Review Article

Primary CNS Lymphoma

and Neurologic
Complications of
Hematologic
Malignancies
Lakshmi Nayak, MD; Elena Pentsova, MD;
Tracy T. Batchelor, MD, MPH
ABSTRACT
Purpose of Review: This article provides a practical clinical approach to diagnose
primary CNS lymphoma and recognize neurologic complications of lymphomas and
leukemias. This includes current diagnostic and treatment recommendations for primary
CNS lymphoma and complications related to hematologic malignancies.
Recent Findings: Primary CNS lymphoma is an uncommon, aggressive non-Hodgkin
lymphoma confined to the CNS in the absence of systemic disease. Diagnosis can be
made by brain biopsy, CSF analysis, or vitreous fluid analysis. Primary CNS lymphoma is
typically diffuse large B cell in histology. Evaluation of extent of disease should be
performed before initiation of therapy. Initial induction treatment includes high-dose
methotrexateYbased chemotherapy. Several studies have demonstrated improved outcome using consolidative whole-brain radiation therapy or high-dose chemotherapy and
autologous stem cell transplantation. Neurologic complications can result from direct or
indirect effects of leukemia and lymphoma or may be treatment-induced.
Summary: Early diagnosis and treatment of patients with primary CNS lymphoma is
critical to maintaining neurologic and cognitive function and preserving quality of life. It
is important to recognize neurologic complications from leukemia and lymphoma to
avoid delays in instituting appropriate treatment.

Address correspondence to
Dr Lakshmi Nayak, Dana Farber
Cancer Institute, Center for
Neuro-oncology, 450 Brookline
Avenue, DA2120, Boston,
MA 02215,
Lakshmi_Nayak@dfci.harvard.edu.
Relationship Disclosure:
Dr Nayak has served on the
advisory board of Amgen Inc.
Dr Pentsova reports no
disclosure. Dr Batchelor has
served as a consultant for
Advance Medical; Agenus Inc;
Amgen Inc; Champions
Oncology, Inc; Kyowa Hakko
Kirin Pharma, Inc; Merck &
Co, Inc; Novartis AG;
Proximagen; Roche; and
Spectrum Pharmaceuticals,
Inc. Dr Batchelor has received
personal compensation for
speaking engagements from
Educational Concepts Group,
Incorporated; Imedex;
Research To Practice; and
RMEI, LLC; and for preparation
of educational materials from
UpToDate, Inc, and Oakstone
Publishing, LLC. Dr Batchelor
received research support from
AstraZeneca; Millennium
Pharmaceuticals, Inc; and
Pfizer Inc.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Nayak, Pentsova,
and Batchelor
report no disclosures.
* 2015, American Academy
of Neurology.

Continuum (Minneap Minn) 2015;21(2):355372.

INTRODUCTION
Primary CNS lymphoma is an aggressive
cancer, seen more commonly in immunocompetent patients over 65 years of
age. Histopathologic confirmation by
brain biopsy, CSF analysis, or vitreous
fluid analysis is important before starting treatment. Historically, whole-brain
radiation therapy was a treatment option. The addition of high-dose methotrexate to whole-brain radiation therapy
has improved survival in primary CNS lymphoma. However, long-term neurotoxicity
Continuum (Minneap Minn) 2015;21(2):355372

related to radiation therapy remains the

major concern in patients achieving longterm survival. Recent studies have focused
on reduced-dose whole-brain radiation
therapy and CNS-penetrating highdose chemotherapy followed by autologous stem cell rescue.
Neurologic complications of systemic
lymphoma and leukemia can be devastating. CNS involvement can occur as
a direct effect and is more common
at lymphoma or leukemia relapse. The
peripheral nervous system can also be
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355

CNS Lymphoma and Hematologic Malignancies

KEY POINTS

h Histopathologic diagnosis
of primary CNS lymphoma
can be made by
stereotactic brain biopsy,
CSF cytologic analysis, or
flow cytometry in patients
with leptomeningeal
involvement, or by
vitrectomy or chorioretinal
biopsy in those with
intraocular lymphoma.

h It is recommended to
avoid pretreatment with
corticosteroids before
biopsy when a diagnosis
of primary CNS lymphoma
is considered, as their
use can interfere with
histopathologic diagnosis.

h In more than 90% of

primary CNS lymphoma
cases, the histology
is diffuse large
B-cell lymphoma.

involved; this is seen typically with plasma

cell disorders. Indirect effects of leukemia
and lymphoma can result in vascular, infectious, and paraneoplastic complications.
This article details the clinical features,
diagnosis, and treatment of primary CNS
lymphoma and neurologic complications
of lymphoma and leukemia.

and thalamus, although any part of the

brain can be involved. Nonenhancing
lesions are rare. Primary CNS lymphoma
is a highly cellular tumor. The diffusionweighted MRI derived apparent diffusion coefficient (ADC) is influenced by
the extent of cellular density and may
correlate with outcome.3

PRIMARY CNS LYMPHOMA

Primary CNS lymphoma is a rare and
aggressive extranodal non-Hodgkin lymphoma confined to the CNS (brain, spinal
cord, leptomeninges, or eyes) without
concurrent or prior systemic lymphoma.
It accounts for less than 3% of all primary
CNS tumors. The median age at diagnosis
is 65 years, with an increasing incidence
in the elderly since 2000.1

Diagnosis
Histopathology. The histopathologic diagnosis can be made by stereotactic brain
biopsy, CSF cytologic analysis, or flow
cytometry in patients with leptomeningeal
involvement, or by vitrectomy or chorioretinal biopsy in those with intraocular
lymphoma. As delay in diagnosis may
compromise patient outcomes, stereotactic biopsy is advisable when an enhancing brain lesion is present.4 Additionally,
it is recommended to avoid pretreatment with corticosteroids before biopsy
when a diagnosis of primary CNS lymphoma is considered as their use can
interfere with histopathologic diagnosis.
This is particularly important as corticosteroids are often routinely used in
newly diagnosed intracranial lesions to
alleviate neurologic signs and symptoms
resulting from cytotoxic edema. Radiographic response to corticosteroids may
be suggestive but not diagnostic of primary CNS lymphoma, and the differential diagnosis includes demyelinating,
inflammatory, or autoimmune conditions
or sarcoidosis.
In more than 90% of cases, the histology is diffuse large B-cell lymphoma.
Burkitt, lymphoblastic, indolent B-cell,
or T-cell lymphomas account for the rest.
Diffuse large B-cell lymphoma expresses
panYB-cell antigens, such as CD19, CD20,
and CD79a. Other markers, such as CD10,
B-cell CLL/lymphoma2 (BCL2), B-cell
CLL/lymphoma 6 (BCL6), and melanoma
associated antigen (mutated) 1 (MUM1)/
interferon regulatory factor 4 (IRF4),
may carry prognostic importance. EBV is
often detected by in situ hybridization

