Review Article

Primary CNS Lymphoma

Address correspondence to
Dr Lakshmi Nayak, Dana Farber
Cancer Institute, Center for
Neuro-oncology, 450 Brookline

and Neurologic Avenue, DA2120, Boston,

MA 02215,
Lakshmi_Nayak@dfci.harvard.edu.

Complications of Relationship Disclosure:

Dr Nayak has served on the
advisory board of Amgen Inc.

Hematologic Dr Pentsova reports no

disclosure. Dr Batchelor has
served as a consultant for
Advance Medical; Agenus Inc;

Malignancies Amgen Inc; Champions

Oncology, Inc; Kyowa Hakko
Kirin Pharma, Inc; Merck &
Lakshmi Nayak, MD; Elena Pentsova, MD; Co, Inc; Novartis AG;
Proximagen; Roche; and
Tracy T. Batchelor, MD, MPH Spectrum Pharmaceuticals,
Inc. Dr Batchelor has received
personal compensation for
speaking engagements from
ABSTRACT Educational Concepts Group,
Purpose of Review: This article provides a practical clinical approach to diagnose Incorporated; Imedex;
Research To Practice; and
primary CNS lymphoma and recognize neurologic complications of lymphomas and RMEI, LLC; and for preparation
leukemias. This includes current diagnostic and treatment recommendations for primary of educational materials from
CNS lymphoma and complications related to hematologic malignancies. UpToDate, Inc, and Oakstone
Publishing, LLC. Dr Batchelor
Recent Findings: Primary CNS lymphoma is an uncommon, aggressive non-Hodgkin received research support from
lymphoma confined to the CNS in the absence of systemic disease. Diagnosis can be AstraZeneca; Millennium
made by brain biopsy, CSF analysis, or vitreous fluid analysis. Primary CNS lymphoma is Pharmaceuticals, Inc; and
Pfizer Inc.
typically diffuse large B cell in histology. Evaluation of extent of disease should be
Unlabeled Use of
performed before initiation of therapy. Initial induction treatment includes high-dose Products/Investigational
methotrexateYbased chemotherapy. Several studies have demonstrated improved out- Use Disclosure:
come using consolidative whole-brain radiation therapy or high-dose chemotherapy and Drs Nayak, Pentsova,
and Batchelor
autologous stem cell transplantation. Neurologic complications can result from direct or report no disclosures.
indirect effects of leukemia and lymphoma or may be treatment-induced. * 2015, American Academy
Summary: Early diagnosis and treatment of patients with primary CNS lymphoma is of Neurology.
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.

Continuum (Minneap Minn) 2015;21(2):355–372.

INTRODUCTION related to radiation therapy remains the

Primary CNS lymphoma is an aggressive
cancer, seen more commonly in immu-
nocompetent patients over 65 years of
age. Histopathologic confirmation by
brain biopsy, CSF analysis, or vitreous
fluid analysis is important before start-
ing treatment. Historically, whole-brain
radiation therapy was a treatment op-
tion. The addition of high-dose metho-
trexate to whole-brain radiation therapy
has improved survival in primary CNS lym-
phoma. However, long-term neurotoxicity
major concern in patients achieving long-
term survival. Recent studies have focused
on reduced-dose whole-brain radiation
therapy and CNS-penetrating high-
dose chemotherapy followed by autol-
ogous stem cell rescue.
Neurologic complications of systemic
lymphoma and leukemia can be devas-
tating. CNS involvement can occur as
a direct effect and is more common
at lymphoma or leukemia relapse. The
peripheral nervous system can also be

