When a Reactive Process Wasn't Reactive: EBV-Positive Diffuse Large B-Cell Lymphoma Unveiled

Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified (EBV-positive DLBCL), is an aggressive lymphoid malignancy that may resemble infectious mononucleosis or a reactive EBV-associated lymphoproliferative process. Diagnosis may be particularly challenging when initial limited tissue sampling is nondiagnostic or when prominent atypical T cells raise concern for a separate T-cell neoplasm.

A 69-year-old woman with a remote history of ductal carcinoma in situ presented with approximately more than 6 months of progressive fatigue, poor appetite, and a 32-pound unintentional weight loss. Several months earlier, she had developed bilateral cervical lymphadenopathy. A needle biopsy of a left cervical lymph node was negative for malignancy, and her clinical presentation was initially attributed to EBV reactivation with infectious mononucleosis. Although the cervical lymphadenopathy improved, her constitutional symptoms persisted.

Further evaluation revealed new pelvic lymphadenopathy. PET/CT revealed extensive, intensely hypermetabolic lymphadenopathy involving the neck, chest, abdomen, and pelvis, with splenic involvement and multiple FDG-avid subcutaneous nodules, raising strong concern for a disseminated lymphoid malignancy. Because of the progressive clinical and radiographic findings despite the initially negative biopsy, an excisional biopsy of an axillary lymph node was performed.

Initial examination of the axillary lymph node revealed an atypical EBV-positive lymphoid proliferation. In addition to the abnormal B-cell population, a prominent atypical T-cell proliferation raised concern for a possible concurrent T-cell lymphoma. Given the complex findings, the specimen was referred for expert hematopathology review.

Expert review revealed  EBV-positive large B-cell neoplasm arising in a background of atypical T-cell proliferation. The neoplastic B cells expressed PAX5, CD30, BCL2, and MUM1 and showed diffuse EBV positivity, while CD10, BCL6, BCL1, CD15, and ALK were negative. These findings established the diagnosis of EBV-positive DLBCL. The accompanying atypical T-cell population was favored to represent a reactive process associated with the EBV-positive B-cell lymphoma rather than a separate T-cell malignancy.

Given extensive nodal disease above and below the diaphragm with splenic involvement, the lymphoma was classified clinically as stage IV. The patient was started on curative-intent R-CHOP with growth-factor support. Treatment is being continued with close monitoring.

This case shows how EBV-positive diffuse large B-cell lymphoma can masquerade as reactive EBV infection, particularly early in its course. Persistent B symptoms and progressive lymphadenopathy despite initially reassuring pathology should prompt repeat excisional biopsy. Close collaboration between clinicians and expert hematopathologists is critical for distinguishing reactive EBV-associated changes from aggressive lymphoma and ensuring timely initiation of curative-intent chemoimmunotherapy.