Clinical Features
The clinical presentation of primary CNS
lymphoma depends on the site of the
CNS involved. The majority of patients
present with focal neurologic deficits;
about one-half present with cognitive
and behavioral changes, and one-third
present with raised intracranial pressure.
Seizures are uncommon, likely because
of involvement of deep brain structures
in most patients. The majority of patients
with primary CNS lymphoma are immunocompetent. AIDS-related lymphoma
has declined with the use of highly active antiretroviral therapies, as noted in
recent population studies.2 In addition
to HIV/AIDS, Epstein-Barr virus (EBV)Y
positive CNS lymphoma may be seen in
patients with other immunocompromised
states, such as those with autoimmune
conditions on chronic immunosuppressive therapies.
Radiographic Features
Primary CNS lymphoma occurs as a solitary contrast-enhancing lesion on MRI or
CT scans in up to 70% of patients. The
most common sites are the cerebral hemispheres, corpus callosum, basal ganglia,

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April 2015

of EBV-encoded RNA in immunocompromised patients.

Extent-of-disease evaluation. The
International PCNSL Collaborative Group
(IPCG) recommends baseline staging
and provides guidelines on pathologic,
clinical, laboratory, and extent-of-disease
evaluation to rule out systemic lymphoma
and to document CSF or eye involvement (Case 5-1).5 All newly diagnosed
patients must undergo a comprehensive
physical, neurologic, and cognitive evalua-

tion. Laboratory evaluation should include

serum lactate dehydrogenase (LDH), hepatic and renal function tests, evaluation of
creatinine clearance, and a test for HIV. A
contrast-enhanced MRI or CT scan (in
patients who cannot tolerate MRI) of the
brain should be obtained, and MRI of
the total spine in those with spinal symptoms. A detailed examination by an ophthalmologist is recommended to rule
out vitreous, retinal, and optic nerve involvement. Lumbar puncture should be

KEY POINT

h The International PCNSL

Collaborative Group
(IPCG) recommends
baseline staging and
provides guidelines on
pathologic, clinical,
laboratory, and
extent-of-disease
evaluation to rule out
systemic lymphoma
and to document CSF
or eye involvement.

Case 5-1
A 68-year-old woman with a known history of hypertension and atrial fibrillation on a direct thrombin
inhibitor noted difficulty with concentration and word finding and change in handwriting over a period
of 1 week. These symptoms progressed over the next week, and she developed additional right-sided
weakness, at which point she presented to the emergency department. Head CT showed hypodensity
in the left frontal region. Subsequent brain MRI with contrast showed contrast-enhancing lesions in
the left frontal lobe extending to the corpus callosum and in the right frontal region with surrounding
T2 changes (Figure 5-1). She underwent stereotactic biopsy of the left frontal lesion, the pathology
of which was consistent with diffuse large B-cell lymphoma. Systemic workup including positron emission
tomography (PET)/CT of the chest, abdomen, and pelvis was negative for lymphoma, as was bone marrow
biopsy. Slit-lamp examination did not show evidence of intraocular lymphoma. Lumbar puncture was
performed, and CSF studies were unrevealing. Serum was tested for HIV antibodies and was negative. She
was diagnosed with primary CNS lymphoma and started treatment on a clinical trial for primary CNS lymphoma,
to which she had a complete response in the brain and complete recovery of her neurologic function.
Comment. Patients who present with brain lymphoma should undergo a rapid and thorough
workup to rule out systemic disease, including a search for intraocular and CSF involvement.

FIGURE 5-1

Imaging of the patient in Case 5-1. Brain MRI showing a contrast-enhancing lesion in the corpus callosum
on postcontrast T1-weighted image (A), dark on apparent diffusion coefficient (ADC) image (B), and
surrounding hyperintense signal change on fluid-attenuated inversion recovery (FLAIR) image (C ).

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357

CNS Lymphoma and Hematologic Malignancies

KEY POINTS

h To evaluate the extent

of disease in primary
CNS lymphoma, MRI
brain (and MRI spine,
if clinically indicated);
detailed ophthalmologic
examination (slit-lamp
examination); and
lumbar puncture for CSF
studies, including cell
count, protein,
glucose, "2-microglobulin,
cytology, flow cytometry,
and immunoglobulin
heavy chain (IgH) gene
rearrangement studies,
should be performed.

h Body positron emission

tomography (PET)/CT
bone marrow biopsy,
and testicular
ultrasound in older
men should be
performed for systemic
staging of primary
CNS lymphoma.

h Age and performance

status are two
independent baseline
prognostic variables that
influence outcome in
patients with newly
diagnosed primary
CNS lymphoma.

h High-dose
methotrexateYbased
chemotherapy is
considered the first-line
treatment for newly
diagnosed primary
CNS lymphoma.