Continuum (Minneap Minn) 2015;21(2):355–372 www.ContinuumJournal.com 355

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 CNS Lymphoma and Hematologic Malignancies
KEY POINTS
h Histopathologic diagnosis involved; this is seen typically with plasma
of primary CNS lymphoma cell disorders. Indirect effects of leukemia
can be made by and lymphoma can result in vascular, in-
stereotactic brain biopsy, fectious, and paraneoplastic complications.
CSF cytologic analysis, or This article details the clinical features,
flow cytometry in patients diagnosis, and treatment of primary CNS
with leptomeningeal lymphoma and neurologic complications
involvement, or by of lymphoma and leukemia.
vitrectomy or chorioretinal
biopsy in those with PRIMARY CNS LYMPHOMA
intraocular lymphoma.
Primary CNS lymphoma is a rare and
h It is recommended to aggressive extranodal non-Hodgkin lym-
avoid pretreatment with phoma confined to the CNS (brain, spinal
corticosteroids before cord, leptomeninges, or eyes) without
biopsy when a diagnosis
concurrent or prior systemic lymphoma.
of primary CNS lymphoma
It accounts for less than 3% of all primary
is considered, as their
use can interfere with
CNS tumors. The median age at diagnosis
histopathologic diagnosis. is 65 years, with an increasing incidence
in the elderly since 2000.1
h In more than 90% of
primary CNS lymphoma
Clinical Features
cases, the histology
is diffuse large The clinical presentation of primary CNS
B-cell lymphoma. 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 immu-
nocompetent. AIDS-related lymphoma
has declined with the use of highly ac-
tive 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 immunosuppres-
sive therapies.
Radiographic Features
Primary CNS lymphoma occurs as a sol-
itary contrast-enhancing lesion on MRI or
CT scans in up to 70% of patients. The
most common sites are the cerebral hemi-
spheres, corpus callosum, basal ganglia,
356 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and thalamus, although any part of the
brain can be involved. Nonenhancing
lesions are rare. Primary CNS lymphoma
is a highly cellular tumor. The diffusion-
weighted MRI derived apparent diffu-
sion coefficient (ADC) is influenced by
the extent of cellular density and may
correlate with outcome.3
Diagnosis
Histopathology. The histopathologic di-
agnosis can be made by stereotactic brain
biopsy, CSF cytologic analysis, or flow
cytometry in patients with leptomeningeal
involvement, or by vitrectomy or chorio-
retinal biopsy in those with intraocular
lymphoma. As delay in diagnosis may
compromise patient outcomes, stereotac-
tic biopsy is advisable when an enhanc-
ing brain lesion is present.4 Additionally,
it is recommended to avoid pretreat-
ment with corticosteroids before biopsy
when a diagnosis of primary CNS lym-
phoma is considered as their use can
interfere with histopathologic diagnosis.
This is particularly important as corti-
costeroids are often routinely used in
newly diagnosed intracranial lesions to
alleviate neurologic signs and symptoms
resulting from cytotoxic edema. Radio-
graphic response to corticosteroids may
be suggestive but not diagnostic of pri-
mary CNS lymphoma, and the differen-
tial diagnosis includes demyelinating,
inflammatory, or autoimmune conditions
or sarcoidosis.
In more than 90% of cases, the his-
tology 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
April 2015
 KEY POINT
of EBV-encoded RNA in immunocom- tion. Laboratory evaluation should include h The International PCNSL
promised patients. serum lactate dehydrogenase (LDH), he- Collaborative Group
Extent-of-disease evaluation. The patic and renal function tests, evaluation of (IPCG) recommends
International PCNSL Collaborative Group creatinine clearance, and a test for HIV. A baseline staging and
(IPCG) recommends baseline staging contrast-enhanced MRI or CT scan (in provides guidelines on
and provides guidelines on pathologic, patients who cannot tolerate MRI) of the pathologic, clinical,
clinical, laboratory, and extent-of-disease brain should be obtained, and MRI of laboratory, and
evaluation to rule out systemic lymphoma the total spine in those with spinal symp- extent-of-disease
and to document CSF or eye involve- toms. A detailed examination by an oph- evaluation to rule out
ment (Case 5-1).5 All newly diagnosed thalmologist is recommended to rule systemic lymphoma
and to document CSF
patients must undergo a comprehensive out vitreous, retinal, and optic nerve in-
or eye involvement.
physical, neurologic, and cognitive evalua- volvement. Lumbar puncture should be

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 ).

Continuum (Minneap Minn) 2015;21(2):355–372 www.ContinuumJournal.com 357

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 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 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
performed for CSF studies, including cell
count, protein, glucose, "2-microglobulin,
cytology, flow cytometry, and immuno-
globulin heavy chain (IgH) gene rear-
rangement 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 Surgery. The role of surgery in pri-
In many studies, age and performance
status are two baseline prognostic vari-
ables that influence outcome in patients
with newly diagnosed primary CNS lym-
phoma.6 Two scoring systems, the In-
ternational 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 scor-
ing 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 prog-
nostic 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 ove-
rall and progression-free survival.9
Treatment
The treatment for newly diagnosed pri-
mary CNS lymphoma involves induction
and consolidation phases. Induction
treatment is the initial treatment em-
ployed to induce a remission, includ-
ing 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, chemo-
therapy, or high-dose chemotherapy fol-
lowed 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.
mary CNS lymphoma is limited to ste-
reotactic biopsy for histopathologic
diagnosis because of the infiltrating na-
ture of the tumor and lack of survival
benefit from resection.10,11 Recently pub-
lished results from a subset analysis
of the German PCNSL Study Group-1
(G-PCNSL-SG1) trial demonstrated im-
proved outcomes for patients with sub-
total or gross total resection, although
the survival benefit was lost when ad-
justed for the total number of lesions.12
Other studies have not demonstrated
a survival advantage for resection. There
is not sufficient evidence to advise resec-
tion 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 ma-
jority of the single-arm phase 2 studies
with multiagent chemotherapy have dem-
onstrated 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,
April 2015

