Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al5 and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.2 It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.6 Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.7 It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.4,8
Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.6 A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.6,9 Rare cases of primary cutaneous involvement also have been described.7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.4 Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.12 Detection of EBV by in situ hybridization is required for the diagnosis.
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.13
Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.14 Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.8 Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.4 Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.15 No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.13,15 Further studies are required to determine optimal treatment strategies.
Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.