358

performed for CSF studies, including cell

count, protein, glucose, "2-microglobulin,
cytology, flow cytometry, and immunoglobulin heavy chain (IgH) gene rearrangement studies. Body positron emission
tomography (PET)/CT, bone marrow biopsy,
and testicular ultrasound in older men
should be performed for systemic staging.
. rognostic Factors
P
In many studies, age and performance
status are two baseline prognostic variables that influence outcome in patients
with newly diagnosed primary CNS lymphoma.6 Two scoring systems, the International Extranodal Lymphoma Study
Group (IELSG) score and the Memorial
Sloan Kettering Cancer Center (MSKCC)
prognostic score, have been published
that stratify patients into three risk groups
to predict outcome and incorporate in
clinical trial design.7,8 The IELSG scoring system identifies five parameters as
poor prognostic factors: age older than
60, Eastern Cooperative Oncology Group
(ECOG) performance status greater than
1, elevated serum LDH, high CSF protein
concentration, and deep brain involvement.
The MSKCC model is based on three prognostic classes: age younger than 50, age
50 or older and Karnofsky Performance
Status Scale score greater than or equal
to 70, and age 50 or older and Karnofsky
Performance Status Scale score less than
70. A complete radiographic response
after two courses of chemotherapy is also
found to be predictive of improved overall and progression-free survival.9
Treatment
The treatment for newly diagnosed primary CNS lymphoma involves induction
and consolidation phases. Induction
treatment is the initial treatment employed to induce a remission, including a radiographic response. High-dose
methotrexateYbased chemotherapy is
typically used for induction. Despite a
complete radiographic response after

initial treatment, a high rate of recurrence

exists. Consolidation involves additional
treatment in the form of radiation, chemotherapy, or high-dose chemotherapy followed by autologous stem cell rescue to
eliminate any residual disease. The goal
of consolidation is to reduce recurrence
rates, improve overall survival rates, and
potentially cure this disease.
Surgery. The role of surgery in primary CNS lymphoma is limited to stereotactic biopsy for histopathologic
diagnosis because of the infiltrating nature of the tumor and lack of survival
benefit from resection.10,11 Recently published results from a subset analysis
of the German PCNSL Study Group-1
(G-PCNSL-SG1) trial demonstrated improved outcomes for patients with subtotal or gross total resection, although
the survival benefit was lost when adjusted for the total number of lesions.12
Other studies have not demonstrated
a survival advantage for resection. There
is not sufficient evidence to advise resection of primary CNS lymphoma.
Chemotherapy. High-dose methotrexateY
based chemotherapy is considered the
first-line treatment for newly diagnosed
primary CNS lymphoma. Doses of 3 g/m2
or more are thought to attain adequate
cytotoxic levels in CSF. Studies utilizing
single-agent high-dose methotrexate at
3.5 g/m2 to 8 g/m2 have demonstrated
objective response rates of 35% to 74%,
with a higher proportion of radiographic
responses when more than six induction
cycles are delivered.13,14 In these studies,
the median progression-free survival was
10 to 12.8 months, and median overall
survival was 25 to 55 months. The majority of the single-arm phase 2 studies
with multiagent chemotherapy have demonstrated higher durable response rates
ranging from 71% to 94% with a caveat
of higher associated toxicity.6 Various
agents have been used in conjunction
with high-dose methotrexate, including
temozolomide, rituximab, procarbazine,

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vincristine, carmustine, cytarabine, etoposide, ifosfamide, and cyclophosphamide.

Induction chemotherapy is followed
by consolidation therapy consisting of
whole-brain radiation therapy or other
types of chemotherapy. Survival rates
have varied considerably given the different regimens and doses of wholebrain radiation therapy, with median
progression-free survival ranging from
13 to 24 months and median overall
survival from 30 to 60 months. While
consensus exists on using combination
chemotherapy as induction treatment,
the choice of chemotherapy in addition to high-dose methotrexate is not
standardized. A randomized phase 2 trial
conducted in 79 patients demonstrated
improved efficacy by combining highdose cytarabine to high-dose methotrexate versus high-dose methotrexate
alone (objective response rate 69% versus
40%, P=.009). Based on the survival benefit in systemic lymphoma, recent studies
have included rituximab, a monoclonal
antibody directed against CD20, in the
induction regimen to achieve objective
response rates of 77% to 93%.4,15 The
ongoing randomized Hemato-Oncologie
voor Volwassenen Nederland/Australasian
Leukaemia & Lymphoma Group (HOVON/
ALLG) intergroup study is addressing
the role of rituximab in primary CNS
lymphoma. Another randomized trial conducted by the IELSG is currently investigating high-dose methotrexate and cytarabine
with or without thiotepa and with or
without rituximab, in three different combinations of induction treatments.
Intensive chemotherapy alone without whole-brain radiation therapy or
autologous stem cell transplantation has
shown impressive sustained responses.
The Bonn protocol utilized systemic
chemotherapy with high-dose methotrexate, high-dose cytarabine, vincristine,
vindesine, ifosfamide, cyclophosphamide, and intraventricular methotrexate,
cytarabine, and prednisolone.16 Patients
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younger than age 60 were treated with

this regimen and achieved a median
progression-free survival of 21 months
and median overall survival of 50 months.
However, this was associated with significant treatment-related toxicity, including
19% intra-Ommaya infections and 9%
mortality. In a more recent multicenter
study conducted by the Cancer and
Leukemia Group B (CALGB), patients
(with no age cutoff) were treated with
high-dose methotrexate, rituximab, and
temozolomide, followed by high-dose
etoposide/cytarabine, which was welltolerated with 2% treatment-related
mortality.4 The median progression-free
survival was 29 months, with an estimated
4-year overall survival of 65%.
The role of intraventricular or intrathecal chemotherapy is unclear. Given
the high intra-Ommaya infection rate
with the Bonn protocol, the same investigators studied the same systemic
chemotherapy without the intraventricular chemotherapy, but were unable to
reproduce similar results.17 Retrospective studies have shown no benefit in
response rates or survival.18,19
Radiation therapy. Whole-brain radiation therapy was considered the standard
treatment for primary CNS lymphoma
until the introduction of high-dose methotrexate in the late 1980s. Subsequently,
for many years it has been used in combination with high-dose methotrexateY
based treatment. Because of the associated neurotoxicity, studies have been
conducted to determine if lower doses
of radiation therapy can achieve similar
results, or if the addition of radiation
therapy contributes to survival benefit.
Long-term results of a study in 31 patients who achieved a complete remission with high-dose methotrexateYbased
induction therapy and were subsequently treated with a consolidating
reduced dose of whole-brain radiation therapy (23.4 Gy) demonstrated a
2-year progression-free survival of 77%

KEY POINT

h While consensus exists

on using combination
chemotherapy as
induction treatment, the
choice of chemotherapy
in addition to high-dose
methotrexate is
not standardized.