vincristine, carmustine, cytarabine, etopo-
side, 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 dif-
ferent regimens and doses of whole-
brain 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 addi-
tion to high-dose methotrexate is not
standardized. A randomized phase 2 trial
conducted in 79 patients demonstrated
improved efficacy by combining high-
dose cytarabine to high-dose metho-
trexate versus high-dose methotrexate
alone (objective response rate 69% versus
40%, P=.009). Based on the survival ben-
efit 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 con-
ducted by the IELSG is currently investigat-
ing high-dose methotrexate and cytarabine
with or without thiotepa and with or
without rituximab, in three different com-
binations of induction treatments.
Intensive chemotherapy alone with-
out whole-brain radiation therapy or
autologous stem cell transplantation has
shown impressive sustained responses.
The Bonn protocol utilized systemic
chemotherapy with high-dose metho-
trexate, high-dose cytarabine, vincristine,
vindesine, ifosfamide, cyclophospha-
mide, and intraventricular methotrexate,
cytarabine, and prednisolone.16 Patients
Continuum (Minneap Minn) 2015;21(2):355–372
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
younger than age 60 were treated with h While consensus exists
this regimen and achieved a median on using combination
progression-free survival of 21 months chemotherapy as
and median overall survival of 50 months. induction treatment, the
However, this was associated with signif- choice of chemotherapy
icant treatment-related toxicity, including in addition to high-dose
19% intra-Ommaya infections and 9% methotrexate is
mortality. In a more recent multicenter not standardized.
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 well-
tolerated 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 intra-
thecal chemotherapy is unclear. Given
the high intra-Ommaya infection rate
with the Bonn protocol, the same in-
vestigators studied the same systemic
chemotherapy without the intraventric-
ular chemotherapy, but were unable to
reproduce similar results.17 Retrospec-
tive studies have shown no benefit in
response rates or survival.18,19
Radiation therapy. Whole-brain radi-
ation therapy was considered the standard
treatment for primary CNS lymphoma
until the introduction of high-dose meth-
otrexate in the late 1980s. Subsequently,
for many years it has been used in com-
bination with high-dose methotrexateY
based treatment. Because of the associ-
ated 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 pa-
tients who achieved a complete remis-
sion with high-dose methotrexateYbased
induction therapy and were subse-
quently treated with a consolidating
reduced dose of whole-brain radia-
tion therapy (23.4 Gy) demonstrated a
2-year progression-free survival of 77%
www.ContinuumJournal.com 359
 CNS Lymphoma and Hematologic Malignancies
KEY POINT
h High-dose chemotherapy and 3-year overall survival of 87%.20
followed by autologous Additionally, comprehensive neuropsy-
stem cell transplantation chiatric testing showed improvement in
appears to be a promising baseline executive function and verbal
consolidative strategy, memory after induction chemotherapy and
especially in younger and relatively stable scores in some measures
healthy patients. 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 whole-
brain radiation therapy.21 There was no
significant progression-free survival or
overall survival benefit with up-front whole-
brain radiation therapy, but this was a
noninferiority trial that was underpowered,
with a high dropout rate in the whole-
brain 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 com-
bined 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 ab-
normalities compared with those who
received high-dose methotrexate alone.23
Currently, some experts in the field uti-
lize reduced-dose whole-brain radiation
therapy, and many experts agree to de-
fer whole-brain radiation therapy in
older patients. An ongoing randomized
multicenter phase 2 trial is being con-
ducted by the Radiation Therapy On-
cology Group (RTOG 1114, NCT01399372)
investigating the role of reduced-dose
whole-brain radiation therapy after
induction therapy with a high-dose
methotrexateYbased regimen.
360 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
High-dose chemotherapy and au-
tologous stem cell transplantation.
Consolidative whole-brain radiation ther-
apy may benefit disease-free survival,
but, owing to the concern of neurotox-
icity, impaired quality of life in survivors,
and lack of conclusive evidence that it
improves overall survival, the focus has
been on treating patients with chemo-
therapy alone, particularly with the use of
consolidative high-dose chemotherapy
and autologous stem cell transplanta-
tion. This involves leukapheresis and
peripheral blood stem cell collection,
followed by conditioning chemother-
apy and reinfusion of the stem cells
to restore blood cell production. The
conditioning treatment is high-dose che-
motherapy, which can attain high con-
centrations in the brain and eliminate
any residual malignant cells in addition to
blood stem cells. Different condition-
ing regimens across studies have led to
varied outcomes, although thiotepa-
based 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 che-
motherapy 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 pa-
tients younger than age 70 and demon-
strated 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 over-
all 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 whole-
brain radiation therapy, and seven of the
April 2015

eight patients alive were in excellent
health with no neurotoxicity.27 All studies
except one have reported no treatment-
related mortality.24,25,28 High-dose
chemotherapy followed by autologous
stem cell transplantation appears to be
a promising consolidative strategy, espe-
cially in younger and healthy patients.
Randomized multicenter trials being
conducted in the United States (Alli-
ance 51101, NCT01511562) and Europe
(IELSG 32, NCT01011920; Association des
Neuro-Oncologues d’Expression Fran0aise
and Groupe Ouest Est des Leucémies
et Autres Maladies du Sang [ANOCEF-
GOELAMS], NCT00863460) are compar-
ing the role of whole-brain radiation
therapy or chemotherapy versus high-
dose chemotherapy and autologous stem
cell transplantation for consolidation.
Salvage treatment. No consensus
exists on treatment for relapsed or refrac-
tory primary CNS lymphoma. Prospec-
tive 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 retro-
spective studies with the same drugs. In
a retrospective study with procarbazine,
CCNU (lomustine), and vincristine, an
objective response rate of 86% was re-
ported. Rechallenge with high-dose
methotrexate led to an objective response
rate of 91% to the first salvage in a retro-
spective review, with median overall sur-
vival 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 re-
sponse 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 busul-
fan, thiotepa, cyclophosphamide, and
Continuum (Minneap Minn) 2015;21(2):355–372
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
autologous stem cell transplantation h The optimal therapy for
demonstrated median progression-free primary CNS lymphoma is
survival of 11.6 months and 2-year overall controversial, with few
survival of 45%.29 The same group reported randomized trials to guide
5-year overall survival probability of 51% treatment decisions.
with high-dose chemotherapy and h CNS involvement in
autologous stem cell transplantation in systemic non-Hodgkin
a retrospective review, and this may be lymphoma can present
considered as an option, especially in at the time of diagnosis,
younger patients.30 Age, performance but most frequently
status, previous therapy, and duration develops at the time of
of prior response can be used to guide disease relapse.
the choice of salvage treatment.6
Summary
The optimal therapy for primary CNS lym-
phoma is controversial, with few random-
ized trials to guide treatment decisions.
The choice of cytostatic agents; the role
of rituximab; and the consolidative treat-
ment in the form of chemotherapy,
whole-brain radiation therapy, or high-
dose 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 complica-
tions are discussed in the article ‘‘Neuro-
logic 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 non-
Hodgkin 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.
www.ContinuumJournal.com 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.
Incidence and risk factors. The risk
of CNS recurrence is between 5% and
25% for Burkitt lymphoma, acute lym-
phoblastic lymphoma, and aggressive
diffuse large B-cell lymphoma, and sig-
nificantly less for those with indolent and
T-cell lymphomas.31Y33 Some studies
report a decreased incidence of CNS in-
volvement 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, epi-
dural 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 non-
Hodgkin lymphoma. Patients may present
with single or multiple cranial neuropathies
(Figure 5-2). Other symptoms include
altered mental status, headaches, gait dif-
ficulty, radicular pain, back pain, focal
weakness, and seizures. Occasionally,
brain metastases presenting with focal
deficits or both brain and leptomen-
ingeal 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 differ-
entiated from other causes of peripheral
neuropathy or plexopathy. Spinal cord
compression from vertebral body or para-
spinal lesions, or plexopathies from direct
compression or infiltration by a lympho-
matous mass, can occur. The clinical pre-
sentation and medical history should be
carefully obtained. Neuroimaging with
MRI of the brain (and the total spine if
clinically indicated) with gadolinium con-
trast 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 cytol-
ogy and provides information about the
immunophenotype of the lymphocytes

