 and CD4 of lymphoma cells are weaker than normal T cells. And epithelial cells are negative for CD3 and CD4.

a b

c d

e f

g

Inter Med 49: 1801-1805, 2010 DOI: 10.2169/internalmedicine.49.3164

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Figure 3. PCR of the IgH chain. It showed a discrete band, indicating IgH rearrangement.

Table 1. PBL Cases in the Japanese Literature

NR: not reported, CRF: chronic renal failure, PNS: Paranasal sinus, PE: pleural effusion, LN: lymph node, Cx: chemotherapy, RT: radiation therapy, S: surgery

which is the master gene throughout B cell development

from pro-B to the mature B cell stage. PAX-5 expression

was negative in our case. Loss of PAX-5 may cause de-

differentiation to the immature lymphoid cell and lead to the

development of lymphoid malignancy (19, 20).

The possibility of extraosseous plasmacytoma (21) was

also considered. As a differential diagnosis, plasmacytoma is

the most difficult to distinguish from our case. EBV is not

normally harbored in normal plasma cells and neoplastic

plasma cells in immunocompetent individuals (22). Thus,

plasmacytomas do not express EBER, and therefore plasma-

cytoma was ruled out in this case. However, recently,

EBER-positive plasmacytoma was reported (22). The defini-

tion of PBL is still confusing. The clinical course of the

present case followed the typical clinical course of lym-

phoma, but not plasmacytoma.

From the results of a literature review, we found 9 Japa-

nese cases with PBL among the studies published in Japa-

nese (23-31) (Table 1). Considering these patients along

with the present patient, their ages ranged from 33 to 84

years (median, 59 years) with male dominance. As to the

background disease of PBL, only one patient (10%) was

HIV-positive. However, in Western countries the majority

(81%) of cases arise in the setting of HIV infection (6).

Prognoses were also reported in nine cases; three cases

were alive with complete response (CR) and the other six

died or had refractory cases. PBL is considered to be a

highly aggressive lymphoma and the prevalence of disease-

related death was 59.6% over a mean period of 10.4 months

from diagnosis (6, 32). Interestingly, case 9 underwent sur-

gery only but has survived without recurrence for more than

two years. The clinical course of PBL varies and standard

therapies for PBL have not yet been developed.

We reported CD3- and CD4-positive PBL arising in an

HIV-negative patient. Its clinicopathological features were

very unique. To our knowledge, this is the first report of pa-

tient with PBL expressing CD3 and CD4. We hope that,

with the accumulation of clinicopathologic data of PBL

cases, we will be able to elucidate the mechanism(s) in-

volved in the development of PBL, to confirm the most suit-

able treatment.

AcknowledgementWe would like to thank all of our colleagues, especially Mr.

Kusaba, who assisted PCR of IgH rearrangement assays.

We obtained no financial support from any company.

Inter Med 49: 1801-1805, 2010 DOI: 10.2169/internalmedicine.49.3164

1805

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