Professional Documents
Culture Documents
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.
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
355
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.
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,
356
www.ContinuumJournal.com
April 2015
KEY POINT
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 ).
www.ContinuumJournal.com
357
KEY POINTS
h High-dose
methotrexateYbased
chemotherapy is
considered the first-line
treatment for newly
diagnosed primary
CNS lymphoma.
358
www.ContinuumJournal.com
April 2015
KEY POINT
www.ContinuumJournal.com
359
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
www.ContinuumJournal.com
April 2015
KEY POINTS
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.
www.ContinuumJournal.com
361
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.
FIGURE 5-2
362
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.
www.ContinuumJournal.com
April 2015
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
37
www.ContinuumJournal.com
363
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.
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.
364
www.ContinuumJournal.com
April 2015
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
www.ContinuumJournal.com
365
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.
FIGURE 5-5
44
366
www.ContinuumJournal.com
April 2015
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.
www.ContinuumJournal.com
367
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.
368
www.ContinuumJournal.com
April 2015
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
370
www.ContinuumJournal.com
April 2015
371
372
www.ContinuumJournal.com
April 2015