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359

CNS Lymphoma and Hematologic Malignancies

KEY POINT

h High-dose chemotherapy
followed by autologous
stem cell transplantation
appears to be a promising
consolidative strategy,
especially in younger and
healthy patients.

360

and 3-year overall survival of 87%.20

Additionally, comprehensive neuropsychiatric testing showed improvement in
baseline executive function and verbal
memory after induction chemotherapy and
relatively stable scores in some measures
at 48-month follow-up. The G-PCNSL-SG
conducted a phase 3 trial in which 318
patients were randomly assigned to be
treated with high-dose methotrexateY
based treatment with or without wholebrain radiation therapy.21 There was no
significant progression-free survival or
overall survival benefit with up-front wholebrain radiation therapy, but this was a
noninferiority trial that was underpowered,
with a high dropout rate in the wholebrain radiation therapy arm. Nevertheless,
intent-to-treat analysis demonstrated no
difference in overall survival between
the whole-brain radiation therapy and
the nonYwhole-brain radiation therapy
arms. Retrospective studies have suggested
improved progression-free survival, but
no overall survival advantage to adding
whole-brain radiation.22 Moreover, the
risk of neurotoxicity increases with age,
longer progression-free survival, and combined chemotherapy and radiation. One
study showed that patients treated with
high-dose methotrexate and whole-brain
radiation therapy did poorly on cognitive
assessment as well as on quality-of-life
measures and additionally had MRI
evidence of extensive white matter abnormalities compared with those who
received high-dose methotrexate alone.23
Currently, some experts in the field utilize reduced-dose whole-brain radiation
therapy, and many experts agree to defer whole-brain radiation therapy in
older patients. An ongoing randomized
multicenter phase 2 trial is being conducted by the Radiation Therapy Oncology Group (RTOG 1114, NCT01399372)
investigating the role of reduced-dose
whole-brain radiation therapy after
induction therapy with a high-dose
methotrexateYbased regimen.

High-dose chemotherapy and autologous stem cell transplantation.

Consolidative whole-brain radiation therapy may benefit disease-free survival,
but, owing to the concern of neurotoxicity, impaired quality of life in survivors,
and lack of conclusive evidence that it
improves overall survival, the focus has
been on treating patients with chemotherapy alone, particularly with the use of
consolidative high-dose chemotherapy
and autologous stem cell transplantation. This involves leukapheresis and
peripheral blood stem cell collection,
followed by conditioning chemotherapy and reinfusion of the stem cells
to restore blood cell production. The
conditioning treatment is high-dose chemotherapy, which can attain high concentrations in the brain and eliminate
any residual malignant cells in addition to
blood stem cells. Different conditioning regimens across studies have led to
varied outcomes, although thiotepabased treatments have demonstrated
better results.6,11,24 In a phase 2 trial of
30 patients younger than age 65 treated
with high-dose methotrexate, cytarabine,
and thiotepa, followed by high-dose chemotherapy with carmustine and thiotepa
and autologous stem cell transplantation
and then whole-brain radiation therapy
(45 Gy), 5-year overall survival was 69%.25
The same study group conducted a pilot
study with a similar regimen deferring
whole-brain radiation therapy in 13 patients younger than age 70 and demonstrated a 3-year overall survival of 77%.24
A retrospective analysis of 66 patients
treated with high-dose chemotherapy
and autologous stem cell transplantation
showed 2-year and 5-year overall survival
of 82% and 77%, respectively.26 An overall survival rate of 35% was reported at
10-year follow-up of patients treated
with high-dose methotrexate, high-dose
busulfan-thiotepa, and autologous stem
cell transplantation with or without wholebrain radiation therapy, and seven of the

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eight patients alive were in excellent

health with no neurotoxicity.27 All studies
except one have reported no treatmentrelated mortality.24,25,28 High-dose
chemotherapy followed by autologous
stem cell transplantation appears to be
a promising consolidative strategy, especially in younger and healthy patients.
Randomized multicenter trials being
conducted in the United States (Alliance 51101, NCT01511562) and Europe
(IELSG 32, NCT01011920; Association des
Neuro-Oncologues dExpression Fran0aise
and Groupe Ouest Est des Leucemies
et Autres Maladies du Sang [ANOCEFGOELAMS], NCT00863460) are comparing the role of whole-brain radiation
therapy or chemotherapy versus highdose chemotherapy and autologous stem
cell transplantation for consolidation.
Salvage treatment. No consensus
exists on treatment for relapsed or refractory primary CNS lymphoma. Prospective trials with agents such as topotecan,
temozolomide, rituximab, combination
rituximab and temozolomide, and
pemetrexed have demonstrated objective
response rates of 14% to 55% and 1-year
overall survival of 31% to 71%.11 Higher
response rates have been shown in retrospective studies with the same drugs. In
a retrospective study with procarbazine,
CCNU (lomustine), and vincristine, an
objective response rate of 86% was reported. Rechallenge with high-dose
methotrexate led to an objective response
rate of 91% to the first salvage in a retrospective review, with median overall survival of 62 months. Whole-brain radiation
therapy can be considered in patients
who have not received it as a part of
initial therapy. Overall radiographic response rates of 74% to 79% and median
overall survival of 10 to 16 months were
observed with whole-brain radiation
therapy. A prospective multicenter trial of
high-dose etoposide/cytarabine followed
by high-dose chemotherapy with busulfan, thiotepa, cyclophosphamide, and
Continuum (Minneap Minn) 2015;21(2):355372

autologous stem cell transplantation

demonstrated median progression-free
survival of 11.6 months and 2-year overall
survival of 45%.29 The same group reported
5-year overall survival probability of 51%
with high-dose chemotherapy and
autologous stem cell transplantation in
a retrospective review, and this may be
considered as an option, especially in
younger patients.30 Age, performance
status, previous therapy, and duration
of prior response can be used to guide
the choice of salvage treatment.6

KEY POINTS

h The optimal therapy for

primary CNS lymphoma is
controversial, with few
randomized trials to guide
treatment decisions.

h CNS involvement in
systemic non-Hodgkin
lymphoma can present
at the time of diagnosis,
but most frequently
develops at the time of
disease relapse.

