Clinical Review & Education

JAMA Clinical Challenge

Multiple Cerebral Infarctions
and Intracranial Vessel Abnormalities
Eline A. Oudeman, MD; Catharina J. M. Frijns, MD, PhD; Catharina J. M. Klijn, MD, PhD

A Brain magnetic resonance imaging (MRI)

B Digital subtraction angiography

Figure 1. A, Axial MRI using fluid-attenuated inversion recovery (left)
demonstrating hyperintense multifocal lesions involving mainly the subcortical
white matter; axial diffusion-weighted MRI (right) showing hyperintense lesions
consistent with recent infarctions. B, Digital subtraction angiography of the

intracranial vessels showing widespread areas of vessel wall irregularity, which
consist of zones of focal stenosis and luminal tapering in many third-order and
fourth-order branches.

Several months before being admitted to the hospital, a 65-yearold woman noted relapsing fevers, night sweats, fatigue, and a 16-kg
weight loss. In the weeks before her hospital admission, she developed subacute cognitive deterioration and
progressive headaches. On presentation
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she has difficulties initiating speech (nonfluent aphasia) and responds slowly and inconsistently to questions.
Otherwise, her physical examination is unremarkable. Laboratory
studies reveal an elevated erythrocyte sedimentation rate (ESR)
(135 mm/h), anemia (hemoglobin level, 9.5 g/dL), and high serum levels of soluble interleukin 2 receptor (sIL2R) (36 551 pg/mL), lactate dehydrogenase (LDH) (448 U/L), and β2-microglobulin (3.1 mg/L), with
normal renal function, liver enzyme levels, and serum immunological
and microbiological findings. Analysis of the cerebrospinal fluid (CSF)
demonstrates a mildly increased leukocyte count (11 × 106/L) and total
protein concentration (0.10 g/dL). Magnetic resonance imaging of the
brain shows multiple infarctions, and digital subtraction angiography
of the intracranial vessels demonstrates abnormalities suggestive of vasculitis (Figure 1). An electrocardiogram, computed tomography scans
of the chest and abdomen, 18-fluorodeoxyglucose positron emission
tomography, transesophageal echocardiography, inspection of the skin,
and ophthalmologic evaluation are unremarkable.
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WHAT WOULD YOU DO NEXT?

A. Initiate secondary preventive treatment for multiple infarctions with antiplatelet agents.
B. Initiate treatment for cerebral vasculitis with corticosteroids.
C. Postpone treatment; obtain a brain biopsy including the leptomeninges.
D. Postpone treatment; obtain random
skin biopsies and a bone marrow biopsy.

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JAMA Clinical Challenge Clinical Review & Education

Diagnosis
Intravascular large B-cell lymphoma of the central nervous system
(CNS).

A

B

What to Do Next
D. Postpone treatment; obtain random skin biopsies and a bone marrow biopsy.
The key clinical features in this case are the need for pathological confirmation of the diagnosis and the low positive predictive value
of digital subtraction angiography for cerebral vasculitis. In addition
to the neurologic findings, the presence of systemic illness and laboratory findings suggest a diagnosis of intravascular CNS lymphoma.
This diagnosis can be confirmed with skin or bone marrow biopsy.1,2

Discussion
Intravascular large B-cell lymphoma is a systemic disease typically occurring in elderly patients (median age, 67 years).2 Previously known
as “neoplastic angioendotheliomatosis,” the disease is characterized by
multifocal proliferation of pleomorphic large lymphoid cells within mediumtosmallvessels.3 Vesselwallsandtissuessurroundingtheinvolved
vesselsarespared,andlymphadenopathyisusuallyabsent.3 Thetumor
may possibly originate from post–germinal center cells.2 Immunophenotyping usually identifies the tumor cells as mature B cells, although
there are reports of T-cell or natural killer-cell tumor types.2
In Western countries, the CNS and skin are most frequently involved,althoughalmosteveryotherorgancanbeaffected.2-4 Fifty-five
percentto85%ofpatientspresentwithconstitutionalB-cellsymptoms
(fevers, night sweats, and weight loss) together with symptoms attributabletoocclusionofsmallvesselsofaffectedorgans.5 CNSinvolvement
canpresentasfocalneurologicdeficits,alterationofconsciousness,seizures, or rapidly progressive dementia. The most common laboratory
abnormalities are anemia, elevated ESR, and elevated serum levels of
sIL2R, LDH, and β2-microglobulin.2 With intravascular CNS lymphoma,
analysis of CSF usually shows a mildly increased leukocyte count and
proteinconcentration.Flowcytometricimmunophenotypingandconventional cytologic examination of the CSF are typically unrevealing.
The diagnosis of intravascular large B-cell lymphoma is confirmed
by cutaneous lesion or random biopsy of normal skin, bone marrow
biopsy, or biopsy of other sites of suspected involvement such as the
brain.2,6 Because vessels containing intravascular lymphoma are
mainly located in the subcutaneous fat, subcuticular tissues should
be included in skin biopsies.6 Patients with vascular disease are frequently treated with antiplatelet agents, but these should be avoided
if brain biopsy is being considered. Corticosteroids may mask cliniARTICLE INFORMATION
Author Affiliations: Department of Neurology and
Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands.
Section Editor: Huan J. Chang, MD, Associate Editor.
Corresponding Author: Eline A. Oudeman, MD,
Department of Neurology and Neurosurgery, University Medical Center Utrecht, PO Box 85500, 3508 GA
Utrecht, the Netherlands (e.a.oudeman@gmail.com).
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Klijn
reported receiving grants from the Netherlands
Heart Foundation and the Brain Foundation. No
other disclosures were reported.

