Epstein-Barr Virus-Positive Primary Cutaneous Diffuse Large B-Cell Lymphoma in an Immunocompetent Patient

Dear Editor:

Epstein-Barr virus (EBV) is known to induce a number of malignancies, including diffuse large B-cell lymphoma (DLBCL) in immunosuppressed patients. Recently, however, age-related immune impairment was recognized as a predisposing factor in the development of EBV-driven lymphoproliferative processes in elderly patients1. Herein, we present a case of EBV-positive primary cutaneous DLBCL in an immunocompetent patient.

A 66-year-old woman presented with a 6-month history of multiple erythematous macules and patches on her trunk and both extremities (Fig. 1). There was no specific past history except for hypertension. A skin biopsy was performed and histological examination of the specimen revealed multifocal and nodular infiltrates of atypical medium- and large-sized mononuclear cells with enlarged nuclei showing one or more prominent nucleoli (Fig. 2A, B). Immunohistochemical examination revealed that the tumor cells were positive for CD20, bcl-2 and latent membrane protein 1 (LMP1), but negative for CD3, CD5, CD10, CD30, and bcl-6. In situ hybridization for EBV-encoded RNA (EBER) was positive in the majority of tumor cells (Fig. 2C). Bone marrow biopsy revealed no lymphomatous involvement. Based on these findings, the patient was diagnosed with EBV-positive primary cutaneous DLBCL. She was treated with combination chemotherapy (R-CHOP) and reached complete remission. After a year, however, the disease recurred. She was treated with radiotherapy, but the disease progressed.

Fig. 1
Multiple erythematous macules and patches were observed on her trunk (A) and both extremities (B).

• Click for larger image

Fig. 2
(A, B) Skin biopsy revealed multifocal and nodular infiltrates of atypical medium- and large-sized mononuclear cells with enlarged nuclei showing one or more prominent nucleoli (H&E; A: ×40, B: ×400). (C) In situ hybridization for Epstein-Barr virus-encoded RNA was positive in the majority of tumor cells (×200).

• Click for larger image

Primary cutaneous DLBCL is a malignant proliferation of large B cells, presenting primarily in the skin with solitary or clustered erythematous or reddish-brown tumors. Histologically, dense diffuse infiltrates characterized by predominance of large cells with round nuclei are observed. Tumor cells express B-cell markers (CD20, CD79a). Most of the cases are positive for bcl-2 protein and multiple myeloma oncogene-1 (MUM-1), but are negative for CD10. EBV-related primary cutaneous DLBCL in non-immunocompromised patients is extremely rare. So far, only 11 cases have been reported1. All of the cases in the literature were of DLBCL except for 1 case. All of the cases of DLBCL occurred in elderly patients (over 55 years), presenting more frequently with multiple lesions at various locations. Many cases of DLBCL required combination chemotherapy, although one case underwent spontaneous remission1.

Immunohistochemistry and in situ hybridization are the most important tests for the diagnosis of EBV-positive DLBCL. The tumor cells are usually positive for CD45 as well as for B-cell markers such as CD20, CD19, CD79a, and PAX-5. The cases are usually negative for germinal center markers, CD10 and bcl-6, and frequently positive for MUM-1. EBV-associated latent antigens such as LMP1 and EBNA-2 are positive in 94% and 28% of cases, respectively. Moreover, up to 50% of cases express CD30 but are negative for CD15. EBER in situ hybridization is the most reliable method for the diagnosis of EBV-positive DLBCL. It has the highest diagnostic sensitivity in the diagnosis of EBV-positive DLBCL2.

So far, the prognosis of the newly recognized subtype of DLBCL remains in doubt, and there is no uniformly accepted treatment due to the small number of reported cases. On the basis of several literatures, EBV-positive DLBCLs seem to have worse response to chemotherapy than EBV-negative DLBCLs3-5. However, the response to rituximab-containing regimens has not yet been properly evaluated, and further studies are needed to clarify the role of rituximab and EBV-targeted therapy in EBV-positive DLBCL2.

The proportion of EBV-related DLBCL cases in the elderly may be higher than that estimated at present. Therefore, we propose that EBV expression should be assessed in primary cutaneous DLBCLs. More information needs to be obtained regarding this new entity and further investigation is necessary.