FIGURE 5-2 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.

362 www.ContinuumJournal.com April 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


in a sample. IgH gene rearrangement
testing analyzes the clonality of the anti-
bodies being produced and has a high
specificity for detecting active disease even
if only intraparenchymal lesions are ob-
served on neuroimaging. The role of cancer-
specific 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 metho-
trexate is associated with high objective
response rates, but responses are not dura-
ble and the prognosis is poor.38 High-dose
methotrexate followed by high-dose che-
motherapy and autologous stem cell trans-
plantation in young patients achieves
2-year overall survival of 54% to 68%
(Case 5-2).39,40 Intrathecal or intraventric-
ular chemotherapy can be considered in
patients with leptomeningeal metastasis.
Whole-brain radiation therapy is an option
for recurrent or refractory disease. CNS pro-
phylaxis is recommended only in high-risk
patients with non-Hodgkin lymphoma.41
KEY POINT
ulomatous angiitis, is a noninfectious vas- h CNS involvement of
culitis involving small and medium-sized non-Hodgkin lymphoma
blood vessels of the leptomeninges, brain, can be treated with
and spinal cord without angiitis in other high-dose methotrexate
systems.43 Patients may present with or high-dose methotrexate
strokes, headache, or encephalopathy. followed by high-dose
Serologic markers of inflammation are chemotherapy and
typically normal. CSF analysis may be autologous stem
normal, and elevations in total protein cell transplantation in
level or white blood cell count may be young patients. Intrathecal
or intraventricular
observed. MRI of the brain is abnormal in
chemotherapy can
more than 90% of patients, but not specific
be considered in
(Figure 5-5A, B, and C44). Cerebral angi- patients with
ography has a low sensitivity and low leptomeningeal metastasis.
specificity as primary angiitis of the CNS
affects small vessels in a skipped and seg-
mental pattern. Primary angiitis of the CNS

Neurologic Complications of
Hodgkin Lymphoma
CNS involvement. CNS involvement by
Hodgkin lymphoma is rare, with an
incidence of 0.2% to 0.5%.42 Immuno-
suppression, 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, menin- FIGURE 5-3 Neurolymphomatosis. A, Fluorodeoxyglucose-positron
emission tomography (FDG-PET) showing linear
geal, or spinal metastases) CNS inva- FDG uptake (arrow) in the posterior aspect of
sion, indirect neurologic complications the left upper thigh, corresponding to the left sciatic nerve.
B, Similar mild increased FDG uptake in the proximal right
of Hodgkin lymphoma (primary angiitis sciatic nerve (arrow on the left) is also noted.
and paraneoplastic/immune complica- Modified with permission from Pentsova E, et al, Leuk Lymphoma.
37

tions) can be observed. B 2012 Informa Plc. informahealthcare.com/doi/abs/10.3109/

10428194.2012.656632.
Primary angiitis of the CNS. Primary
angiitis of the CNS, also known as gran-
Continuum (Minneap Minn) 2015;21(2):355–372 www.ContinuumJournal.com 363

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 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. Diagno-
sis is difficult and often made by biopsy
(Figure 5-5D44). Treatment includes cor-
ticosteroids and immunosuppression.
Paraneoplastic neurologic syndromes.
Paraneoplastic neurologic syndromes in
hematologic malignancies are relatively
rare and more frequently associated with
Hodgkin lymphoma rather than non-
Hodgkin lymphoma.45 They can occur at
any stage of the disease and not particu-
larly before initial diagnosis as with solid
tumors. The most frequent type of para-
neoplastic neurologic syndrome is para-
neoplastic 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 inflam-
matory 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 involve-
ment of Waldenström 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. Imag-
ing demonstrates enhancing abnormal-
ities 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 vari-
able. 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 www.ContinuumJournal.com April 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Continued from page 364

FIGURE 5-4 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).

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):355–372 www.ContinuumJournal.com 365

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 CNS Lymphoma and Hematologic Malignancies

KEY POINTS
h CNS involvement of
Waldenström
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 Waldenström
macroglobulinemia and
IgA or IgG myeloma can
lead to hyperviscosity
syndrome, resulting in
reduced flow through
the cerebral and
retinal vasculature.

FIGURE 5-5 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.
44
Reprinted with permission from Fuehrer N, et al, Neurology. B 2011 AAN Enterprises, Inc. www.neurology.org/
content/77/19/e110.long.

IgM-producing malignant cell clone intra-
thecally.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, plasma-
blastic morphology, extramedullary disease
(21% of patients with multiple myeloma),
and cytogenetic abnormalities.48,49 It typi-
cally presents as leptomeningeal me-
tastasis. Diagnosis can be made by MRI
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. Waldenström
macroglobulinemia and IgA or IgG myeloma
can lead to hyperviscosity syndrome, result-
ing in reduced flow through the cerebral
and retinal vasculature. Patients typically
present with TIAs and blurry vision. Plasma
exchange and treatment of Waldenström
macroglobulinemia result in symp-
tom alleviation.

