Epstein-Barr virus-positive plasmacytoma in an immunocompetent female: A case report

Abstract

Plasmacytoma is defined as a plasma cell neoplasm forming a solitary osseous or extramedullary tumor without evidence of myeloma or organ damage related to a plasma cell neoplasm. Epstein-Barr virus (EBV) is associated with various B-cell neoplasms, particularly in patients with immune dysregulation; however, plasmacytoma is typically negative for EBV. Here, a case of EBV-positive sternal plasmacytoma in an immunocompetent female is presented. A 76-year-old female with no immunodeficiency presented with a tumor on the anterior thoracic wall. Imaging analysis revealed a 6.3 cm-sized tumor at the manubrium, and a needle biopsy was performed. The tumor in the bone was composed of a diffuse proliferation of plasmacytes with eccentric nuclei and a perinuclear halo. By immunohistochemistry and in situ hybridization, tumor cells were CD20-, CD3-, CD138+, κ+, λ-, EBER+, and the Ki67-labeling index was approximately 20%. Subsequent studies identified IgG κ monoclonal protein in serum but no evidence of plasma cell neoplasm-related organ damage, such as hypercalcemia, anemia, or renal dysfunction. No plasma cell neoplasm was detected in the bone marrow in the morphological and flowcytometric studies. Accordingly, the diagnosis was EBV-positive plasmacytoma. The patient was treated with local radiation therapy and achieved complete remission. EBV-positive plasmacytoma is rare in immunocompetent patients and should be carefully distinguished from plasmablastic lymphoma, another EBV-positive neoplasm with a plasma cell phenotype and an aggressive clinical course. This case also raises an important question: “when to perform EBER in situ hybridization in diagnosing plasma cell neoplasm?”, which prompts further large case-series studies.

INTRODUCTION

Plasmacytoma is a plasma cell neoplasm (PCN) forming a solitary osseous or extramedullary tumor without evidence of myeloma or end-organ damages due to PCN, such as hypercalcemia, renal dysfunction, or anemia.¹ While solitary plasmacytoma of bone arises in bones with active hematopoiesis, extramedullary plasmacytoma is mostly observed in the upper respiratory tract.¹

Epstein-Barr virus (EBV) or human helps virus type 4 (HHV4) is an oncovirus associated with diverse lymphoproliferative disorders and lymphomas.² Most EBV-associated lymphomas are of B-cell lineage, including EBV-positive diffuse large B-cell lymphoma and plasmablastic lymphoma (PBL), and these EBV-positive lymphomas are more prevalent in patients with immune dysregulation than immunocompetent patients.³ In contrast, plasmacytoma is typically negative for EBV; however, recent studies have reported rare cases of EBV-positive plasmacytoma even in patients without immunodeficiency.^4–6

Here, a case of EBV-positive sternal plasmacytoma in an immunocompetent female is reported. The differential diagnosis from PBL, another EBV-positive malignancy with plasma cell immunophenotype, is also discussed.

CASE REPORT

A 76-year-old female presented with a sternal tumor and was initially evaluated at a primary care clinic. She was immunocompetent and had a medical history of appendicitis treated with appendectomy, an endometrial polyp, hyperlipidemia, diabetes mellitus, hypertension, and glaucoma. Computed tomography (CT) showed a 6.3 cm-sized tumor at the manubrium infiltrating outward (Figure 1A). The bone cortex was irregular, and the ventral aspect showed osteolysis. Subsequently, the patient was referred to an orthopedist for consultation. ¹⁸F-fluorodeoxyglucose-position emission tomography/CT (FDG-PET/CT) revealed mild FDG uptake in the tumor, with a maximum standardized uptake value of 4.81 (Figure 1B). The bone lesion was solitary and no other osseous or extraosseous lesions were identified. After analysis of the imaging, a needle biopsy was performed.

Fig. 1.

CT and PET/CT. Computed tomography (CT) (A) and 18F-fluorodeoxyglucose-position emission tomography/CT (FDG-PET/CT, B) of Epstein-Barr virus-positive plasmacytoma are indicated.

