Leptomeningeal Mets Final

8/8/2019 Leptomeningeal Mets Final

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LEPTOMENINGEAL METASTASES

4 CASE REPORTS AND A SHORT DISCUSSION

Dr. T. Sujit

AMO , V N C C



CASE – 1CASE – 1

Mrs.M , 48 / F

Clinical stage : T4b N3 M1 ( liver , adrenal , contralateral axilla )

Bone scan – no bone mets

Plan : Palliative chemotherapy

Received 1 cycle chemo – FAC

On presentation for 2nd cycle chemo , c/o headache and vomiting



CASE – 1 ( contd. )CASE – 1 ( contd. )

MRI brain



CASE – 2CASE – 2

Mrs.K , 38 / F

Diagnosed in 7/2008 with Ca Lt. Breast – Stage IV ( Bil SC nodes; Noother metastatic site )


FAC x 6 --> Taxanes x 6 --> achieved CR --> Tamoxifen x 2 mths

--> skin nodules --> Capecitabine x 4 --> disease progression -- >Carboplatin + Gemcitabine x 3 -- > Vinorelbine x 2 cycles --> c/o

generalised weakness of both upper and lower limbs, no headache




MRI brain :- brain mets ; leptomeningeal mets

Plan : Palliative whole brain radiation therapy ( WBRT )

30 Gy / 10 # / 300 cGy per #

Post WBRT, referred to Raksha in view of progressive disease.



CASE - 3CASE - 3

Mrs.S , 50/ F ,

Ca breast - treated elsewhere; presented with bone mets. No other site of metastatic disease.


Palliative chemo + Bisphosphonates x 3 mths --> c/o headache

MRI - Brain mets --> RT --> FEC x 7 , static disease --> Tamoxifen x5 mths --> liver and bone mets with ascites --> symptomatic Rx .



CASE - 3CASE - 3

MRI brain :

Received WBRT 30 Gy / 10 # / 300 cGy per #

followed by

Palliative chemotherapy FEC x 7, static disease --> Tamoxifen x 5 mth

Developed liver and bone mets with ascites --> symptomatic Rx .



CASE - 4CASE - 4

Mrs.B , 39/F

Presented with locally advanced Ca Lt Breast ( T2 N2 ) ,

Plan : neo-adjuvant chemo followed by surgery & adjuvant chemoRT

NACT – FAC x 3 --> MRM --> ypT2N0 --> RT --> Adjuvant chemo-- > Tamoxifen x 3 mths

While on follow up, c/o difficulty in swallowing – OGD scopy normal.




MRI brain – leptomeningeal carcinomatosis.



LEPTOMENINGEAL METASTASESLEPTOMENINGEAL METASTASES

First recognized by Eberth in 1870

Incidence appears to be increasing

~ most chemotherapeutic agents do not penetrate the blood-brain

barrier (BBB) to any significant degree.~ awareness of this complication and the ability of MRI to diagnose

leptomeningeal metastasis.

LM may be seeded from :~ extracranial solid tumors – breast, lung, melanoma, etc

~ haematologic malignancies – ALL , NHL, AML

~ Primary CNS tumors - medulloblastoma, primary CNS lymphoma



LM FROM SOLID TUMORSLM FROM SOLID TUMORS

3-8% of patients with solid tumors will develop LM during the course of their illness.

LM from solid tumors typically occurs with advanced stage disease

when patients have diffuse systemic metastases.

20% of patients have isolated LM while approximately 30% of patientswith LM have concomitant brain or epidural metastases

Frequency : Breast (51%) , Lung – NSCLC (17%), Melanoma (13%),Genito-Urinary tumors (4.8%), GI tumors (1.6%), H&N tumors (1.6%),Unknown primary (2.4%)



LM FROM SOLID TUMORSLM FROM SOLID TUMORS

The observed incidence of LM from solid tumors appears to beincreasing for a variety of reasons.

~ Cytologic methods of diagnosis have improved.

~ As patients with cancer continue to live longer, this complicationhas more time to develop.

~ Improvements in imaging – increased detection.

On the other hand, intrathecal prophylaxis has caused LM to becomeless common in patients with haematological malignancies likeleukemia and non-Hodgkin's lymphoma.



M - HAEMATOLOGIC MALIGNANCIESM - HAEMATOLOGIC MALIGNANCIES

Approximately 10-30% of patients with acute leukemia will have LMdissemination at diagnosis

Children, particularly those younger than two years are at highest risk

Disease-specific CNS prophylaxis has dramatically decreased the riskof LM relapse to less than 5%

Rarely seen in patients with CLL, CML or multiple myeloma.