366 www.ContinuumJournal.com April 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Neuropathy. Neuropathy can be seen in
monoclonal gammopathy of undetermined
significance (MGUS), multiple myeloma,
and Waldenström 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 glycopro-
tein (MAG) can be found in many patients
with IgM MGUS. Up to 50% of patients
with IgM MGUS develop a severe symp-
tomatic neuropathy, some with demye-
linating 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
Waldenström 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, mono-
clonal 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 pred-
nisone, melphalan, thalidomide, or local
radiation. In patients with refractory neu-
ropathy due to multiple myeloma, high-
dose chemotherapy and autologous stem
cell transplantation have been tried.52
Amyloid polyneuropathy is seen more
commonly in multiple myeloma and is
rare in Waldenström 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):355–372
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
Waldenström macroglobulinemia, mul- h Neuropathy can be
tiple myeloma, and MGUS can cause an seen in monoclonal
epineurial vasculitis leading to nerve gammopathy of
ischemia and neuropathy. undetermined
significance, multiple
Neurologic Complications of myeloma, and
Leukemias Waldenström
Leptomeningeal involvement. Acute macroglobulinemia.
leukemias have a high incidence of h A variety of neurologic
leptomeningeal metastasis, typically symptoms attributed
occurring at relapse. With the intro- to chloroma are related
duction of CNS prophylaxis in induc- to compression of
tion treatment, the risk is reduced, but underlying brain, nerves,
approximately 5% to 15% of adults with or spinal cord, such as
single or multiple
acute lymphoblastic leukemia (ALL)
compression neuropathies,
develop leptomeningeal metastasis.53
low back pain, and
Treatment includes craniospinal radiation, cord compression.
intensive systemic chemotherapy, intra-
thecal chemotherapy, or high-dose che- h Chloromas are
radiosensitive tumors,
motherapy followed by autologous stem
and radiation therapy
cell transplantation. Chronic leukemias results in excellent
rarely develop leptomeningeal metastasis. local disease control
Chloromas. Chloroma is a rare ex- and palliation of
tramedullary tumor of immature myeloid symptoms without
cells most commonly related to acute significant toxicity.
myelogenous leukemia (AML), often oc- h Leukemic cell
curring in the skull or spine. A variety of infiltration can
neurologic symptoms attributed to chlo- cause venous
roma are related to compression of un- sinus thrombosis
derlying brain, nerves, or spinal cord, such and associated
as single or multiple compression neu- hemorrhagic infarctions.
ropathies, low back pain, and cord com-
pression. Chloromas are radiosensitive
tumors, and radiation therapy results in
excellent local disease control and pal-
liation of symptoms without significant
toxicity (Case 5-3).54
Intracranial hemorrhage. Intracra-
nial hemorrhage is a common neuro-
logic complication in acute leukemias,
with a high mortality rate (20%). It may
result from disseminated intravascular co-
agulation (common in acute promyelocytic
leukemia), thrombocytopenia, blast crisis,
or leukocytosis (more than 300,000 cells/HL).
Disseminated mucormycosis or aspergil-
losis and L-asparaginaseYinduced intracra-
nial dural sinus thrombosis can also lead
to intracranial hemorrhage. Leukemic
www.ContinuumJournal.com 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 hemor-
rhagic infarctions.
Lymphomatoid Granulomatosis
of the CNS
Lymphomatoid granulomatosis is a rare
EBV-positive lymphoproliferative disor-
der characterized by B-cell proliferation
associated with T-cell infiltration, graded I
to III based on the proportion of large, EBV-
positive 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 de-
pend on the location of involvement. This
may also manifest as immune reconstitu-
tion syndrome in immunocompromised
patients. Brain biopsy helps with diagno-
sis. Treatment consists of corticosteroids,
chemotherapy, or radiation therapy for
high-grade lesions.
Summary
Neurologic complications of hemato-
logic malignancies may involve the CNS
as well as the peripheral nervous system.
Direct involvement may result from inva-
sion or compression and is more com-
mon 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. Neuro-
logic complications from indirect effects
of hematologic malignancies may be vas-
cular, infectious, or paraneoplastic. Neu-
ropathy in plasma cell disorders can
result from autoantibodies, cryoglob-
ulinemia, or amyloid deposition or as a
side effect of the treatment.
CONCLUSION
Primary CNS lymphoma is an aggressive
brain tumor with poor prognosis. Diag-
nosis can be made by CSF or vitreous
fluid analysis or by stereotactic brain
biopsy. Baseline staging is recommen-
ded before starting treatment. Age and
performance status are important prog-
nostic factors. High-dose methotrexateY
based treatment achieves high response

