Neoplastic meningitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis is the development of meningitis due to infiltration of the subarachnoid space by tumor cells. Neoplastic meningitis was first reported in the 1870’s.^[1] Neoplastic meningitis refers to the spread of malignant cells through the cerebrospinal fluid space. These cells can be originated both in primary CNS tumors (e.g. drop-metastases), as well as from distant tumors that have metastasized (hematogenous spread).^[2] The microscopic pathology of neoplastic meningitis may vary according to the primary cancer involved. Generally, on microscopic histopathological analysis, neoplastic meningitis is characterized by large, hyperchromatic cells.^[3] Common causes of neoplastic meningitis include primary intracerebral malignancies (glioblastoma multiforme, anaplastic astrocytoma, medulloblastoma) and metastatic disease (breast cancer, lung cancer, melanoma, lymphoma, leukemia).^[4] Neoplastic meningitis must be differentiated from infections (meningitis, Lyme disease, neurocysticercosis), neoplastic (intracerebral metastasis, dural metastasis), inflammatory (rheumatoid arthritis, multiple sclerosis, polychondritis), and granulomatous disorders (sarcoidosis, histiocytosis, Wegener’s granulomatosis, vasculitis).^[5] Neoplastic meningitis occurs in approximately 3-5% of patients with solid tumor, 5-15% of patients with leukemia, and 1-2% of patients with primary brain tumors.^[6][7] Neoplastic meningitis has a widely disseminated and progressive presentation. If left untreated, neoplastic meningitis may progress to develop seizures, hydrocephalus, encephalopathy, and ultimately death.^[8] Complications of neoplastic meningitis include hydrocephalus, encephalopathy, empyema​, cerebritis, cerebral abscess, and stroke.^[8] The median survival time of patients without treatment of neoplastic meningitis is 4-6 weeks.^[9] Neoplastic meningitis should be suspected if there are simultaneous occurrence of symptoms or signs in more than one area of the neuraxis.^[10] Symptoms of neoplastic meningitis include headaches, confusion, memory loss, seizures, double vision, hearing loss, paresthesia and pain in the neck and back, and limb weakness.^[11] Common physical examination findings of neoplastic meningitis include altered mental status, dementia, hemiparesis, ptosis, nuchal rigidity, bowel and bladder dysfunction, and papilledema.^[11] Laboratory findings consistent with the diagnosis of neoplastic meningitis include abnormal CSF analysis (increased opening pressure, increased leukocytes, elevated protein, decreased glucose, and positive tumor markers). Only 50% of those suspected with neoplastic meningitis are actually diagnosed and only the presence of malignant cells in the CSF is diagnostic.^[12] Brain MRI is helpful in the diagnosis of neoplastic meningitis. On MRI, neoplastic meningitis is characterized by normal T1- and T2-weighted images. On contrast administration, there may be leptomeningeal enhancement scattered over the brain in a ‘sugar coated’ manner, which is fairly diagnostic for neoplastic meningitis.^[13] Other diagnostic studies for neoplastic meningitis include meningeal biopsy, which may be diagnostic if there are no systemic manifestations and the CSF analysis remain inconclusive.^[14] The mainstay of therapy for neoplastic meningitis is intrathecal chemotherapy.^[11] Radiotherapy may be used in patients with neoplastic meningitis for palliation of symptoms, reduce the bulky tumors, and correction of cerebrospinal fluid flow abnormalities.^[11] Supportive care should be directed towards all patients with neoplastic meningitis, regardless of the treatment regimen (anticonvulsants, corticosteroids, and opiates).^[11] Surgery is not the first-line treatment option for patients with neoplastic meningitis. Surgery is usually reserved for patients who need an intraventricular catheter placement for administration of cytotoxic drugs or placement of a ventriculoperitoneal shunt in patients with symptomatic hydrocephalus.^[11]

• The first case of neoplastic meningitis was described by Eberth in the 1870s.

There is no classification system established for neoplastic meningitis.