LM - LYMPHOMALM - LYMPHOMA

Observed in <3% of indolent lymphomas, 5% of aggressive

lymphomas (diffuse large B-cell and peripheral T-cell lymphomas) and24% of Burkitt's and lymphoblastic lymphomas.

Actuarial risk at one year after diagnosis of 4.5% - can be reduced to<2% if patients are treated with chemotherapy that includes intrathecaland systemic HD-MTX.

RISK FACTORS : Advanced disease, increased serum levels of LDH,certain extranodal sites of disease, highly aggressive lymphoma

histologies .

Higher frequency of cranial nerve signs as initial manifestations of LM



LM – PRIMARY CNS TUMORSLM – PRIMARY CNS TUMORS

Relatively rare, but is clinically relevant for patients withmedulloblastoma, primary CNS lymphomas and germ cell tumors.

MECHANISMS

DIRECT CONTACT : A tumor might be in direct contact with the CSFpathways, as in the case of a medulloblastoma or intraventricular tumor.

DIRECT EXTENSION : Tumor cells might invade the leptomeningeal

space by moving through and/or displacing normal brain parenchyma,then eroding through the pia mater or ependyma..

DIRECT INOCULATION : Tumor cells might be directly "inoculated"into the CSF at the time of a surgical procedure, such as a craniotomyor CSF shunt.



LM – PRIMARY CNS TUMORSLM – PRIMARY CNS TUMORS



PATHOPHYSIOLOGY PATHOPHYSIOLOGY

Once the tumor cells gain access to the CSF, there is direct

communication with the entire subarachnoid space.

Tumor cells are carried by bulk flow, with most deposits occurring atthe base of the skull or spine.

Hematogenous spread to involve the brain parenchyma or choroidplexus - rupture and seeding of leptomeninges with micrometastases.

In leukemia, malignant cells enter the subarachnoid space via thin-walled microscopic veins in the arachnoid membrane and seed the

meninges

Paravertebral spread along the cranial or spinal nerve roots, Invasionof the perineural spaces by the primary focus, Cervical lymph nodescommunicating directly with the subarachnoid space, and Tumor growth into the subdural space.



CLINICAL FEATURESCLINICAL FEATURES

Multi-focal symptoms and signs related to different levels of the

neuraxis – hallmark of leptomeningeal metastases.

Isolated neurologic symptoms occur in 30-53 % of patients with LM,

MECHANISMS:~ obstruction of CSF flow - increased intracranial pressure (ICP)

~ meningeal irritation

~ focal signs from brain, cranial nerves, spinal cord / nerves

~ cerebral infarction from a cerebral vasculopathy

~ changes in brain metabolism & reduction in cerebral blood flowcausing a diffuse encephalopathy

Symptoms can be divided into CNS, cranial neuropathies or spinal /

radicular symptoms.




CNS symptoms and signs :

Headache associated with nausea, vomiting or lightheadedness

Meningismus and nuchal rigidity

Alteration in mental status and gait disturbances

UMN weakness

Central hypoventilation



blahblah

Cranial neuropathies :

Solid tumors more commonly affects the oculomotor nerves.

Hematological malignancies affects the facial nerves .

MC cranial nerve affected : CN II and III

COMMON : Diplopia, numbness, visual loss, hearing loss or vertigo

LESS COMMON : altered taste, dysarthria, swallowing difficulty,hoarseness or glossopharyngeal neuralgia

The differential diagnosis of cranial neuropathies in cancer patientsinclude base of skull metastasis, infiltration of extra cranial nervestructures, or infection.





Spinal / radicular symptoms and signs :

More than 50 % of patients with LM have spinal symptoms

The cauda equina is a common site of nodular formation.

Pain – low back pain, worse in a supine position & occurs in the

morning

Segmental or diffuse lower extremity weakness, radicular pain,paresthesias, generalized or focal sensory loss, leg cramps, andbowel or bladder dysfunction.

Cauda equina lesions may present with flaccid paraparesis mimickingepidural cord compression

Loss of deep tendon reflexes - in 70% patients; may also be due toprevious chemotherapy.



DIAGNOSIS – CSF ANALYSISDIAGNOSIS – CSF ANALYSIS

CSF PRESSURE : Elevated CSF pressure is seen in approximately50 % of patients.

CELL COUNT : white blood cell count is elevated in approximately50% of patients ; Red blood cells or xanthochromia can be seen from

bleeding due to LM ; Elevated CSF protein in 70-85 %, Low glucose in40% of patients.