368 www.ContinuumJournal.com April 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

rates, but recurrences occur frequently.
There is no consensus on consolidative
therapy; reduced-dose whole-brain radia-
tion therapy and high-dose chemotherapy
followed by autologous stem cell trans-
plant 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 leuke-
mia; CNS prophylaxis is routinely incor-
porated in these patients. In contrast to
primary CNS lymphoma, CNS involve-
ment of systemic lymphoma or leukemia
usually manifests as leptomeningeal dis-
ease. Vascular complications in the form
of ischemic events can occur with intra-
vascular lymphoma characterized by lym-
phoma cells within the vascular lumen,
primary angiitis in Hodgkin lymphoma,
or related to hyperviscosity syndrome in
Waldenström macroglobulinemia. Acute
leukemias may cause intracranial hemor-
rhage. 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 neuro-
logic recovery and improved outcomes.
REFERENCES
1. Dolecek TA, Propp JM, Stroup NE, Kruchko
C. CBTRUS statistical report: primary brain
and central nervous system tumors
diagnosed in the United States in 2005Y2009.
Neuro Oncol 2012;14(suppl 5):v1Yv49.
doi:10.1093/neuonc/nos218.
2. O’Neill BP, Decker PA, Tieu C, Cerhan JR.
The changing incidence of primary central
nervous system lymphoma is driven
primarily by the changing incidence in
young and middle-aged men and differs
from time trends in systemic diffuse large
B-cell non-Hodgkin’s lymphoma. Am J
Continuum (Minneap Minn) 2015;21(2):355–372
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Hematol 2013;88(12):997Y1000.
doi: 10.1002/ajh.23551.
3. Barajas RF Jr, Rubenstein JL, Chang JS, et al.
Diffusion-weighted MR imaging derived
apparent diffusion coefficient is predictive
of clinical outcome in primary central
nervous system lymphoma. AJNR Am J
Neuroradiol 2010;31(1):60Y66.
doi:10.3174/ajnr.A1750.
4. Rubenstein JL, Hsi ED, Johnson JL, et al.
Intensive chemotherapy and
immunotherapy in patients with newly
diagnosed primary CNS lymphoma: CALGB
50202 (Alliance 50202). J Clin Oncol
2013;31(25):3061Y3068. doi:10.1200/
JCO.2012.46.9957.
5. Abrey LE, Batchelor TT, Ferreri AJ, et al.
Report of an international workshop
to standardize baseline evaluation and
response criteria for primary CNS lymphoma.
J Clin Oncol 2005;23(22):5034Y5043.
doi:10.1200/JCO.2005.13.524.
6. Korfel A, Schlegel U. Diagnosis and
treatment of primary CNS lymphoma.
Nat Rev Neurol 2013;9(6):317Y327.
doi:10.1038/nrneurol.2013.83.
7. Ferreri AJ, Blay JY, Reni M, et al. Prognostic
scoring system for primary CNS lymphomas:
the International Extranodal Lymphoma Study
Group experience. J Clin Oncol 2003;21(2):266Y272.
doi:10.1200/JCO.2003.09.139.
8. Abrey LE, Ben-Porat L, Panageas KS, et al.
Primary central nervous system lymphoma:
the Memorial Sloan-Kettering Cancer Center
prognostic model. J Clin Oncol 2006;24(36):
5711Y5715. doi:10.1200/JCO.2006.08.2941.
9. Pels H, Juergens A, Schirgens I, et al. Early
complete response during chemotherapy
predicts favorable outcome in patients with
primary CNS lymphoma. Neuro Oncol 2010;
12(7):720Y724. doi:10.1093/neuonc/noq010.
10. Bellinzona M, Roser F, Ostertag H, et al.
Surgical removal of primary central nervous
system lymphomas (PCNSL) presenting as
space occupying lesions: a series of 33
cases. Eur J Surg Oncol 2005;31(1):100Y105.
doi:10.1016/j.ejso.2004.10.002.
11. Nayak L, Batchelor TT. Recent advances in
treatment of primary central nervous
system lymphoma. Curr Treat Options
Oncol 2013;14(4):539Y552. doi:10.1007/
s11864-013-0252-6.
12. Weller M, Martus P, Roth P, et al.
Surgery for primary CNS lymphoma?
Challenging a paradigm. Neuro Oncol
2012;14(12):1481Y1484.
doi:10.1093/neuonc/nos159.
www.ContinuumJournal.com 369
 CNS Lymphoma and Hematologic Malignancies
13. Batchelor T, Carson K, O’Neill A, et al.
Treatment of primary CNS lymphoma with
methotrexate and deferred radiotherapy:
a report of NABTT 96-07. J Clin Oncol
2003;21(6):1044Y1049. doi:10.1200/
JCO.2003.03.036.
14. Herrlinger U, Kuker W, Uhl M, et al.
NOA-03 trial of high-dose methotrexate in
primary central nervous system lymphoma:
final report. Ann Neurol 2005;57(6):843Y847.
doi:10.1002/ana.20495.
15. Shah GD, Yahalom J, Correa DD, et al.
Combined immunochemotherapy with
reduced whole-brain radiotherapy for
newly diagnosed primary CNS lymphoma.
J Clin Oncol 2007;25(30):4730Y4735.
doi:10.1200/JCO.2007.12.5062.
16. Pels H, Schmidt-Wolf IG, Glasmacher A,
et al. Primary central nervous system
lymphoma: results of a pilot and phase
II study of systemic and intraventricular
chemotherapy with deferred radiotherapy.
J Clin Oncol 2003;21(24):4489Y4495.
doi:10.1200/JCO.2003.04.056.
17. Pels H, Juergens A, Glasmacher A, et al.
Early relapses in primary CNS lymphoma
after response to polychemotherapy
without intraventricular treatment:
results of a phase II study. J Neurooncol
