December 2016

A 74 year old woman with fatigue

Stephanie Wright, MD, and David Howell, MD, PhD


A 74 year old woman with no significant past medical history has a 3 month history of gradually increasing fatigue, and episodes of sweating at night. Physical exam reveals bilateral cervical lymphadenopathy. An excisional biopsy of a cervical lymph node was performed.

Gross and Microscopic Description

The lymph node is diffusely effaced by a polymorphous infiltrate, consisting of small lymphocytes and large immunoblastic cells with prominent central nucleoli. No residual normal nodal architecture remains.

Image 1) H&E, 40X: Nodal effacement by polymorphous infiltrate.
Image 2) IHC, 40X: Small lymphocytes are CD3 positive.
Image 3) IHC, 40X: CD20 highlights large immunoblastic cells
Image 4) ISH, 40X: The large cells are EBER-positive.

The large cells stain positive with CD20, Pax5, and EBER, and they are negative for CD10, bcl6, CD5, CD30, CD15, and CD138.


What is the most likely diagnosis?


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In the 2008 WHO classification, this entity was called EBV-positive diffuse large B-cell lymphoma of the elderly, and could only be diagnosed in patients over the age of 50. In the 2016 WHO update, this entity is classified as EBV-positive DLBCL, NOS, as more cases are being recognized in patients who are younger than the prior arbitrary age cutoff. 1,2

The Epstein-Barr virus is the etiologic agent of infectious mononucleosis. The virus is ubiquitous, with upwards of 95% of the world’s population having had exposure.2-4 EBV is transmitted through saliva, and initially infects the epithelial cells of the oropharynx. The virus establishes a lytic cycle which shunts the host’s cellular processes toward replication of the complete virion, with eventual lytic destruction of the cell.2-4 Acute infection may not be clinically apparent. Latent infection occurs when the virus infects the B-cells of Waldeyer’s ring within the oropharynx. Instead of active viral replication, the virus utilizes a limited number of essential gene products to establish a viral epitope, which is replicated in tandem with the host cell’s DNA during cellular division.2-4 One of the gene products is a constitutionally active latent membrane protein, LMP1, which activates the NF-KB pathway, leading to upregulation of Bcl-2, an antiapoptotic protein which serves to “immortalize” the infected B-cells. This effect of LMP1 is thought to provoke oncogenesis.2

Latent EBV is associated with a variety of lymphoid neoplasms, which have three distinct patterns of expression of latency proteins.4 Type I is expressed in Burkitt lymphoma, and has the minimum number of EBV proteins required for maintenance of the viral genome, which includes EBNA1 and EBER. Latency pattern II adds membrane proteins LMP1 and 2, and is expressed in Hodgkin lymphoma. The complete expression of latency genome proteins characterizes latency pattern III which is seen most commonly with malignancies associated with immunodeficient states, including post-transplant lymphoproliferative disorders and HIV-associated lymphomas. EBV+DLBCL most commonly demonstrates latency pattern III. Immunosenescence predisposes older patients to this entity, which is why its latency profile most closely resembles lymphomas of immunodeficiency.2-4

EBV+DLBCL may be monomorphic or polymorphic.  This case is polymorphic, with small bland T-cells surrounding large immunoblastic B-cells, with thick nuclear membranes and prominent nucleoli. They are of the non-germinal-center, activated-B-cell type (CD10 and Bcl6 negative). EBV+DLBCL can be of the germinal center type, and this does not affect the prognosis.2 The B-cells in this case closely resemble Reed-Sternberg cells of Hodgkin lymphoma. ICH may be necessary to differentiate these neoplasms, as RS cells are CD15 positive and CD20 negative, while the B-cells of EBV+DLBCL are CD20 positive and CD15 negative. A notable pitfall is that both DLBCL and HL can have CD30 and EBER positivity.2,5-6 Another confounding differential is infectious mononucleosis. The reactive B-cells of IM share the markers of EBV+DLBCL, therefore it is critical to evaluate the architecture at low power. Maintenance of nodal architecture suggests IM, while a diagnosis of EBV+DLBCL requires the diffuse effacement of the lymph node.5-6

The current treatment strategy for EBV+DLBCL is R-CHOP, however, this neoplasm is largely resistant to chemotherapy, and has a poorer prognosis than typical DLBCL. New therapies are being sought out, focusing on shifting the EBV from the latent program into an active lytic cycle, which would allow it to be affected by antiviral drugs.2,4


1) Swerdlow S, Campo E, Pileri S, et al. 2016 WHO Classification of Lymphoid Neoplasms. Blood. 2016; prepublished online. doi:10.1182/blood-2016-01-643569

2) Ok C, Papathomas T, Medeiros L, Young K. EBV-positive diffuse large B-cell lymphoma of the elderly. Blood. 2013; 122 (3): 328-340. doi:10.1182/blood-2013-03-489708

3) Sullivan J, Luzuriaga K. Virology of Epstein-Barr virus. Last updated 10/21/2015.

4) Neparidze N, Lacy J. Malignancies Associated With Epstein-Barr Virus: Pathobiology, Clinical Features, and Evolving Treatments. Clin Adv Hematol Oncol. 2014; 12(6): 358-371.

5) Ioachim H, Ratech H. Ioachim’s Lymph Node Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.

6) Swerdlow S, Campo E, Harris N, et al. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon 2008.