BIOCHEMICAL MARKERS :CEA, AFP, Beta-HCG, PSA. etcMetastases outside the leptomeninges, such as parenchyma brainmetastases, do not usually elevate these markers.

The initial diagnosis of LM is established most reliably when a volumeof atleast 10.5 mL is processed, with CSF obtained near the site of clinical or radiological disease and when sample processing is notdelayed.



DIAGNOSTIC IMAGINGDIAGNOSTIC IMAGING

CT is not as sensitive as MRI, although nodular enhancement may be

seen in some cases.

Contrast-enhanced MRI reveals abnormalities in up to 80% of patientswith LM ; more likely to be abnormal in patients with solid tumors (90-100%) than in those with hematological malignancies (40-55%).

Diagnostic of LM : leptomeningeal or subependymal enhancement ineither the brain (indicated by enhancement extending into the sulci of the cerebral hemispheres or into the folia of the cerebellum), spinalcord, or cauda equina

Suggestive of LM : dural enhancement ( focal or diffuse enhancementover the convexity of the brain surface but not extending into sulci ),superficial cerebral lesions in close proximity to the subarachnoidspace or within sulci, enhancement of cranial nerves, or communicating hydrocephalus



DIAGNOSTIC IMAGINGDIAGNOSTIC IMAGING

An MRI fluid-attenuated inversion-recovery (FLAIR) image

demonstrating abnormally high signal intensity in the cisterns,ventricles, sulci, or any pial surface is also consistent with thediagnosis of LM.

A comparison found that unenhanced FLAIR images had a sensitivityof 12%, contrast-enhanced FLAIR images had a sensitivity of 41%,and contrast-enhanced Tl-weighted images had a sensitivity of 59%;The combined overall sensitivity is 65%.

The high rate of involvement of the lower spinal column may justify anenhanced only MRI study of the lumbar spine as an efficient screen for LM in the high risk patient with negative cytology and no localizedfindings



TREATMENT OF LMTREATMENT OF LM

Treatment of neoplastic meningitis is multimodal and encompasses the

entire neuraxis.

Treatment consists of involved-field radiotherapy, systemic chemotherapyand intrathecal chemotherapy.

Because of meningeal dissemination in the setting of advanced systemictumor, treatment is usually considered palliative.

The exception is childhood CNS leukemia, where durable remissionsmay be obtained in patients who present with CNS disease at diagnosisor who have CNS relapse after initial therapy.

Adult patients with breast cancer or lymphoma have median survivalsaveraging 7-10 months, suggesting that there is a subset of patients withneoplastic meningitis who have meaningful palliation following treatment.

TREATMENT OF LM




STANDARD THERAPY FOR LEPTOMENINGEAL METASTASIS

Radiotherapy to sites of symptomatic and bulky disease and to sites of CSF flow obstruction

Intra-CSF chemotherapy - intrathecal , intra-ventricular.- Methotrexate- Cytarabine- Thio-TEPA

Ommaya Reservoir

Concurrent systemic treatment of primary tumor





RADIATION THERAPY FOR LEPTOMENINGEAL CANCER

Rationale :

~ Several patients present with significant symptoms such ascranial nerve palsies, sphincter dysfunction, limited ambulation,pain, obstructive hydrocephalus, etc., which benefit from RT.

~ approximately one-half of all patients with leptomeningealdisease die as a direct consequence of compartmentalprogression of their disease, as opposed to systemicprogression, suggesting that control of disease within thecerebrospinal fluid (CSF) compartment holds some potential for modestly improving survival.

Cranio-spinal RT vs Focal RT.





NEWER / INVESTIGATIONAL TREATMENTS

Drugs : microcrystalline preparation of Temozolomide, Mafosfamide,intrathecal Gemcitabine etc.

Intrathecal radio-isotope therapy

Intrathecal immunoconjugates - antibodies coupled to radioisotopes

Interferon and unconjugated monoclonal antibodies

CONCLUSIONCONCLUSION

CONCLUSIONCONCLUSION



CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION

Not all patients with this disease fare equally poorly.

Patients with good performance status, limited systemic diseasewithout fixed neurologic deficits, and with certain "sensitive" tumor types such as breast cancer, and several pediatric hematologic tumorshave a better prognosis.

Unfortunately, the therapeutic approaches in this disease have notbeen tested using rigorous clinical trial methodology, because many of these patients are often too ill to be eligible for very aggressiveinterventions.

Multicenter, prospective, randomized trials should be stronglyencouraged and conducted to address questions of most relevance tothe patient, namely neurological status and overall survival.



- Mother- MotherTeresaTeresa

Leptomeningeal Mets Final

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