• The pathophysiology of neoplastic meningitis involves spread of cancer cells to the meninges and subarachnoid space. The location could be the brain or the spinal cord. It could be from a distant source or from a primary CNS tumor (drop metastasis).
• Cancer from a distant source enter the CSF by means of the following:[3]
  • Hematogenous Spread from a distant primary tumor site – cancer cells produce enzymes that allows them to microscopically invade blood vessels to reach the subarachnoid space through the systemic arterial circulation or by the Batsons venous plexus.
  • Invasion from a primary brain tumor to the meninges – when cancer cells lodge into small arteries causing local ischemia and blood vessel damage leading to spillage of neoplastic cells to the Virchow-Robin spaces thereby providing access to the subarachnoid space.
  • Infiltration to the spinal cord – Cancer cells gain access to the subarachnoid space through this route via the perivascular tissues the surround the blood vessels at the brain entrance. Direct infiltration of the spinal nerve roots (dorsal and ventral) has also been documented.
  • Cancer spread a neural pathways to reach the meninges – The CSF carries cancer cells through the brain tracts. This occurs mostly in tumors of the head and neck.[5]
  • Iatrogenic – from surgical procedures involving removal of a primary brain tumor
• Primary neoplastic meningitis has also been documented particularly with melanoma.^[15]

• Common causes of neoplastic meningitis include primary intracerebral malignancies (glioblastoma multiforme, anaplastic astrocytoma, medulloblastoma) and metastatic disease (breast cancer, lung cancer, melanoma, lymphoma, leukemia).^[4]

• Neoplastic meningitis must be differentiated from infections (meningitis, Lyme disease, neurocysticercosis), neoplastic (intracerebral metastasis, dural metastasis), inflammatory (rheumatoid arthritis, multiple sclerosis, polychondritis), and granulomatous disorders (sarcoidosis, histiocytosis, Wegener’s granulomatosis, vasculitis).^[5]

• Neoplastic meningitis occurs in approximately 3-5% of patients with solid tumor, 5-15% of patients with leukemia, and 1-2% of patients with primary brain tumors.^[6][7]

• Factors that have been known to increase the risk of neoplastic meningitis involves:[4]
  • Brain metastasis is one of the more obvious risk factors for neoplastic meningitis. Coexisting brain metastasis are associated with neoplastic meningitis in breast cancer (33-54%), lung cancer (56-82%) and melanoma (87-96%).
  • Primary brain cancer always poses a risk for the development of neoplastic meningitis. It is diagnosed in 1-2% of cases of ependymoma, medulloblastoma, germinoma and glioblastoma combined.
  • Brain surgery increases the chance of developing neoplastic meningitis. It has been observed after resection of brain tumor (particularly piecemeal resection vs en-block resection) particularly tumors located in the cerebellum. Other cranial surgeries done with involvement of ventricular system manipulation in a patient with known brain metastasis increases the risk. Furthermore, the incidence of neoplastic meningitis seem higher in patient treated with surgery followed by stereotactic radiosurgery compared with radiosurgery alone.
  • ER-, PR-positivity in beast cancer increases incidence of neoplastic meningitis. Triple negative breast cancer and the HER2/neu gene positivity displays tropism for CNS metastasis. Among the histologic subtypes of breast cancer, loblular carcinoma demonstrated the highest prevalence for neoplastic meningitis.

• There is insufficient evidence to recommend routine screening for neoplastic meningitis.^[16]

• Neoplastic meningitis has a widely disseminated and progressive presentation. If left untreated, neoplastic meningitis may progress to develop seizures, hydrocephalus, encephalopathy, and ultimately death.^[8]
• Complications of neoplastic meningitis include hydrocephalus, encephalopathy, empyema​, cerebritis, cerebral abscess, and stroke.^[8] The median survival time of patients without treatment of neoplastic meningitis is 4-6 weeks.^[9]

There is no established system for the staging of choroid plexus papilloma.^[17]

• When evaluating a patient for neoplastic meningitis, you should take a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, and a thorough family and past medical history review.
• Other specific areas of focus when obtaining the history include review of common associated conditions such as intracerebral metastases and the distant primary tumors. Neoplastic meningitis should be suspected if there are simultaneous occurrence of symptoms or signs in more than one area of the neuraxis.^[18]
• Symptoms of neoplastic meningitis include headaches, confusion, memory loss, seizures, double vision, hearing loss, paresthesia and pain in the neck and back, and limb weakness.^[11]

• Common physical examination findings of neoplastic meningitis include altered mental status, dementia, hemiparesis, ptosis, nuchal rigidity, bowel and bladder dysfunction, and papilledema.^[11]

• Laboratory findings consistent with the diagnosis of neoplastic meningitis include abnormal CSF analysis (increased opening pressure, increased leukocytes, elevated protein, decreased glucose, and positive tumor markers). Only 50% of those suspected with neoplastic meningitis are actually diagnosed and only the presence of malignant cells in the CSF is diagnostic.^[12]