2009;91(3):299Y305.
doi:10.1007/s11060-008-9712-4.
18. Khan RB, Shi W, Thaler HT, et al. Is intrathecal
methotrexate necessary in the treatment of
primary CNS lymphoma? J Neurooncol
2002;58(2):175Y178. doi:10.1023/
A:1016077907952.
19. Sierra Del Rio M, Ricard D, Houillier C, et al.
Prophylactic intrathecal chemotherapy
in primary CNS lymphoma. J Neurooncol
2012;106(1):143Y146.
doi:10.1007/s11060-011-0649-7.
20. Morris PG, Correa DD, Yahalom J, et al.
Rituximab, methotrexate, procarbazine, and
vincristine followed by consolidation
reduced-dose whole-brain radiotherapy and
cytarabine in newly diagnosed primary CNS
lymphoma: final results and long-term
outcome. J Clin Oncol 2013;31(31):3971Y3979.
doi:10.1200/JCO.2013.50.4910.
21. Thiel E, Korfel A, Martus P, et al. High-dose
methotrexate with or without whole
brain radiotherapy for primary CNS
lymphoma (G-PCNSL-SG-1): a phase 3,
randomised, non-inferiority trial. Lancet
Oncol 2010;11(11):1036Y1047.
doi:10.1016/S1470-2045(10)70229-1.
22. Omuro A, Taillandier L, Chinot O, et al.
Primary CNS lymphoma in patients younger
370 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
than 60: can whole-brain radiotherapy be
deferred? J Neurooncol 2011;104(1):323Y330.
doi:10.1007/s11060-010-0497-x.
23. Correa DD, Shi W, Abrey LE, et al. Cognitive
functions in primary CNS lymphoma after
single or combined modality regimens.
Neuro Oncol 2012;14(1):101Y108.
doi:10.1093/neuonc/nor186.
24. Illerhaus G, Muller F, Feuerhake F, et al.
High-dose chemotherapy and autologous
stem-cell transplantation without consolidating
radiotherapy as first-line treatment for
primary lymphoma of the central nervous
system. Haematologica 2008;93(1):147Y148.
doi:10.3324/haematol.11771.
25. Illerhaus G, Marks R, Ihorst G, et al. High-dose
chemotherapy with autologous stem-cell
transplantation and hyperfractionated
radiotherapy as first-line treatment of
primary CNS lymphoma. J Clin Oncol
2006;24(24):3865Y3870. doi:10.1200/
JCO.2006.06.2117.
26. Schorb E, Kasenda B, Atta J, et al. Prognosis
of patients with primary central nervous
system lymphoma after high-dose
chemotherapy followed by autologous
stem cell transplantation. Haematologica
2013;98(5):765Y770. doi:10.3324/
haematol.2012.076075.
27. Kiefer T, Hirt C, Spath C, et al. Long-term
follow-up of high-dose chemotherapy
with autologous stem-cell transplantation
and response-adapted whole-brain
radiotherapy for newly diagnosed primary
CNS lymphoma: results of the multicenter
Ostdeutsche Studiengruppe Hamatologie
und Onkologie OSHO-53 phase II study.
Ann Oncol 2012;23(7):1809Y1812.
doi:10.1093/annonc/mdr553.
28. Montemurro M, Kiefer T, Schuler F, et al.
Primary central nervous system lymphoma
treated with high-dose methotrexate,
high-dose busulfan/thiotepa,
autologous stem-cell transplantation
and response-adapted whole-brain
radiotherapy: results of the multicenter
Ostdeutsche Studiengruppe Hamato-Onkologie
OSHO-53 phase II study. Ann Oncol
2007;18(4):665Y671. doi:10.1093/
annonc/mdl458.
29. Soussain C, Hoang-Xuan K, Taillandier L, et al.
Intensive chemotherapy followed by
hematopoietic stem-cell rescue for refractory
and recurrent primary CNS and intraocular
lymphoma: Societe Francaise de Greffe de
Moelle Osseuse-Therapie Cellulaire. J Clin
Oncol 2008;26(15):2512Y2518. doi:10.1200/
JCO.2007.13.5533.
April 2015
30. Soussain C, Choquet S, Fourme E, et al.
Intensive chemotherapy with thiotepa,
busulfan and cyclophosphamide and
hematopoietic stem cell rescue in relapsed
or refractory primary central nervous system
lymphoma and intraocular lymphoma:
a retrospective study of 79 cases.
Haematologica 2012;97(11):1751Y1756.
doi:10.3324/haematol.2011.060434.
31. Bernstein SH, Unger JM, Leblanc M, et al.
Natural history of CNS relapse in patients
with aggressive non-Hodgkin’s lymphoma: a
20-year follow-up analysis of SWOG
8516Vthe Southwest Oncology Group. J
Clin Oncol 2009;27(1):114Y119. doi:10.1200/
JCO.2008.16.8021.
32. Chihara D, Oki Y, Matsuo K, et al. Incidence
and risk factors for central nervous system
relapse in patients with diffuse large B-cell
lymphoma: analyses with competing risk
regression model. Leuk Lymphoma
2011;52(12):2270Y2275. doi:10.3109/
10428194.2011.596966.
33. Ferreri AJ, Assanelli A, Crocchiolo R, Ciceri F.
Central nervous system dissemination
in immunocompetent patients with
aggressive lymphomas: incidence,
risk factors and therapeutic options.
Hematol Oncol 2009;27(2):61Y70.
doi:10.1002/hon.881.
34. Villa D, Connors JM, Shenkier TN, et al.
Incidence and risk factors for central
nervous system relapse in patients with
diffuse large B-cell lymphoma: the impact
of the addition of rituximab to CHOP
chemotherapy. Ann Oncol 2010;21(5):
1046Y1052. doi:10.1093/annonc/mdp432.
35. Zhang J, Chen B, Xu X. Impact of rituximab
on incidence of and risk factors for central
nervous system relapse in patients with
