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.41-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):248Y2575-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

Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

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 tumor2-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

2-Marc C., The Neurologist 2006;12: 179–187

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 Dxof LM› 0-22.6 yr

Median interval times› Solid tumor 2 yr

› Hematologic primary tumor 11 months

2-Marc C., The Neurologist 2006;12: 179–187

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.

Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

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 perivascularspaces

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

Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

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.

Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

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

11-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 2005

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.

11-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 200512-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):328–342.

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

12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate

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 neoplasticlymphocytes 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.

Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

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 reseviors1. 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 noncommunicatinghydrocephalus.

› Patients with lower extremity weakness, or bladder or bowel dysfunction, generally receive lumbosacralspine 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 placementMarc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180

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


Introduction

Epidemiology

Pathophysiology


Diagnosis

Treatment

Case discussion

A 40 year-old women presented with progressive headache for 3 weeks. She notices that the headache was aggrevatedby 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 neoadjuvantchemotherapy (doxorubicin and cyclophosphamide), followed by docetaxeland 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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