Central nervous system intravascular lymphoma leading to rapidly progressive dementia

Abstract

Intravascular lymphoma is an uncommon subtype of B-cell lymphoma with neoplastic cells limited to the lumen of small blood vessels. We report a case of a 52-year-old man who presented with constitutional symptoms and rapidly progressive dementia. He was found to have diffuse leptomeningeal and faint parenchymal enhancement on magnetic resonance imaging and was subsequently diagnosed with intravascular lymphoma following a brain biopsy. He responded remarkably well to systemic and intrathecal chemotherapy. The diagnosis and treatment of intravascular lymphoma have been guided by a few case reports and are largely based on expert opinion.

Intravascular lymphoma (IVL) is a rare subtype of B-cell lymphoma characterized by proliferation of neoplastic cells within the lumen of small blood vessels. Patients with central nervous system (CNS) IVL often present with heterogeneous neurological symptoms and have nonspecific neuroimaging findings. Given the diversity of symptoms and remarkably low yield from laboratory testing and imaging, the diagnosis remains a challenge. When faced with a worrisome clinical picture of neurologic decline and nonspecific but clearly inflammatory brain imaging findings, an early brain biopsy could be lifesaving. We present an unusual case of a patient with rapidly progressive dementia caused by IVL, with review of imaging, pathology, and treatment.

CASE DESCRIPTION

A 52-year-old man was admitted with a 3-month history of a 50-pound unintentional weight loss, fever, and progressive impairment in walking and speech. On admission, he was cachexic with mild scleral icterus and slow cognitive processing. He declined quickly, and shortly after admission he began to have fever (Tmax 102.8°F) and progressed to a global aphasia with paratonic rigidity and hyperreflexia. Cranial computed tomography showed generalized volume loss and chronic ischemic changes.

The initial laboratory evaluation was notable for mild transaminitis and negative hepatitis panel and serum HIV test. He was found to have a low positive rapid plasma reagin (1:4 titer) with positive serum treponemal antibody, high lactate dehydrogenase (638 U/L), elevated ferritin (2148 ng/mL), and elevated erythrocyte sedimentation rate (97 mm/hr). His cerebrospinal fluid was notable for 3/µL leukocytes, 11/µL red blood cells, glucose 56 mg/dL, protein 262 mg/dL, and reactive Venereal Disease Research Laboratory test (1:1 titer). Broad-spectrum antibiotics were replaced with intravenous benzathine penicillin G for presumed neurosyphilis; however, he continued to decline. Repeat cerebrospinal fluid analysis showed 10/µL leukocytes (92% lymphocytes), glucose 68 mg/dL, and protein 437 mg/dL. Cytology was negative.

Magnetic resonance imaging (MRI) of the brain showed diffuse leptomeningeal enhancement and multifocal areas of punctate diffusion restriction in the bilateral subcortical white matter with faint contrast enhancement (Figure 1). Magnetic resonance angiography of the intracranial vessels was normal. Meningeal biopsy demonstrated large atypical intraluminal cells distending vessels without granulomatous inflammation. The cells were strongly CD20 immunoreactive, indicative of IVL (Figure 2). Bone marrow biopsy revealed large B cell lymphoma involving 5% to 10% of the bone marrow.

Figure 1.

MRI of the brain and lumbar spine. T1 post-contrast MRI sequence of the brain, (a) axial view and (b) coronal view, showing diffuse leptomeningeal enhancement and punctate hyperintensities in the subcortical white matter. T1 post-contrast MRI sequence of the lumbar spine showing (c) leptomeningeal enhancement of the distal spinal cord in the sagittal view and (d) cauda equina in the axial view, as indicated by white arrows.

Figure 2.

Brain biopsy, which consists of cortex and white matter with mild gliosis and occasional perivascular mature lymphocytes. The large vessels (in circle) at the periphery contain large atypical intraluminal cells, which distend the vessels. Hematoxylin-eosin stain, (a) 100× magnification, (b) 400× magnification. (c) Large atypical intraluminal cells are highlighted by immunohistochemical stain CD20, indicative of hematolymphoid B-cell origin. CD20, 200× magnification.

After he started rituximab, high-dose methotrexate, and cytarabine with intrathecal methotrexate 12 mg, his cognitive function improved quickly. After the second cycle, he was switched to rituximab-hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) for cycles 3 to 8 with intrathecal methotrexate chemotherapy on cycles 5 to 8. Follow-up bone marrow biopsy was normal, and repeat brain MRI showed resolution of the leptomeningeal enhancement.

DISCUSSION

This case illustrates a rare cause of rapidly progressive dementia resulting from IVL. If patients are not diagnosed and treated early, life expectancy is <1 year, and in many cases the diagnosis may be postmortem.¹ In a retrospective cohort of 740 patients, predictors of poor outcomes were age ≥70 years, lactate dehydrogenase ≥700 IU/L, and CNS disease.¹ Neurological symptoms, seen in 41% of patients with IVL, may include progressive cognitive decline, stroke, or seizures.² Other common initial sites of disease are skin, bone marrow, spleen, and lungs. Hepatic involvement has been described in only 1% of the cases.¹

The leptomeningeal and parenchymal enhancement seen in the MRI is not specific for IVL and requires consideration of infectious or autoimmune meningoencephalitis. While neurosyphilis may cause leptomeningeal enhancement, it would not explain this patient’s constitutional symptoms and lack of treatment response. Brain biopsy remains an important part of the diagnostic evaluation for rapidly progressive dementia, particularly when low positive serologies fail to yield a diagnosis that adequately represents the pathology. One retrospective study found that of patients with rapid cognitive decline of unknown origin who underwent brain biopsy, 26% were positive for CNS lymphoma and around 40% of the biopsies led to a change in management.³ The brain biopsy in IVL typically shows small vessels filled with lymphoma cells (CD20+) and perivascular reactive lymphocytes, as seen in this case.

Treatment of IVL consists of combined anthracycline-based systemic chemotherapy, which remains the cornerstone of therapy,^4–7 and intrathecal chemotherapy. Patients who receive rituximab double their median survival rate.¹ Intrathecal methotrexate-based chemotherapy with rituximab is currently considered the first line of treatment for IVL.⁷ Our patient’s chemotherapy was switched to rituximab plus hyper-CVAD due to concern for systemic disease, given he had bone marrow involvement. Hyper-CVAD was found to be superior to other regimens, with higher complete remission rates and lower CNS relapse.⁸ In this case, the patient had sustained remission with normal neurocognitive function at 4 months from treatment. We rarely think of CNS IVL as part of a differential for unexplained acute dementia, although given the difficulty in securing a diagnosis, an early brain biopsy may be the best approach in these circumstances.