• There are no CT scan findings associated with neoplastic meningitis.^[11]

• On MRI, neoplastic meningitis is characterized by normal T1- and T2-weighted images. On contrast administration, there may be leptomeningeal enhancement scattered over the brain in a ‘sugar coated’ manner, which is fairly diagnostic for neoplastic meningitis.^[13]

• There are no other imaging findings associated with neoplastic meningitis.^[11]

• Other diagnostic studies for neoplastic meningitis include meningeal biopsy, which may be diagnostic if there are no systemic manifestations and the CSF analysis remain inconclusive.^[14]

The mainstay of therapy for neoplastic meningitis is intrathecal chemotherapy.^[11] Radiotherapy may be used in patients with neoplastic meningitis for palliation of symptoms, reduce the bulky tumors, and correction of cerebrospinal fluid flow abnormalities.^[11] Supportive care should be directed towards all patients with neoplastic meningitis, regardless of the treatment regimen (anticonvulsants, corticosteroids, and opiates).^[11]

Surgery is not the first-line treatment option for patients with neoplastic meningitis. Surgery is usually reserved for patients who need an intraventricular catheter placement for administration of cytotoxic drugs or placement of a ventriculoperitoneal shunt in patients with symptomatic hydrocephalus.^[11]

There are no primary or secondary preventive measures available for neoplastic meningitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis was first reported in the 1870’s.^[1]

• The first case of neoplastic meningitis was described by Eberth in the 1870s. Afterwhich, information regarding the historical development of the disease have been poorly documented.
• The metastatic site was first identified in the same decade in a patient with lung cancer ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

There is no classification system established for neoplastic meningitis.

• There is no classification system established for neoplastic meningitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis refers to the spread of malignant cells through the cerebrospinal fluid space. These cells can be originated both in primary CNS tumors (e.g. drop-metastases), as well as from distant tumors that have metastasized (hematogenous spread). The microscopic pathology of neoplastic meningitis may vary according to the primary cancer involved. Generally, on microscopic histopathological analysis, neoplastic meningitis is characterized by large, hyperchromatic cells.

Neoplastic meningitis most commonly occurs secondary to other malignancies, when the malignant cells spread to meningeal layer through reaching to cerebrospinal fluid . The primary region of this malignant cells can be both inside the CNS or outside the CNS, which is going to be considered as distant metastasis.^[1]

From primary cancer to the meninges

• It is hypothesized that the primary source malignant cells that contribute to neoplastic meningitis has the capability to secrete a specific enzyme. This is enzyme has the capability to distort blood vessels at a microscopic level, thus helping the metastatic cells to enter blood vessels, traveling through the body and seed in any part of the body they want. These cells can secrete these enzymes to penetrate through blood-brain-barrier, and reach to CSF and thud to brain. As the CSF is the primary source of fluid in the CNS, it continues to carry these metastatic cells all over the CNS, helping them spread in CNS.
• The cancerous cells can also obstruct small CNS vessels, probably due to a more adhesive property that they have. By obstructing small CNS vessels, they can cause cerebral ischemia. They also can make damage to these small CNS vessels while occluding them, and reach to Virchow-Robin spaces by this damage. Through this space, they can reach subarachnoid space.^[2]

Invasion routes

• Hematogenous spread occurs either through the venous plexus of Batson or by arterial dissemination. This occurs with arterioles as a result of tumor cells being lodged in vessels that feed the meninges and later causing leakage into the meninges and CSF. This same situation also appears with spinal arteries where leakage of tumor cells is into the nerve roots. Tumor cells may also seed the choroid plexus, where CSF is produced, and ultimately gaining direct access to the CSF. Seeding of the choroid plexus is most common in patients with third and lateral ventricular hydrocephalus.^[2]
• Venous spread may occur when intra-abdominal or thoracic pressure increases and venous flow is retrograde which then allows the tumor cells in the systemic venous system to enter the vertebral venous system.
• Centripetal migration from systemic tumors along perineural, invasion of nerve space, or perivascular spaces. Malignant cells can migrate along spinal or cranial nerve (epineurium–perineurium), invade the subpial space, travel along blood vessels into the endoneurial space, or invade the nerve parenchyma.
• Often, the infiltration happens at the base of the brain, dorsal surface, and especially at the cauda equina which is largely due to the effect of gravity. Once in the CSF, malignant cells can extend along the membrane surfaces or spread freely in the CSF and attach to other locations. These cells have the ability to penetrate the pial membrane and invade the spinal cord and cranial nerves.

