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7 December 2016 - Case of the Week #409

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Case of the Week #409

Clinical history:
An 80 year old man with myasthenia gravis, treated for 10 years with azathioprine and prednisone, presented with a subacute gait disturbance and cognitive impairment. Magnetic resonance imaging (MRI) showed a poorly delimited lesion next to the posterior horn of the right lateral ventricle, with significant edema and mass effect and peripheral enhancement after gadolinium administration. Thoraco-abdominal CT showed only an asymptomatic pulmonary embolism. Despite high dose intravenous steroids and broad spectrum antibiotics, his neurologic status declined rapidly, affecting motor balance. The patient died within 2.5 months of the onset of symptoms, and definitive diagnosis was made at autopsy.

Gross images:

Micro images:

What is your diagnosis?

Epstein Barr Virus associated diffuse large B cell lymphoma (EBV associated DLBCL) of the central nervous system (formerly included under Primary CNS lymphoma), see editorial comment below


Special stains were obtained:







Although EBV associated DLBCL may occur at any anatomical site, there seems to be a predilection for the brain. Active EBV infection is usually acquired during childhood infectious mononucleosis, and eventually enters a latent phase with viral DNA persisting as episomes in the nuclei of B lymphocytes. Immunosuppression triggers uncontrolled proliferation of EBV infected B cells (Pathobiology 2013;80:310).

Historically most cases occurred in immunocompromised individuals, typically AIDS patients. However, the introduction of highly active anti retroviral therapy (HAART) has dramatically decreased these cases, raising the proportion due to iatrogenic immunosuppression for organ transplantation or autoimmune disorders such as myasthenia gravis. Rarely, EBV associated DLBCL may develop in individuals with no known primary or secondary immune deficiency, and is termed EBV positive DLBCL of the elderly for those age 50+ years (J Neuropathol Exp Neurol 2014;73:478).

The micrographs show a tumor composed of sheets of pleomorphic, round, dyscohesive cells with large nuclei and moderate eosinophilic cytoplasm. Mitotic figures and apoptotic bodies are extremely common and there is extensive necrosis. There is a prominent angiocentric and angiodestructive growth pattern, particularly at the periphery of the tumor masses, with tumor cells seeming to accumulate in the perivascular space, where they infiltrate and destroy vessel walls. CD20, a marker of mature B cell lineage, stains the tumor cells diffusely, and CD3 and CD5 highlight the small population of reactive T lymphocytes. EBER-SISH highlights the tumor cell nuclei (marker for EBV encoded RNA) and the Ki-67 proliferative index is extremely high.

Clinically, these patients may present with a wide variety of symptoms depending on the extent and anatomical location of the lesion in the brain, including those suggestive of space occupying / mass lesion. The diagnosis may be difficult in small biopsies due to extensive necrosis, and it is imperative for the pathologist to seek out any clinical history which may bring this entity to the forefront in the differential diagnosis.

Ancillary studies may be helpful even in necrotic material in experienced hands (J Neuropathol Exp Neurol 2014;73:478). Although historically high dose steroids were thought to cause "vanishing lymphoma" (Int J Clin Exp Pathol 2015;8:7798), recent studies have challenged this assumption, demonstrating that a diagnosis was still possible in a most cases following steroid therapy (Can J Neurol Sci 2016;43:721, Ann Neurol 2008;63:662).

Apart from the acquisition of biopsy material, surgical resection offers no benefit, and the role of radiation as a single treatment modality is limited to cases with incipient cerebral herniation. Protocols utilizing combined modalities (high dose methotrexate in combination with CNS penetrating agents followed by whole brain irradiation) have shown promise in certain settings, as has recombinant monoclonal chimeric anti-CD20 monoclonal antibody therapy (rituximab, Blood 2013;122:2318).

The differential diagnosis of a mass forming lesion in the elderly, immunosuppressed population includes:

Primary CNS malignancies, typically glioma.
Metastatic carcinoma: clinical history, cohesive pattern of growth, expression of keratins and other lineage specific markers.
Other lymphomas, including CNS T cell lymphoma: may also demonstrate perivascular growth pattern with cells spilling into surrounding tissue, but are not EBV or immunosuppression associated. T cell markers highlight intermediate sized T cells with cytologic atypia, and may demonstrate loss of certain pan T cell markers (CD5, CD7); demonstration of clonal rearrangement of T cell receptor may be critical in reaching a definitive diagnosis.
Brain abscess / infection (e.g. Toxoplasmosis): lacks highly atypical lymphoid population with prominent perivascular pattern; serological studies suggest infection, organisms appreciated on special stains.

Editorial Comment:
The term "primary CNS lymphoma" is now restricted to primary B cell lymphoma confined to the CNS (+/- eye) in immunocompetent patients. Excluded are lymphomas of the dura, intravascular large B cell lymphoma, lymphoma with evidence of systemic involvement / secondary disease and lymphoma in immunocompromised hosts, such as this one (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th ed, 2008).

Discussion by: Dr. Belinda Lategan, St. Boniface Hospital (Canada)

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