Histopathologically, the sternal tumor was composed of a diffuse proliferation of plasmacytes with eccentric nuclei and perinuclear halo (Figure 2). Plasmablasts accounted for about 15% of the total neoplastic cells, while the remaining 85% were mature plasma cells. Only a small number of mitoses were observed. There was no necrosis. Immunohistochemistry and in situ hybridization showed that the tumor cells were positive for CD19, CD79a, CD38, CD138, MUM1/IRF4, and the EBV-encoded small RNA (EBER), and negative for CD3, CD20, CD56, and ALK (Figure 3). Both latent membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2) were negative by immunohistochemistry, representing type I latency of EBV infection. The Ki67-labeling index was approximately 15%. These neoplastic cells were exclusively positive for immunoglobulin (Ig) κ light chain, representing light chain restriction. Break-apart fluorescence in situ hybridization for MYC and CCND1 revealed no split signals, although a subset of cells had a low copy number gain.

Fig. 2.

Histopathology of Epstein-Barr virus-positive plasmacytoma. Low-power magnification (A) and high-power magnification (B).

Fig. 3.

Immunophenotype of Epstein-Barr virus-positive plasmacytoma. Immunohistochemically, neoplastic cells exhibited CD20- (A), CD79a+ (B), CD138+ (C) with light chain restriction to κ (κ, D; λ, E). EBER in situ hybridization revealed Epstein-Barr virus (EBV) positivity in neoplastic cells (F).

Following the diagnosis of EBV-positive plasmacytoma, laboratory testing was performed (Table 1). The patients’ serum IgG level was slightly elevated (1,854 mg/dL), whereas IgA and IgM levels were within normal limits. The κ free light chain (κ-FLC) level was 125.9 mg/dL, and the FLC ratio (κ/λ) was 7.41. Serum immunoelectrophoresis detected monoclonal IgG κ protein, and the urine was positive for Bence-Jones protein. The EBV genome in whole blood was elevated at 20,000 copies/mL. Other laboratory tests revealed no evidence of hypercalcemia, anemia, or renal dysfunction. Bone marrow examination revealed slightly hypoplastic marrow with trilineage hematopoiesis. Plasmacytes were observed only in 1.4% of all nucleated cells and exhibited no light chain restriction by in situ hybridization. There was no clonal plasma cell population detected by flow cytometry.

Table 1. Summary of laboratory testing.

TP	7.5	g/dl	WBC	6,000	/µL	IgG	1,854	mg/dL
Alb	4.1	g/dl	RBC	411×104	/µL	IgA	292	mg/dL
ChE	317	U/L	Hb	13.1	g/dL	IgM	121	mg/dL
T-Bil	0.8	mg/dL	Ht	40.5	%
D-Bil	0.2	mg/dL	MCV	98.5	fl	Free κ chain	125.9	mg/L
ALP (IFCC)	91	U/L	MCH	31.9	pg	Free λ chain	17	mg/L
γ-GT	21	U/L	MCHC	32.3	g/dL	κ/λ ratio	7.41
LDH (IFCC)	176	U/L	PLT	288×103	/µL
AST	16	U/L
ALT	12	U/L	Stab	0	%	EBV genome	2×104	copy/mL
BUN	12.5	mg/dL	Steg	73	%
Cr	0.68	mg/dL	Neut	73	%
CRP	0.1	mg/dL	Eo	0	%
Na	1.39	mmol/L	Ba	1	%
K	4.1	mmol/L	Mo	3	%
Cl	106	mmol/L	Ly	23	%
Ca	9.6	mg/dL

TP, total protein; Alb, albumin; ChE, cholinesterase; T-Bil, total bilirubin; D-Bil, direct bilirubin; ALP, alkaline phosphatase; IFCC, international federation of clinical chemistry and laboratory medicine; γ-GT, γ-glutamyl transpeptidase; LDH, lactose dehydrogenase; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Cr, creatinine; CRP, C-reactive protein; WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; Ht, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; HCHC, mean corpuscular hemoglobin concentration; PLT, platelet; Stab, stab leukocyte; Seg, segmented leukocyte; Neut, neutrophil; Eo, eosinophil; Ba, basophil; Mo, monocyte; Ly, lymphocyte; EBV, Epstein-Barr virus.

Based on these clinical and pathological findings, a diagnosis of EBV-positive plasmacytoma was established. The patient was treated with radiotherapy of 50 Gy. She achieved complete remission eight months after the treatment.