diffuse large B-cell lymphoma: a systematic
review and meta-analysis. Leuk Lymphoma
2014;55(3):509Y514. doi:10.3109/
10428194.2013.811239.
36. Yamamoto W, Tomita N, Watanabe R, et al.
Central nervous system involvement in diffuse
large B-cell lymphoma. Eur J Haematol 2010;85(1):
6Y10. doi:10.1111/j.1600-0609.2010.01438.x.
37. Pentsova E, Rosenblum M, Holodny A, et al.
Chemotherapy-related mangnetic resonance
imaging abnormalities mimicking disease
progression following intraventricular liposomal
cytarabine and high dose methotrexate for
neurolymphomatosis. Leuk Lymphoma 2012;
53(8):1620Y1622. doi:10.3109/
10428194.2012.656632.
38. Fischer L, Korfel A, Kiewe P, et al. Systemic
high-dose methotrexate plus ifosfamide is
Continuum (Minneap Minn) 2015;21(2):355–372
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
highly effective for central nervous system
(CNS) involvement of lymphoma. Ann
Hematol 2009;88(2):133Y139. doi:10.1007/
s00277-008-0575-8.
39. Bromberg JE, Doorduijn JK, Illerhaus G,
et al. Central nervous system recurrence of
systemic lymphoma in the era of stem cell
transplantationVan International Primary
Central Nervous System Lymphoma Study
Group project. Haematologica
2013;98(5):808Y813. doi:10.3324/
haematol.2012.070839.
40. Korfel A, Elter T, Thiel E, et al. Phase II
study of central nervous system
(CNS)-directed chemotherapy including
high-dose chemotherapy with autologous
stem cell transplantation for CNS relapse
of aggressive lymphomas. Haematologica
2013;98(3):364Y370. doi:10.3324/
haematol.2012.077917.
41. McMillan A, Ardeshna KM, Cwynarski K,
et al. Guideline on the prevention of
secondary central nervous system
lymphoma: British Committee for
Standards in Haematology. Br J Haematol
2013;163(2):168Y181. doi:10.1111/bjh.12509.
42. Gerstner ER, Abrey LE, Schiff D, et al. CNS Hodgkin
lymphoma. Blood 2008;112(5):1658Y1661.
doi:10.1182/blood-2008-04-151563.
43. Birnbaum J, Hellmann DB. Primary
angiitis of the central nervous system.
Arch Neurol 2009;66(6):704Y709.
doi:10.1001/archneurol.2009.76.
44. Fuehrer NE, Hammack JE, Morris JM, et al.
Teaching neuroimages: granulomatous
angiitis of the CNS associated with Hodgkin
lymphoma. Neurology 2011;77(19):e110Ye111.
doi:10.1212/WNL.0b013e318236eefb.
45. Graus F, AriDo H, Dalmau J. Paraneoplastic
neurological syndromes in Hodgkin and
non-Hodgkin lymphomas. Blood
2014;123(21):3230Y3238. doi:10.1182/
blood-2014-03-537506.
46. Malkani RG, Tallman M, Gottardi-Littell N,
et al. Bing-Neel syndrome: an illustrative
case and a comprehensive review of the
published literature. J Neurooncol 2010;96(3):
301Y312. doi:10.1007/s11060-009-9968-3.
47. Zetterberg H. Pathognomonic
cerebrospinal fluid findings in Bing-Neel
syndrome. J Neurooncol 2011;104(2):615.
doi:10.1007/s11060-010-0510-4.
48. Fassas AB, Ward S, Muwalla F, et al. Myeloma
of the central nervous system: strong association
with unfavorable chromosomal abnormalities
and other high-risk disease features. Leuk
Lymphoma 2004;45(2):291Y300. doi:10.1080/
10428190310001597964.
www.ContinuumJournal.com 371
 CNS Lymphoma and Hematologic Malignancies
49. Rasche L, Bernard C, Topp MS, et al. Features
of extramedullary myeloma relapse: high
proliferation, minimal marrow involvement,
adverse cytogenetics: a retrospective
single-center study of 24 cases. Ann
Hematol 2012;91(7):1031Y1037. doi:10.1007/
s00277-012-1414-5.
50. Lunn MP, Nobile-Orazio E. Immunotherapy
for IgM anti-myelin-associated glycoprotein
paraprotein-associated peripheral
neuropathies. Cochrane Database
Syst Rev 2012;5:CD002827. doi:10.1002/
14651858.CD002827.pub3.
51. Richardson PG, Xie W, Mitsiades C, et al.
Single-agent bortezomib in previously untreated
multiple myeloma: efficacy, characterization of
peripheral neuropathy, and molecular
correlations with response and neuropathy.
J Clin Oncol 2009;27(21):3518Y3525.
doi:10.1200/JCO.2008.18.3087.
52. Dispenzieri A. POEMS syndrome: 2014 update
on diagnosis, risk stratification, and
372 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
management. Am J Hematol2014 89(2):214Y223.
doi:10.1002/1jh.23644.
53. Reman O, Pigneux A, Huguet F, et al. Central
nervous system involvement in adult acute
lymphoblastic leukemia at diagnosis and/or
at first relapse: results from the GET-LALA
group. Leuk Res 2008;32(11):1741Y1750.
doi:10.1016/j.leukres.2008.04.011.
54. Bakst R, Wolden S, Yahalom J. Radiation therapy
for chloroma (granulocytic sarcoma). Int J
Radiat Oncol Biol Phys 2012;82(5):1816Y1822.
doi:10.1016/j.ijrobp.2011.02.057.
55. Katzenstein AL, Doxtader E, Narendra S.
Lymphomatoid granulomatosis: insights gained
over 4 decades. Am J Surg Pathol 2010;34(12):
e35Ye48. doi:10.1097/PAS.0b013e3181fd8781.
56. Lucantoni C, De Bonis P, Doglietto F, et al.
Primary cerebral lymphomatoid granulomatosis:
report of four cases and literature review. J
Neurooncol 2009;94(2):235Y242. doi:10.1007/
s11060-009-9834-3.
April 2015