Leptomeningeal metastasis

 Introduction
 Epidemiology
 Pathophysiology
 Clinical Presentation
 Diagnosis
 Treatment
 Case discussion

 Leptomeninges – defined as the Pia mater
and the arachnoid.
 Ability to metastasize from the primary
tumor and spread to distant sites in the
body is a cardinal feature of malignancy.
 Invasion of leptomeninges or CSF by cancer
is called leptomeningeal metastasis (LM) or
neoplastic meningitis.

 Carcinomatous meningitis → carcinoma
 Meningeal gliomatosis → malignant glial
tumors
 Leptomeningeal metastasis → solid tumors
 Lymphomatous meningitis → lymphoma
 Leukemic meningitis → leukemia

 Historically, LM were often diagnosed at
autopsy.
 1978 : Among 2375 autopsies of cancer pts,
LM occurred in 8%1
 2008 : Metastasis to the brain parenchyma
is relatively common, occurring in 9% to 15%
of cases in autopsy studies of patients who
die of cancer,3 and tumors can also
metastasize to the dura or to the
leptomeninges.4
1-Postner, Intracranial metastanses from systemic cancer, Advances in Neurology 1978
3-DeAngelis L, Posner J. Neurological complications of cancer. 2nd ed. New York,NY: Oxford University Press, 2008
4-Suki D, Abouassi H, Patel AJ, et al. Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to
the posterior fossa. J Neurosurg 2008;108(2):248Y257

 LM known for well over 100 years5; it was
once thought to be rare but has been
diagnosed more frequently in recent years.
3-DeAngelis L, Posner J. Neurological complications of cancer. 2nd ed. New York,NY: Oxford University Press, 2008
4-Suki D, Abouassi H, Patel AJ, et al. Comparative risk of leptomeningeal disease after resection or stereotactic
radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008;108(2):248Y257
5-Eberth C. Zur Entwickelung des Epithelioms (Cholesteatoms) der Pia und der Lunge. Virchows Arch 1870;49:51Y63

 Multiple reasons for the increased
frequency of diagnosis of LM
› Improved diagnostic methods → MRI
› More frequency use of MRI
› Survive longer → more effective Tx, and
LM tends to be a late-stage development
› Use of agents that do not cross the blood
brain barrier eg, trastuzumab in breast
cancer and gefitinib or erlotinib in non-
small cell lung cancer

 Clinically diagnosed LM affect ~ 5% of pt
with metastatic cancer but undiagnosed or
asymptomatic involvement is more
common2
 In Autopsy studies → the frequency of LM
averages 19% of pts with cancer pts.6
 LM is diagnosed in 7
› 4-15% of pt with solid tumors
› 5-15% of pt with leukemia and lymphoma
› 1-2% of pt with primary brain tumor
2-Marc C., The Neurologist 2006;12: 179–187
6-Glass JP, Melamed M, Chernik NL, et al. Malignant cells in cerebrospinalfluid (CSF): the meaning of a positive CSF cytology.
Neurology 1979;29:1369 –1375.
7-Chamberlain MC. Carcinomatous meningitis. Arch Neurol. 1997;54:16–17.

 Adenocarcinoma is the most frequent
histology.2
 Breast, lung and melanoma are the most
common primary sites to LM.2
 >70% presents in pts with widely
disseminated and progressive systemic
cancer 2
 20% present after a disease-free interval2
 5-10% be the first manisfestation of
cancer2

Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180

Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):328–342.

 Median age
› 56 yr (19-87 yr)
 Median Karnofsky Performance Scale Score
› 70 (10-100)
 Length of time from initial cancer Dx to Dx
of LM
› 0-22.6 yr
 Median interval times
› Solid tumor 2 yr
› Hematologic primary tumor 11 months

 Mortality/Morbidity8
› Median survival;
 7 months for LM from Breast cancers
 4 months for LM from Small cell lung cancers
 3.6 months for LM from Melanomas
› Without therapy, survive 4-6 weeks (death
with progressive neurologic dysfunction)
› With therapy, most pts die from the systemic
complication of their cancer
8-R Andrew Sewell, Leptomeningeal Carcinomatosis , Medscape

 Treatment remains palliative, and median
survival is typically in the range of 2 to 3
months.
 In the MSKCC series
› Overall median survival was 2.4 months (95% CI,
1.9-3.1).
› Median survival for patients with solid tumors was
2.3 months (95% CI,1.7-2.6)
› Median survival for patients with hematopoietic
tumors was a slightly better 4.7 months
(95%CI, 2.7-6.8)
12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.