Figure 2. Left occipital brain biopsy specimen (original magnification ×200). A,
Hematoxylin-eosin stain showing large, atypical, pleomorphic cells with large nuclei
within the capillaries. B, Tumor cells in the vessel are highlighted (brown) by immunohistochemical staining for CD20 capillaries.

cal symptoms and may reduce the chances of identifying the pathology in biopsy specimens. Awaiting the effect from these treatments
will also lead to a delay in diagnosis.
Because intravascular lymphoma is not common and has inconsistent clinical presentations, it is often difficult to establish the diagnosis
antemortem.5 Because clinical trials for intravascular large B-cell lymphoma are lacking, treatment recommendations are based on results
from studies of other, more common lymphomas. Treatment for intravascular lymphoma usually consists of cyclophosphamide, doxorubicin, vincristine, prednisone, and the recombinant anti-CD20 antibody
rituximab (R-CHOP). Intrathecal chemotherapy (prophylactic or therapeutic) directed toward the CNS is also appropriate.2,3 The prognosis
ofintravascularlymphomahasimprovedsincetheadditionofrituximab
to chemotherapy. Three-year survival rates now range from 53% to
81%.2 Long-term survival is possible and is more likely when the diagnosis is made early and treatment is initiated early.2

Patient Outcome
Deep skin biopsies at 2 different locations of clinically unaffected skin
and bone marrow biopsy showed no abnormalities. A biopsy of the
left occipital lesion demonstrated proliferation of large atypical lymphoid cells in the vessels, producing luminal obstruction surrounded
by necrotic lesions consistent with cerebral infarctions (Figure 2A).
The neoplastic cells were positive for CD20 and CD79a and negative
for CD5 (Figure 2B), which confirmed the diagnosis of intravascular
largeB-cellcentralnervoussystemlymphoma.Thepatientwastreated
with R-CHOP chemotherapy and intrathecal methotrexate. Her aphasia and cognitive functioning improved within several days after treatment initiation. After 6 months, her aphasia had recovered almost
completely, but some residual cognitive impairment persisted.

Additional Contributions: We thank L. J. Kappelle
(Brain Center Rudolf Magnus) for his thoughtful
reviews of the manuscript and W. G. M. Spliet
(Department of Pathology, University Medical
Center Utrecht) for his help in analyzing the
specimens. We thank the patient and her guardian
for providing permission to share her information.

3. Zuckerman D, Seliem R, Hochberg E.
Intravascular lymphoma: the oncologist’s “great
imitator.” Oncologist. 2006;11(5):496-502.

REFERENCES
1. Kadkhodayan Y, Alreshaid A, Moran CJ, et al.
Primary angiitis of the central nervous system at
conventional angiography. Radiology.
2004;233(3):878-882.

5. Ferreri AJ, Campo E, Seymour JF, et al.
Intravascular lymphoma. Br J Haematol.
2004;127(2):173-183.

2. Shimada K, Kinoshita T, Naoe T, Nakamura S.
Presentation and management of intravascular
large B-cell lymphoma. Lancet Oncol.
2009;10(9):895-902.

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4. Ponzoni M, Ferreri AJ, Campo E, et al. Definition,
diagnosis, and management of intravascular large
B-cell lymphoma. J Clin Oncol. 2007;25(21):31683173.

6. Matsue K, Asada N, Odawara J, et al. Random
skin biopsy and bone marrow biopsy for diagnosis
of intravascular large B cell lymphoma. Ann
Hematol. 2011;90(4):417-421.

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