Infiltration to spinal cord

• Infiltration from the subarachnoid space into the spinal cord occurs primarily along the perivascular tissues that surround blood vessels at the brain entrance. Infiltration from the anterior median fissure, a 3mm deep furrow on the anterior side of the spinal cord, to the anterior horn of the spinal cord, the ventral grey matter of the spinal cord, is found along the central artery. Direct infiltration of the nerve roots is also observed, mostly from the dorsal roots (the afferent sensory root of the spinal nerve) than the ventral roots (the efferent motor root of a spinal nerve).
• With mild infiltration, tumor cells are found diffusely in the subarachnoid space from the cervical to sacral levels. In some cases, there are no differences between spine levels. Infiltration from the subarachnoid space into the spinal cord occurs mainly along the perivascular space of the white matter. However, in some cases, direct infiltration into the spinal cord parenchyma is found together with destruction of the piamater.

• The microscopic pathology of neoplastic meningitis may vary according to the primary cancer involved. Generally, on microscopic histopathological analysis, neoplastic meningitis may be characterized by: ^[3]
  • Identical histology to any grade I variant meningioma yet contain increased mitoses (4 – 19/10 HPFs)
  • Increased cellularity or areas of small cell collections
  • Increased cellularity or areas of small cell collections
  • Sheet-like growth pattern
  • Areas of spontaneous necrosis
  • Macronucleoli

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Common causes of neoplastic meningitis include primary intracerebral malignancies (glioblastoma multiforme, anaplastic astrocytoma, medulloblastoma) and metastatic disease (breast cancer, lung cancer, melanoma, lymphoma, leukemia). Neoplastic meningitis is a secondary cancer caused by the spread of tumor cells into the meninges and subarachnoid space from a primary source. Most common solid tumor sources documented are breast, lung, melanoma and hematologic cancers mostly acute lymphocytic leukemia. Cancers not previously thought to be predisposed to neoplastic meningitis but now has documented cases are gastric, prostate, ovarian, cervical and endometrial.

Neoplastic meningitis is a secondary cancer caused by the spread of tumor cells into the meninges and subarachnoid space from a primary source. Most common solid tumor sources documented are breast, lung, melanoma and hematologic cancers mostly acute lymphocytic leukemia. Cancers not previously thought to be predisposed to neoplastic meningitis but now has documented cases are gastric, prostate, ovarian, cervical and endometrial. ^[1]

• Cancers not previously thought to be predisposed to neoplastic meningitis but now has documented cases are gastric, prostate, ovarian, cervical and endometrial.^[2]
• Primary intracerebral malignancies that may cause metastases (drop-metastasis) to the subarachnoid space include:^[3]

• • Glioblastoma multiforme
  • Anaplastic astrocytoma
  • Medulloblastoma
  • Supratentorial primitive neuroectodermal tumors (SPNET)^[4]
  • Ependymoma
  • Germinoma
  • Choroid plexus carcinoma
• Vast majority of leptomeningeal metastases originates from a widespread metastatic disease (hematogenous spread). Common primary sites include:^[3]

• Breast cancer (most common)
• Lung cancer
• Melanoma
• Lymphoma and leukemia

• Sarcomas rarely metastasizes to the meninges.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis must be differentiated from infections (meningitis, Lyme disease, neurocysticercosis), neoplastic (intracerebral metastasis, dural metastasis), inflammatory (rheumatoid arthritis, multiple sclerosis, polychondritis), and granulomatous disorders (sarcoidosis, histiocytosis, Wegener’s granulomatosis, vasculitis).^[1]

Differential Diagnosis for Neoplastic Meningitis:

• Meningitis from infectious causes – infectious meningitis may to some degree manifest like neoplastic meningitis due to meningeal irritation. This include viral, bacterial, fungal and HIV-associated causes of meningitis.
• Neurosarcoidosis.
• Vasculitis – the generalized nature of vessel involvement in these diseases may, to some extent involve the meninges. Vasculitis documented to present like neoplastic meningitis include Kawasaki disease, Takayasu arteritis, Polyarteritis nodosa, microscopic polyarteritis nodosa and Wegener granulomatosis.
• Systemic connective tissue diseases – particularly SLE and Sjogren’s syndrome share some of the manifestation of neoplastic meningitis.