 Cancer cells reach the meninges by
various routes9
1. Direct extension from contiguous tumor
deposits
2. Hematogenous spread, either through the
venous plexus of Batson or by arterial
dissemination
3. Through centripetal migration from systemic
tumors along perineural or perivascular
spaces
9-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 2005

 Tumor cells may also invade the spinal or
cranial nerves, cerebral cortex, or spinal
cord via the Virchow-Robin spaces
 Cancer cells are transported by CSF flow
resulting in disseminated and multifocal
neuraxis seeding of LM
 Tumor infiltration is most prominent at the
base of brain (basillar cisterns), the dorsal
surface of the spinal cord, and the cauda
equina

 LM classically presents with pleomorphic
clinical manisfestations encompassing
synmptoms and signs in 3 domains
› Cerebral hemispheres
› Posterior fossa/Cranial nerves
› Spinal cord and roots

 The finding of multifocal neuraxis disease in
a patient with known malignancy is strongly
suggestive of LM
 1/3 patients with LM to present with isolated
syndromes such as symptoms of raised
intracranial pressure, cauda equina
syndrome, or cranial neuropathy.

 The evaluation begins with a careful
history, seeking complaints suggestive of
multifocal involvement.
 The diagnosis of LM is straightforward in
the patient with advanced cancer,
multifocal signs and symptoms, typical
imaging findings, and positive CSF
cytology.
Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate

 MRI and CSF are complementary, and the use
of both increases diagnostic accuracy.10
 An enhanced MRI of the symptomatic region
of brain or spine should be obtained prior to
doing a lumbar puncture (LP) or ventricular
tap.
 A positive CSF cytology establishes the
diagnosis of LM.
10-Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic resonance imaging
and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999; 246:810.

 Patients may be diagnosed with LM when
one of the following criteria is met:11
1. Positive CSF cytology
2. Positive LM biopsy
3. Positive MRI in a pateint with a clinical
syndrome compatible with the diagnosis
4. Abnormal CSF biochemical markers consistent
with LM

 MRI should be performed in pt with
suspected LM.
 MRI with gadolinium enhancement(MR-Gd)
is the technique of choice to evaluate
patients with suspected leptomeningeal
metastasis.
 T1-weighted sequences, with and without
contrast, combined with fat suppression T2-
weighted sequences, constitute the
standard examination.

 Highly sensitive for diagnosis of LM from
solid tumors (76-100%)
 Less sensitive for hematopoieric tumors
 MSKCC
› 98% of solid tumor → MRI positive for LM 88%
› 88% of hematopoietic tumor → MRI positive
for LM 48%

 Typical MRI findings
› Leptomeningeal enhancement in LM can be linear
but often has irrigularity or nodularity
› Often visible in the subarachnoid space, cerebellar
folia, or cortical surface, and tumor masses,
especially at the base of the brain, with or without
hydrocephalus13
 Occasionally, frank LM are not seen on MRI,
but bulky subependymal disease or multiple
small sulcal metastases suggest the diagnosis13
13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate

 In patients with encephalopathy and no
localizing findings on MRI, the diagnosis
may be suggested by positron emission
tomography (PET) demonstrating diffusely
diminished glucose utilization in an
otherwise normal-appearing brain13

 MRI can show linear enhancement of
the entire cord and linear or nodular
enhancement of the cauda equina.13
 Occasionally, clumping of nerve roots at
the cauda equina suggests the diagnosis
if contrast enhancement is not seen.13
 A spinal tumor may obstruct CSF flow,
resulting in hydrocephalus

 CSF analysis is the gold standard for diagnosis of LM.12
 The presence of malignant cells in the CSF is
diagnostic of LM. (sensitivite 71% → 86% → 93% →…)12
 The CSF is abnormal in nearly all patients, but many
abnormalities are non-specific.11
 Abnormalities include11
1. increased opening pressure (200 mm of H2O)
2. Increased leukocytes (4/mm3)
3. elevated protein (50 mg/dL)
4. decreased glucose (60 mg/dL)
› which, though suggestive of LM, are not diagnostic.