Summary
The optimal therapy for primary CNS lymphoma is controversial, with few randomized trials to guide treatment decisions.
The choice of cytostatic agents; the role
of rituximab; and the consolidative treatment in the form of chemotherapy,
whole-brain radiation therapy, or highdose chemotherapy and autologous stem
cell transplantation are questions that
several ongoing randomized trials will
attempt to answer.
NEUROLOGIC COMPLICATIONS
OF LEUKEMIA AND LYMPHOMA
Neurologic complications can result from
direct or indirect effects of leukemia and
lymphoma or may be treatment-induced.
It is important to recognize them and
avoid delays in instituting appropriate
treatment. Treatment-related complications are discussed in the article Neurologic Complications of Chemotherapy
and Radiation Therapy by Craig P.
Nolan, MD, and Lisa M. DeAngelis, MD,
.
FAAN, in this issue of
Neurologic Complications of
Non-Hodgkin Lymphoma
CNS involvement in systemic nonHodgkin lymphoma can present at the
time of diagnosis, but most frequently
develops at the time of disease relapse.
The median time to development of
CNS disease is less than 1 year.
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361

CNS Lymphoma and Hematologic Malignancies

KEY POINTS

h Leptomeningeal
metastasis is the
most common CNS
complication of
non-Hodgkin lymphoma.

h Intramedullary spinal
cord disease is a rare
complication of
non-Hodgkin lymphoma,
as is neurolymphomatosis,
which is direct infiltration
of the peripheral nerves,
nerve roots, plexus or
cranial nerves by
non-Hodgkin lymphoma.

h CSF flow cytometry has

a higher sensitivity
than CSF cytology
for diagnosis of CNS
involvement by
non-Hodgkin lymphoma
and provides
information about
the immunophenotype
of the lymphocytes
in a sample.

FIGURE 5-2

362

Incidence and risk factors. The risk

of CNS recurrence is between 5% and
25% for Burkitt lymphoma, acute lymphoblastic lymphoma, and aggressive
diffuse large B-cell lymphoma, and significantly less for those with indolent and
T-cell lymphomas.31Y33 Some studies
report a decreased incidence of CNS involvement in the rituximab era; however,
these data remain controversial.34Y36
Elevated serum LDH level, age older
than 60, advanced-stage disease, more than
one extranodal site involvement, and high
International Prognostic Index are other
risk factors. Extranodal sites that may be
associated with high risk for development
of CNS disease are bone/bone marrow, epidural space, testes, breast, and paranasal
sinus/orbit. Intravascular lymphoma has
a high incidence of CNS involvement.
Clinical presentation and diagnosis.
Leptomeningeal metastasis is the most
common CNS complication of nonHodgkin lymphoma. Patients may present
with single or multiple cranial neuropathies
(Figure 5-2). Other symptoms include
altered mental status, headaches, gait difficulty, radicular pain, back pain, focal
weakness, and seizures. Occasionally,

brain metastases presenting with focal

deficits or both brain and leptomeningeal metastases can be seen.
Intramedullary spinal cord disease is
rare, as is neurolymphomatosis, which
is direct infiltration of the peripheral
nerves, nerve roots, plexus, or cranial
nerves by non-Hodgkin lymphoma.
Neurolymphomatosis should be differentiated from other causes of peripheral
neuropathy or plexopathy. Spinal cord
compression from vertebral body or paraspinal lesions, or plexopathies from direct
compression or infiltration by a lymphomatous mass, can occur. The clinical presentation and medical history should be
carefully obtained. Neuroimaging with
MRI of the brain (and the total spine if
clinically indicated) with gadolinium contrast should be ordered before the lumbar
puncture. CSF analysis plays the major
role in the diagnosis of leptomeningeal
metastasis in hematologic malignancies.
CSF analysis may show elevated opening
pressure, cell count, and protein, as well as
low glucose levels. CSF flow cytometry
has a higher sensitivity than CSF cytology and provides information about the
immunophenotype of the lymphocytes

Postcontrast T1-weighted brain MRI demonstrates bilateral contrast enhancement of the oculomotor nerves (A),
the trigeminal nerves (B), and the facial nerves (C), as well as enhancement in the cerebellar folia in all images
in a patient with leptomeningeal metastases and non-Hodgkin lymphoma.

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April 2015

in a sample. IgH gene rearrangement

testing analyzes the clonality of the antibodies being produced and has a high
specificity for detecting active disease even
if only intraparenchymal lesions are observed on neuroimaging. The role of cancerspecific antigens, such as "2-microglobulin
in CSF, is nonspecific and can be elevated
in bacterial meningitis. Hypermetabolism
on PET scan (Figure 5-337), delineating
peripheral nerves and roots, can be seen
in neurolymphomatosis and is helpful to
identify possible biopsy sites for confir.mation of diagnosis.
Treatment and prophylaxis. Systemic
chemotherapy with high-dose methotrexate is associated with high objective
response rates, but responses are not durable and the prognosis is poor.38 High-dose
methotrexate followed by high-dose chemotherapy and autologous stem cell transplantation in young patients achieves
2-year overall survival of 54% to 68%
(Case 5-2).39,40 Intrathecal or intraventricular chemotherapy can be considered in
patients with leptomeningeal metastasis.
Whole-brain radiation therapy is an option
for recurrent or refractory disease. CNS prophylaxis is recommended only in high-risk
patients with non-Hodgkin lymphoma.41
Neurologic Complications of
Hodgkin Lymphoma
CNS involvement. CNS involvement by
Hodgkin lymphoma is rare, with an
incidence of 0.2% to 0.5%.42 Immunosuppression, EBV infection, and mixed
cellularity histology are thought to be
associated risk factors. Surgery, radiation,
and different chemotherapeutic regimens
have been used for treatment.
Apart from the direct (brain, meningeal, or spinal metastases) CNS invasion, indirect neurologic complications
of Hodgkin lymphoma (primary angiitis
and paraneoplastic/immune complications) can be observed.
Primary angiitis of the CNS. Primary
angiitis of the CNS, also known as granContinuum (Minneap Minn) 2015;21(2):355372

ulomatous angiitis, is a noninfectious vasculitis involving small and medium-sized

blood vessels of the leptomeninges, brain,
and spinal cord without angiitis in other
systems.43 Patients may present with
strokes, headache, or encephalopathy.
Serologic markers of inflammation are
typically normal. CSF analysis may be
normal, and elevations in total protein
level or white blood cell count may be
observed. MRI of the brain is abnormal in
more than 90% of patients, but not specific
(Figure 5-5A, B, and C44). Cerebral angiography has a low sensitivity and low
specificity as primary angiitis of the CNS
affects small vessels in a skipped and segmental pattern. Primary angiitis of the CNS