Neoplastic meningitis must be differentiated from:^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis occurs in approximately 3000-5000 of 100,000 patients with solid tumors, 5000-15,000 of 100,000 patients with leukemia, and 1000-2000 of 100,000 patients with primary brain tumors.^[1][2]

• Neoplastic meningitis occurs in approximately 3000-5000 of 100,000 patients with solid tumors.
• Neoplastic meningitis occurs in approximately 5000-15,000 of 100,000 patients with leukemia.
• Neoplastic meningitis occurs in approximately 1000-2000 of 100,000 patients with primary brain tumors.^[1][2]

• Observational studies show that neoplastic meningitis develop in 1-5% of solid tumors, of which adenocarcinoma is the most frequently observed histology.
• Neoplastic meningitis typically develop in the setting of an advanced stage and widely disseminated cancer in 70% of the cases. It can also present during the patients disease-free interval or remission in 20% of the time, and even be the first manifestation of cancer (5-10%) occasionally.^[3]

• Neoplastic meningitis occurs more in elderly people, as it is associated with other primary cancer development.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Risk factors for NM includes late stage cancer, primary brain tumor and intracranial surgery.

Factors that have been known to increase the risk of neoplastic meningitis involves:^[1]

• Brain metastasis is one of the more obvious risk factors for neoplastic meningitis. Coexisting brain metastasis are associated with neoplastic meningitis in breast cancer (33-54%), lung cancer (56-82%) and melanoma (87-96%).
• Primary brain cancer always poses a risk for the development of neoplastic meningitis. It is diagnosed in 1-2% of cases of ependymoma, medulloblastoma, germinoma and glioblastoma combined.
• Brain surgery increases the chance of developing neoplastic meningitis. It has been observed after resection of brain tumor (particularly piecemeal resection vs en-block resection) particularly tumors located in the cerebellum. Other cranial surgeries done with involvement of ventricular system manipulation in a patient with known brain metastasis increases the risk. Furthermore, the incidence of neoplastic meningitis seem higher in patient treated with surgery followed by stereotactic radiosurgery compared with radiosurgery alone.
• ER-, PR-positivity in beast cancer increases incidence of neoplastic meningitis. Triple negative breast cancer and the HER2/neu gene positivity displays tropism for CNS metastasis. Among the histologic subtypes of breast cancer, lobular carcinoma demonstrated the highest prevalence for neoplastic meningitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

There is insufficient evidence to recommend routine screening for neoplastic meningitis.

• There is insufficient evidence to recommend routine screening for neoplastic meningitis.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Neoplastic meningitis has a widely disseminated and progressive presentation. If left untreated, neoplastic meningitis may progress to develop seizures, hydrocephalus, encephalopathy, and ultimately death. Complications of neoplastic meningitis include hydrocephalus, encephalopathy, empyema​, cerebritis, cerebral abscess, and stroke. The median survival time of patients without treatment of neoplastic meningitis is 4-6 weeks.

• Neoplastic meningitis has a widely disseminated and progressive presentation.
• If left untreated, neoplastic meningitis may progress to develop seizures, hydrocephalus, encephalopathy, and ultimately death. ^[1]

Complications of neoplastic meningitis include:^[1]

• Hydrocephalus
• Encephalopathy
• Subdural empyema​
• Epidural empyema
• Cerebritis
• Cerebral abscess
• Stroke
• Ventriculitis
• Dural sinus thrombosis

• The median survival time of patients without treatment of neoplastic meningitis is 4-6 weeks.^[2]
• Neoplastic meningitis due to breast cancer has the best prognosis, where the median survival time is approximately 6 months after diagnosis.^[2]
• Favorable prognostic factors for neoplastic meningitis include:^[3]

• Female gender
• Longer duration of neurological symptoms
• Absence of cerebral leptomeningeal clinical involvement
• Absence of elevated CSF protein

• Poor prognostic factors for neoplastic meningitis include:^[2]

• Negative hormone receptor status
• Poor performance status
• Multiple fixed neurological deficits
• Coexistent carcinomatous encephalopathy
• More than 3 chemotherapy regimes
• High Cyfra 21-1 level at diagnosis

• Cyfra 21-1 is a fragment of the cytokeratin-19 and may reflect the tumor burden within the cerebrospinal fluid.

• Neoplastic meningitis patients treated with intra-CSF chemotherapy have a better prognosis.^[3]

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