 Tumor markers (eg, CEA, PSA, CA-15-3, CA-125, and
MART-1 and MAGE-3 in melanoma) may provide
evidence for CSF dissemination of disease, even when
serial cytological evaluations are negative.13
 Level of tumor markers are compared between CSF
and Serum if CSF level greater than 1% of that in the
serum is virtually diagnostic of LM.12

 Use of monoclonal antibodies for
immunohistochemical analysis in LM does not
significantly increase the sensitivity of cytology
alone.
 However, in the case of leukemia and lymphoma,
antibodies against surface markers can be used to
distinguish between reactive and neoplastic
lymphocytes in the CSF.

 Cytogenetic studies have also been evaluated in an
attempt to improve the diagnostic accuracy of LM.
 Flow cytometry and DNA single cell cytometry,
techniques that measure the chromosomal content
of cells, and fluorescent in situ hybridization (FISH) that
detects numerical and structural genetic aberrations
as a sign of malignancy can give additional
diagnostic information but still have a low sensitivity.
 In cases where there is no manifestation of systemic
cancer and CSF examinations remain inconclusive,
a meningeal biopsy may be diagnostic.

 The evaluation of treatment of LM is complicated by
the lack of standard treatments
 The difficulty of determining response to treatment
given the suboptimal sensitivity of the diagnostic
procedures and that most patients will die of
systemic disease, and the fact that most studies are
small, nonrandomized,and retrospective
 However, it is clear that treatment of LM can
provide effective palliation and in some cases result
in prolonged survival.
 Treatment requires the combination of surgery,
radiation, and chemotherapy in most cases

 Goals of treatment
› The goals of treatment include stabilizing or
improving neurologic function, prolonging
survival and if these are not possible
 Prognosis
› depending upon the tumor type and extent
of both neurologic and systemic disease
 Patient
› Good risk vs Poor risk patient

 The palliative regimen can include the
following components:
› RT can be useful for relief of symptoms caused
by localized leptomeningeal metastases.
› Analgesics are given for persistent pain.
› Anticonvulsants should be reserved for patients
with seizures (10 to 20 percent of cases) and
should not be administered prophylactically.
› Serotonin reuptake inhibitors or stimulant
medications (eg, modafinil, methylphenidate)
may be beneficial for patients with significant
depression or fatigue.

 Treatment is directed at controlling the
tumor.
 RT is used to treat bulky or symptomatic
areas of leptomeningeal disease,
intrathecal (IT) or systemic
chemotherapy is given to achieve
therapeutic concentrations in the CSF

 Surgery
 Chemothery
› Regional
› Systemic
 Radiotherapy

 Use in treatment of LM for the placement of
1. Intraventricular catheter and subgaleal
reservoir for administration of cytotoxic drugs
2. Ventriculoperitoneal shunt in pts with
symptomatic hydrocephalus
 Drugs can be instilled into the subarachnoid
space by lumbar puncture or via an
intraventricular reservior system

 2 basic types of reseviors
1. Rickham reservior : a flat rigid reservior placed
over a burr hole
2. Ommaya resevior : a dome-shaped resevior
 Reserviors are generally placed over
nondominant frontal region, catheter is
placed into frontal horn of the lateral
ventricle or close to the foramen of Monro.
 Correct placement of the catheter by
noncontrast CT prior to its use for drug
administration, and frequently it will show a
small amount of air in both frontal horns.

 Used in treatment of LM for
1. Palliation of symptoms, such as a cauda equina
syndrome.
2. To decrease bulky disease such as coexistent
parenchymal brain metastases.
3. To correct CSF flow abnormalities demonstrated
by radionuclide ventriculography.

 RT appears to be more effective at relieving
symptoms than does IT chemotherapy.
 Standard treatment for LM includes
palliative RT (30 to 36 Gy in 3 Gy daily
fractions) to sites of symptomatic or bulky
disease.
 Suggest administering RT to sites of
obstruction of CSF flow, as demonstrated by
a radionuclide CSF flow study, prior to IT
chemotherapy.

 To avoid excess myelosuppression and other
toxicity such as severe fatigue, esophagitis,
diarrhea, and nausea, focal rather than
craniospinal RT is preferred.
 Radiation is usually targeted to symptomatic
areas even in the absence of MRI
abnormalities:
› Cranial irradiation is used in patients with isolated
cranial neuropathies or focal collections of
malignant cells causing noncommunicating
hydrocephalus.
› Patients with lower extremity weakness, or bladder or
bowel dysfunction, generally receive lumbosacral
spine irradiation.