KEY POINT

h CNS involvement of
non-Hodgkin lymphoma
can be treated with
high-dose methotrexate
or high-dose methotrexate
followed by high-dose
chemotherapy and
autologous stem
cell transplantation in
young patients. Intrathecal
or intraventricular
chemotherapy can
be considered in
patients with
leptomeningeal metastasis.

Neurolymphomatosis. A, Fluorodeoxyglucose-positron
emission tomography (FDG-PET) showing linear
FDG uptake (arrow) in the posterior aspect of
the left upper thigh, corresponding to the left sciatic nerve.
B, Similar mild increased FDG uptake in the proximal right
sciatic nerve (arrow on the left) is also noted.

FIGURE 5-3

Modified with permission from Pentsova E, et al, Leuk Lymphoma.

B 2012 Informa Plc. informahealthcare.com/doi/abs/10.3109/
10428194.2012.656632.

37

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363

CNS Lymphoma and Hematologic Malignancies

KEY POINTS

h Primary angiitis of
the CNS may be the
first presentation of
Hodgkin lymphoma.

h Cerebral angiography
has a low sensitivity
and low specificity for
primary angiitis of the
CNS, as this disorder
affects small vessels in a
skipped and segmental
pattern. Diagnosis is
difficult and often made
by biopsy.

h The most frequent type

of paraneoplastic
neurologic syndrome
in Hodgkin lymphoma is
paraneoplastic cerebellar
degeneration, which is
highly associated with
anti-Tr (delta/notchlike
epidermal growth
factorYrelated receptor)
antibodies detected in CSF.

may be the first presentation of Hodgkin

lymphoma. However, it can also be
observed in patients with successfully
treated and controlled disease. Diagnosis is difficult and often made by biopsy
(Figure 5-5D44). Treatment includes corticosteroids and immunosuppression.
Paraneoplastic neurologic syndromes.
Paraneoplastic neurologic syndromes in
hematologic malignancies are relatively
rare and more frequently associated with
Hodgkin lymphoma rather than nonHodgkin lymphoma.45 They can occur at
any stage of the disease and not particularly before initial diagnosis as with solid
tumors. The most frequent type of paraneoplastic neurologic syndrome is paraneoplastic cerebellar degeneration, which
is highly associated with anti-Tr (delta/
notchlike epidermal growth factorYrelated
receptor) antibodies detected in CSF.
Limbic encephalitis (associated with
antibodies to metabotropic glutamate
receptor 5 [mGluR5]), chronic inflammatory demyelinating polyneuropathy

(CIDP), and motor neuron disease can

also be seen. For more information on
paraneoplastic syndromes, refer to the
article Paraneoplastic Disorders by
Eric Lancaster, MD, PhD, in this issue
.
of
Neurologic Complications of
Plasma Cell Disorders
Direct CNS involvement. CNS involvement of Waldenstro
m macroglobulinemia
(IgM paraproteinemia), called Bing-Neel
syndrome, is rare, usually occurs as a late
complication of advanced disease, and
carries a poor prognosis. Patients usually
present with confusion, headaches, focal
neurologic deficits, and seizures. Imaging demonstrates enhancing abnormalities involving the brain, spinal cord, or
leptomeninges.46 CSF analysis may
show lymphocytic pleocytosis, elevated
protein, and IgM kappa or lambda light
chain restriction; cytology results are variable. Immunoblot analysis of serum and
CSF IgM may reveal proliferation of the

Case 5-2
A 52-year-old healthy man developed intermittent episodes of bilateral hand paresthesia and
difficulty typing. Several days later, he woke up with numbness below his left nipple and left arm
numbness. MRI of the cervical and thoracic spine was obtained, which demonstrated a patchy
distribution of contrast-enhancing T2-hyperintense lesions in the upper cervical and thoracic spinal
cord (Figure 5-4A, B). Brain MRI showed no abnormalities. CSF analysis showed no white blood cells,
elevated protein at 96 mg/dL, normal glucose, and negative oligoclonal bands and neuromyelitis optica
antibodies. CSF cytology showed no malignant cells, and a paraneoplastic panel was negative. He received
treatment with IV high-dose methylprednisolone for presumed multiple sclerosis, and multiple rounds
of plasma exchange with temporary resolution of his symptoms. Four weeks later, the patient was
readmitted with worsening of his sensory symptoms, confusion, and mental status changes. MRI of the
spine showed further progression of the previously seen lesions at the cervical and thoracic levels. MRI of
the brain showed multifocal contrast-enhancing lesions, including the splenium of the corpus callosum
(Figure 5-4C, D). Repeat CSF analysis was unrevealing. Systemic workup revealed external iliac
adenopathy with evidence of fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT uptake
in the right testis. A scrotal ultrasound showed multiple hyperintense lesions in the right testicle. The
patient underwent a right orchiectomy, and the pathology was consistent with diffuse large B-cell
lymphoma. Bone marrow aspirate and biopsy showed lymphomatous involvement. The patient started
chemotherapy with high-dose methotrexate expeditiously followed by rituximab, cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-CHOP). He completed six cycles of high-dose methotrexate
and R-CHOP with consolidation therapy with high-dose cytarabine and radiation therapy to the testicles,
followed by high-dose chemotherapy and autologous stem cell transplantation to improve his chances for
durable remission. He has remained in complete remission for 3 years.