DISCUSSION

Plasmacytoma is a monoclonal proliferation of plasmacytes forming a solitary mass, which is distinguished from plasma cell myeloma/multiple myeloma (PCM/MM) by the absence of myeloma-defining events.¹ Plasmacytoma is typically negative for EBV, and EBV negativity has been considered an important pathologic finding that differentiates plasmacytoma from PBL. However, recent studies have reported a relatively small case series of EBV-positive plasmacytoma, posing a diagnostic dilemma.^4–6

There are few studies that have reported the incidence of EBV-positive PCNs in immunocompetent patients. A recent study investigating 122 PCNs arising in immunocompetent patients identified 13 and 2 cases of EBV-positive plasmacytoma and PCM/MM, respectively, representing an EBV-positive rate in PCNs of 12.3%.⁴ Of note, EBV positivity was significantly higher in plasmacytoma than in PCM/MM,⁴ suggesting a distinct EBV association in pathogenesis between plasmacytoma and PCM/MM.

Given the rarity of reported EBV-positive plasmacytomas, their clinicopathological features have not been fully elucidated. Two studies have investigated the clinicopathological differences between EBV-positive and EBV-negative PCN. Zhou et al. compared characteristics of 19 and 27 cases of EBV-positive and -negative plasmacytoma, respectively.⁶ EBV-positive plasmacytoma is characterized by a significantly higher incidence of osseous involvement than EBV-negative plasmacytoma (26.3% vs. 3.7%). Our patient developed a solitary osseous lesion in the sternum. Another feature differentiating EBV-positive and -negative plasmacytoma is the morphological spectrum of neoplastic plasmacytes, which exhibit a wide morphological spectrum from conventional plasmacytic morphology to anaplastic cytology,⁶ while EBV-negative plasmacytoma is more uniform in cytomorphology. Similar morphological features have been noted in another case series reported by Xiao et al.⁴ In contrast, there seem to be no obvious differences in the immunophenotype between EBV-positive and -negative plasmacytoma.^4,6 Regarding prognosis, a meta-analysis reviewing 59 cases of EBV-positive plasmacytoma identified no statistically significant difference in overall survival between patients with EBV-positive and negative plasmacytomas.⁴ Considering the reported clinicopathological features of EBV-positive plasmacytoma, EBV testing appears not to be necessarily essential in conventional PCNs. However, a multicenter, international, retrospective cohort study on PBL reported that EBV-negative status was independently associated with inferior overall survival, suggesting the utility of EBV testing in the risk estimation of PBL.⁷ Therefore, also in the case of plasmacytoma, further studies combining the clinicopathological and molecular features are required to determine whether EBV-positive plasmacytoma is a pathobiologically distinct entity or an immunological variant.

The most important differential diagnosis of EBV-positive plasmacytoma is PBL. PBL is an aggressive neoplasm with a plasma cell immunophenotype, and 60 to 70% of PBL cases show EBV-positivity.⁸ The therapeutic strategy is completely different between PBL and plasmacytoma: intensive systemic chemotherapy, such as infusional etoposide, vincristine and doxorubicin with bolus cyclophosphamide and prednisone (EPOCH), is recommended for patients with PBL,⁸ while local radiation therapy is recommended for solidary plasmacytoma.⁹ Given these differences in prognosis and therapeutic strategy, EBV-positive plasmacytoma should be carefully differentiated from PBL. Zhou et al. compared the clinicopathological features of EBV-positive plasmacytoma and PBL.⁶ According to their study, anatomic distribution is significantly different between EBV-positive plasmacytoma and PBL; the former more frequently has bone lesions than PBL, while skin/soft tissue and gastrointestinal lesions are more common in PBL.⁶ Histopathologically, EBV-positive plasmacytoma is less commonly associated with a “starry-sky” pattern, necrosis, absence of light chain expression, and a high Ki67 index (>75%).⁶ In the present case, the tumor developed a solitary osseous lesion with none of the PBL-associated histopathology reported by Zhou et al.,⁶ rendering the diagnosis of EBV-positive plasmacytoma.

In conclusion, a subset of plasmacytoma is EBV-positive, even when the patient is immunocompetent. It is pivotal to carefully differentiate EBV-positive plasmacytoma from PBL because of their distinct prognoses and therapeutic options. At present, the distinction between EBV-positive and EBV-negative plasmacytoma appears to be clinically insignificant, with comparable overall survival; however, further case-series studies are required.