 Chemotherapy is the only treatment
modality that can treat the entire
neuraxis.
 Systemic VS Intrathecal CMT

 Systemic chemotherapy is limited by
› Penetration of drug into the CNS
› Degree of chemoresistance of primary tumor
 High doses of Methotrexate (3 – 8 g/m2) or
cytarabine (3 g/m2) produce high enough
serum levels to allow for therapeutic levels
in CSF, but very low permeability.
 Capecitebine, thiotepa and temozolomide
cross BBB more effectively and potent for
treatment LM.

 Systemic chemotherary use in pt with
concomitant parenchymal, dural or
systemic metastasis.
 Choice of agent depend on
› Tumor histology
› Prior drug exposure

 IT CMT is the mainstay of treatment for LM.
 IT chemotherapy infuse directly into the
subarachnoid space via
› Lumbar puncture
› Intraventricular reservoir (Ommaya)
 Methotrexate, thiopeta, cytarabine or
sustained-release cytarabine can be used.
 Minimizes systemic S/E and eliminate BBB or
blood-CSF barrier drug penetration.

 Most common toxicity is an acute
aseptic meningitis, occuring 2-4 hr after
drug instillation.
› Corticosteroids can be used to prevent or
treat
 IT injection via LP can result in
inadvertent subdural or epidural drug
delivery.

 LM often causes communicating
hydrocephalus → ↑ ICP
 Elevated ICP is treated initially with
dexamethasone, and a dose of 8 mg twice
a day is usually effective.
› Dexamethasone should be started early and the
dose reduced as quickly as possible until the
lowest effective dose is achieved.
 Dexamethasone → RT →
Ventriculoperitoneal shunting → Reservoir +
IT CMT

Diagnosis
Supportive care Treatment
Poor prognosis Good Prognosis
CNS imaging
Bulking disease
or symptomatic
sites
No bulky diasease
Ommaya placement

Bulking disease
or symptomatic
sites
Supportive care Radiation therapy
Ommaya placement
CSF flow study

CSF flow study
CSF flow block Normal CSF flow
IT ChemotherapyRT to site of block
CSF flow study
CSF flow block Normal CSF flow

 A 40 year-old women presented with
progressive headache for 3 weeks. She
notices that the headache was aggrevated
by lying down or cough. The headache did
not respond to acetaminophen
 She had breast cancer diagnosis 2 years
ago with positive axillary LNs.
 She was treated with neoadjuvant
chemotherapy (doxorubicin and
cyclophosphamide), followed by docetaxel
and tratuzumab with complete cycles.

 Her neurological examination showed
papilledema.
 MRI brain demonstrated T1-weighted
gadolinium-enhanced of leptomeninges
coating along brainstem and cerebellar
folia.
 CSF showed 10 WBC, protein of 82 mg/dL,
and glucose of 64 mg/dL.
 Cytology demonstrated numerous
malignant cells.

 A 60 year-old man presented with
progressive right facial palsy, followed by
bilateral lower extremities weakness and
urinary incontinence for 3 weeks. He also
had mid-thoracic back pain.
 He has been diagnosed with stage IIIA non-
small cell lung cancer with metastasis to
ipsilateral mediastinal LNs.
 He was treated with cisplatin and
etoposide followed by surgery 1 year ago.

 Neurological examination revealed right
facial palsy (UMN), bilateral legs weakness
(gr III), more severe on left side, with
decreased reflex on right knee jerk and left
ankle jerk.
 MRI spine showed gadolinium enhancing
lesion along cauda equine.
 CSF showed 15 WBC, protein 72 mg/dL and
glucose 20 mg/dL.
 Cytology showed malignant cells.

A. brain abscess
B. leptomeningeal carcinomatosis
C. paraneoplastic cerebellar degeneration
D. pseudotumor cerebri
E. viral meningitis

A. breast cancer
B. lung cancer
C.melanoma
D. prostate cancer
E. thyroid cancer

A. intrathecal chemotherapy
B. lumbar CSF drainage
C. radiation therapy
D. surgical debulking
E. systemic chemotherapy

A. basal ganglia
B. cauda equina
C. cerebral cortex
D. cervical spinal cord
E. thalamus

Leptomeningeal metastasis

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