Continued on page 365

364

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April 2015

Continued from page 364

Imaging of the patient in Case 5-2. Sagittal T2-weighted cervical spine MRI demonstrates
hyperintense signal at the C2 to C4 levels (A) with corresponding contrast enhancement on
gadolinium-enhanced T1-weighted fat-saturated MRI (B). Brain MRI shows hyperintensity in
the splenium of the corpus callosum on T2 fluid-attenuated inversion recovery (C) and multifocal
contrast-enhancing lesions on postcontrast T1-weighted image (D).

FIGURE 5-4

Comment. This case is an example of testicular lymphoma with CNS metastases in the brain and
the spinal cord with only neurologic symptoms at the time of diagnosis. Lack of response to standard
therapy for demyelinating disease and progressive neurologic decline should include a more
extensive workup, and a lymphoma diagnosis should be suspected.
Continuum (Minneap Minn) 2015;21(2):355372

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365

CNS Lymphoma and Hematologic Malignancies

KEY POINTS

h CNS involvement of
Waldenstrom
macroglobulinemia,
called Bing-Neel syndrome,
is rare, usually occurs as
a late complication of
advanced disease, and
carries a poor prognosis.

h CNS involvement of
multiple myeloma is
rare and usually is
associated with high
tumor burden,
circulating plasma cells,
plasmablastic morphology,
extramedullary disease, and
cytogenetic abnormalities.

h Waldenstrom
macroglobulinemia and
IgA or IgG myeloma can
lead to hyperviscosity
syndrome, resulting in
reduced flow through
the cerebral and
retinal vasculature.

Primary angiitis of the CNS (also known as granulomatous angiitis). A, Axial

and B, coronal postcontrast T1-weighted images demonstrate extensive
hemispheric and focal cerebellar abnormalities with a perivascular pattern of
enhancement; C, MRI perfusion imaging demonstrates decreased cerebralblood flow in the white
matter; D, Hematoxylin and eosin (H&E) stain demonstrates necrotizing granulomatous angiitis.

FIGURE 5-5

44

Reprinted with permission from Fuehrer N, et al, Neurology.

content/77/19/e110.long.

IgM-producing malignant cell clone intrathecally.47 Treatment includes intrathecal

chemotherapy, high-dose methotrexate,
rituximab, and radiation.
CNS involvement of multiple myeloma
is rare (1% of multiple myeloma patients)
and usually is associated with high tumor
burden, circulating plasma cells, plasmablastic morphology, extramedullary disease
(21% of patients with multiple myeloma),
and cytogenetic abnormalities.48,49 It typically presents as leptomeningeal metastasis. Diagnosis can be made by MRI

366

B 2011 AAN Enterprises, Inc. www.neurology.org/

and examination of the CSF, which may

show plasma cells, elevated protein, and
a monoclonal protein spike. Prognosis is
poor despite aggressive treatment.
Hyperviscosity syndrome. Waldenstro
m
macroglobulinemia and IgA or IgG myeloma
can lead to hyperviscosity syndrome, resulting in reduced flow through the cerebral
and retinal vasculature. Patients typically
present with TIAs and blurry vision. Plasma
exchange and treatment of Waldenstro
m
macroglobulinemia result in symptom alleviation.

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April 2015

Neuropathy. Neuropathy can be seen in

monoclonal gammopathy of undetermined
significance (MGUS), multiple myeloma,
and Waldenstro
m macroglobulinemia.
MGUS is often diagnosed during routine
workup of a sensorimotor peripheral
neuropathy, and patients have no other
symptoms from the underlying disorder.
Antibodies to myelin-associated glycoprotein (MAG) can be found in many patients
with IgM MGUS. Up to 50% of patients
with IgM MGUS develop a severe symptomatic neuropathy, some with demyelinating features like CIDP that can be
treated with IV immunoglobulin or plasma
exchange. Rituximab has been tried in
patients with anti-MAG antibodies with
minimal success.50 Neuropathy related to
Waldenstro
m macroglobulinemia is similar,
and anti-MAG antibodies can be found in
some patients.
Neuropathy is observed in 20% of
patients with multiple myeloma.51 The
neuropathy seen with polyneuropathy,
organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin
changes (POEMS) syndrome is symmetric
and ascending, progresses rapidly, and
is severely disabling. Demyelination and
axonal loss can be seen. Treatment of
the underlying plasma cell disorder may
help with related neuropathy, although
the neuropathy is often not responsive
and, in fact, can be worsened by some
of the drugs used in treating multiple
myeloma. Patients may respond to prednisone, melphalan, thalidomide, or local
radiation. In patients with refractory neuropathy due to multiple myeloma, highdose chemotherapy and autologous stem
cell transplantation have been tried.52
Amyloid polyneuropathy is seen more
commonly in multiple myeloma and is
rare in Waldenstro
m macroglobulinemia.
It is usually painful and characterized by
IgG or IgA lambda paraproteinemia. The
diagnosis is established by the presence
of endoneurial amyloid deposits on nerve
biopsy. Cryoglobulinemia associated with
Continuum (Minneap Minn) 2015;21(2):355372

Waldenstro
m macroglobulinemia, multiple myeloma, and MGUS can cause an
epineurial vasculitis leading to nerve
ischemia and neuropathy.
Neurologic Complications of
Leukemias
Leptomeningeal involvement. Acute
leukemias have a high incidence of
leptomeningeal metastasis, typically
occurring at relapse. With the introduction of CNS prophylaxis in induction treatment, the risk is reduced, but
approximately 5% to 15% of adults with
acute lymphoblastic leukemia (ALL)
develop leptomeningeal metastasis.53
Treatment includes craniospinal radiation,
intensive systemic chemotherapy, intrathecal chemotherapy, or high-dose chemotherapy followed by autologous stem
cell transplantation. Chronic leukemias
rarely develop leptomeningeal metastasis.
Chloromas. Chloroma is a rare extramedullary tumor of immature myeloid
cells most commonly related to acute
myelogenous leukemia (AML), often occurring in the skull or spine. A variety of
neurologic symptoms attributed to chloroma are related to compression of underlying brain, nerves, or spinal cord, such
as single or multiple compression neuropathies, low back pain, and cord compression. Chloromas are radiosensitive
tumors, and radiation therapy results in
excellent local disease control and palliation of symptoms without significant
toxicity (Case 5-3).54
Intracranial hemorrhage. Intracranial hemorrhage is a common neurologic complication in acute leukemias,
with a high mortality rate (20%). It may
result from disseminated intravascular coagulation (common in acute promyelocytic
leukemia), thrombocytopenia, blast crisis,
or leukocytosis (more than 300,000 cells/HL).
Disseminated mucormycosis or aspergillosis and L-asparaginaseYinduced intracranial dural sinus thrombosis can also lead
to intracranial hemorrhage. Leukemic

KEY POINTS

h Neuropathy can be
seen in monoclonal
gammopathy of
undetermined
significance, multiple
myeloma, and
Waldenstrom
macroglobulinemia.

h A variety of neurologic
symptoms attributed
to chloroma are related
to compression of
underlying brain, nerves,
or spinal cord, such as
single or multiple
compression neuropathies,
low back pain, and
cord compression.

h Chloromas are
radiosensitive tumors,
and radiation therapy
results in excellent
local disease control
and palliation of
symptoms without
significant toxicity.

h Leukemic cell
infiltration can
cause venous
sinus thrombosis
and associated
hemorrhagic infarctions.

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367

CNS Lymphoma and Hematologic Malignancies

Case 5-3
A 25-year-old woman with a history of acute myelogenous leukemia (AML), status postYstem cell
transplant, with a history of a chloroma in the left brachial plexus was successfully treated with
radiation therapy. She presented with new symptoms of numbness and pain in the right leg just
above the knee and pain, numbness, and weakness in the right ulnar nerve distribution. A positron
emission tomography (PET) scan of the body showed hypermetabolism in the right psoas and right
deltoid muscles suspicious for tumor recurrence. MRI of the right arm showed a contrast-enhancing
lesion involving the right ulnar nerve at the elbow. CSF studies revealed a white blood cell count of
1 cell/6L and a red blood cell count of 1 cell/6L, protein 20 mg/dL, glucose 51 mg/dL, negative cytology,
and no abnormal B-cell population identified on flow cytometry. The patient underwent a CT-guided
biopsy of the right psoas muscle, which revealed extramedullary myeloid tumor/chloroma. A bone
marrow biopsy showed no evidence of disease. She was treated with radiation therapy to the right
shoulder, elbow, and psoas with complete resolution of her symptoms. Two years later, she developed
low back pain with intermittent radicular symptoms at the L4 dermatome in the right leg. A PET body
scan demonstrated fluorodeoxyglucose uptake at the right iliacus muscle and in the femoral nerve
distribution, which extended from the lumbar root level to the right inguinal canal. MRI of the pelvis
showed a contrast-enhancing lesion between the posterolateral right lower psoas muscle and right iliacus
muscle. The patient received radiation to the right pelvis and right femoral nerve with complete
resolution of her neurologic deficit.
Comment. Neurologic findings in chloromas depend on the tumor location. Appropriate imaging
followed by biopsy helps in diagnosis.

cell infiltration can cause venous sinus

thrombosis and associated hemorrhagic infarctions.
Lymphomatoid Granulomatosis
of the CNS
Lymphomatoid granulomatosis is a rare
EBV-positive lymphoproliferative disorder characterized by B-cell proliferation
associated with T-cell infiltration, graded I
to III based on the proportion of large, EBVpositive atypical B lymphocytes. There may
be a morphological overlap with variants of
diffuse large B-cell lymphoma and potential
malignant transformation.55,56 The clinical
presentation may be nonspecific or depend on the location of involvement. This
may also manifest as immune reconstitution syndrome in immunocompromised
patients. Brain biopsy helps with diagnosis. Treatment consists of corticosteroids,
chemotherapy, or radiation therapy for
high-grade lesions.
Summary
Neurologic complications of hematologic malignancies may involve the CNS

368

as well as the peripheral nervous system.

Direct involvement may result from invasion or compression and is more common in non-Hodgkin lymphoma. The
incidence of CNS involvement by leukemia
has been reduced with prophylaxis. CNS
prophylaxis in non-Hodgkin lymphoma
is reserved for high-risk patients. Neurologic complications from indirect effects
of hematologic malignancies may be vascular, infectious, or paraneoplastic. Neuropathy in plasma cell disorders can
result from autoantibodies, cryoglobulinemia, or amyloid deposition or as a
side effect of the treatment.
CONCLUSION
Primary CNS lymphoma is an aggressive
brain tumor with poor prognosis. Diagnosis can be made by CSF or vitreous
fluid analysis or by stereotactic brain
biopsy. Baseline staging is recommended before starting treatment. Age and
performance status are important prognostic factors. High-dose methotrexateY
based treatment achieves high response

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April 2015

rates, but recurrences occur frequently.

There is no consensus on consolidative
therapy; reduced-dose whole-brain radiation therapy and high-dose chemotherapy
followed by autologous stem cell transplant have shown improved outcomes.
Treatment, particularly the combination
of chemotherapy and radiation, can be
associated with long-term neurotoxicity.
CNS involvement of leukemia and
lymphoma is typically associated with
poor survival. Secondary CNS lymphoma
is commonly seen with highly aggressive
variants of non-Hodgkin lymphoma, such
as Burkitt lymphoma and lymphoblastic
lymphoma/acute lymphoblastic leukemia; CNS prophylaxis is routinely incorporated in these patients. In contrast to
primary CNS lymphoma, CNS involvement of systemic lymphoma or leukemia
usually manifests as leptomeningeal disease. Vascular complications in the form
of ischemic events can occur with intravascular lymphoma characterized by lymphoma cells within the vascular lumen,
primary angiitis in Hodgkin lymphoma,
or related to hyperviscosity syndrome in
Waldenstro
m macroglobulinemia. Acute
leukemias may cause intracranial hemorrhage. Paraneoplastic neurologic disorders
may be seen in association with Hodgkin
lymphoma. Neuropathies may be seen
in association with plasma cell disorders.
Early recognition and prompt treatment
of these conditions may result in neurologic recovery and improved outcomes.
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