Leptomeningeal cancer

Neoplastic meningitis
Other names	Carcinomatous meningitis, leptomeningeal carcinoma, leptomeningeal carcinomatosis, leptomeningeal metastasis, meningeal carcinomatosis, meningeal metastasis, meningitis carcinomatosa, leptomeningeal disease (LMD), neoplastic meningitis
Meningeal carcinomatosis: tumor cell clusters in the subarachnoid space in a brain biopsy
Specialty	Oncology, neurology

Leptomeningeal cancer is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord.^[1] This leads to an inflammatory response, hence the alternative names neoplastic meningitis (NM), malignant meningitis, or carcinomatous meningitis.^[2][3] The term leptomeningeal (from the Greek lepto, meaning 'fine' or 'slight') describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located.^[4] The disorder was originally reported by Eberth in 1870.^[5] It is also known as leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, meningeal metastasis and meningeal carcinomatosis.

It occurs with cancers that are most likely to spread to the

Leptomeningeal disease is becoming more evident because cancer patients are living longer and many chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells.[7]

Signs and symptoms

Depending on where the tumor cells settle, leptomeningeal cancer can cause almost any neurological problem.^[10]

The most common symptoms of leptomeningeal cancer are pain and seizures. The other symptoms may include headaches (usually associated with nausea, vomiting, light-headedness), gait difficulties from weakness or ataxia, memory problems, incontinence, and sensory abnormalities.^[11][1] In some cases, symptoms may include double vision, numb chin,^[6] back pain, leg weakness, sphincter-related problems, hydrocephalus,^[12] loss of urine control, and difficulty walking.

Other symptoms that are less common

• Cerebral hemisphere (15%)
• Cranial nerves (35%)
• Spinal cord and roots (60%)

Signs reported:

• Headache
• Mental status change
• Confusion
• Cognitive impairment
• Seizures
• Hemiparesis
• Gait instability

Related diseases

• Parenchymal disease occurs in 30-40% of those diagnosed with NM. The disease associated with the main functioning body of an organ, in this case the brain.
• Acute cerebellar ataxia is a rare initial presenting feature of NM, particularly in gastric cancer. Paraneoplastic cerebellar degeneration (PCD) is a well-known cause of cerebellar ataxia associated with neoplastic disorders, and commonly, with positivity for various anti-neuronal antibodies.^[13]
• Bilateral
  vestibulocochlear nerves from onset of NM ^[14]
• Subacute confusion: when functioning of the brain such as cognition deteriorates but at a less rapid rate than that of
  acute confusion^[15]

Some patients can develop a leptomeningeal tumor while receiving chemotherapy for their primary tumor.^[citation needed]

Pathology

There are three anatomic patterns by which the tumor can spread in the

Second, there may only be a thin coating of meninges, in some cases with only a single cell layer, but also with shedding of tumor cells into the cerebrospinal fluid. Third, there may be a pattern of nodular deposits of tumor on cranial and spinal nerve roots, frequently without tumor cells being shed into the cerebrospinal fluid.^{[citation needed]}

The first and third patterns are common in solid tumors whereas the second occurs most frequently with leukemia and lymphoma.^[7]

Spinal cord

Neoplastic meningitis (NM) shows diffuse infiltration of tumor cells into the subarachnoid space which may be associated with increased

• Circular necrosis of the white matter in the periphery of the spinal cord was also noted which probably resulted from circulatory disturbance secondary to tumor infiltration.
• Dorsal radiculopathy which is secondary ascending degeneration of the posterior
  funiculus
  may also occur due to malignant cells collecting or a presence of tumor which cause compression of the nerve.
• Tumor cell proliferation is observed around nerve roots as well as loss of myelinated nerve fibers and
  macrophages
  is observed. Nerve root infiltration has shown positive correlation with meningeal dissemination.
• Infiltration of the spinal cord parenchyma is found with destruction of the pia mater. Tumor cell infiltration is associated with spongy changes in the white matter of the spinal cord beneath the pia mater with
  demyelination, axonal swelling, and macrophage infiltration. Transverse necrosis of the spinal cord is usually marked with bleeding from tumor growth in the subarachnoid space and is the result of compression by the hematoma
  in the subarachnoid space.

• Hematogenous spread, or spread through blood vessels, occurs either through the
  nerve roots. More regarding the effects of NM on spinal cord is discussed later. 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
  .
• Venous spread may occur when intra-abdominal or
  venous
  system to enter the vertebral venous system.
• Centripetal migration from systemic tumors along
  endoneurial space, or invade the nerve parenchyma
  .

Infiltration happens most often 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.^[18]

Infiltration to spinal cord

Infiltration from the

With mild infiltration, tumor cells are found diffusely in the subarachnoid space from the cervical to sacral levels. In some cases however 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 pia mater.^[19]

Diagnosis

Screening involves an MRI scan to identify and diagnose tumors in the

Diagnosis is most commonly made by lumbar puncture to detect malignant cells in the CSF, although the tests may be negative in roughly 10% of patients.[5] Diagnosis often requires a high index of suspicion and is confirmed by neuroimaging and cerebrospinal fluid analysis.^[21]

CSF examination is the most useful diagnostic tool for NM. Patients with suspected NM should undergo one or two

NM is multifocal and CSF at a particular site may show no abnormalities if the pathological site is far away. Only 50% of those suspected with NM are actually diagnosed with NM and only the presence of malignant cells in the CSF is diagnosis conclusive.^[citation needed]

Techniques

• MRI: Meningeal findings are described with the following characteristics: Nodular meningeal tumor, meningeal thickening >3 mm and a subjectively strong contrast enhancement. A smooth contrast enhancement of the meninges was judged to be typical for inflammatory, nonneoplastic meningitis.^[23]
• CSF cytology: is performed after drawing the CSF by lumbar puncture.
• Cytogenetic: measures
  chromosomal content of cells and fluorescence in situ hybridization which detects numerical and structural genetic aberrations as a sign of malignancy. This is especially useful for liquid tumors such as leukemia and lymphoma. Some of the techniques that achieve this are flow cytometry
  and DNA single-cell cytometry. However, cytogenetic only assist in diagnosis and is less preferred.
• Meningeal Biopsy: may be performed when all of the above criteria is inconclusive. Biopsy is only effective when performed at the region where there's enhancement on the MRI.^{[citation needed]}

Cerebral spinal fluid

Criteria for CSF abnormalities include:^{[citation needed]}

• Increased opening pressure (> 200mm of H2O)
• Increased Leukocytes (>4/mm3)
• Elevated protein (>50 mg/dL)
• Decreased glucose (<60 mg/dL)

Tumor markers

These markers can be good indirect indicator of NM but most are not sensitive enough to improve cytogical diagnosis:^{[citation needed]}

• Carcinoembryonic antigen (CEA)
• alpha-fetoprotein
• beta-human chorionic gonadotropin
• carbohydrate antigen19-9
• creatine-kinase BB
• isoenzyme
• tissue polypeptide antigen
• Beta-2 microglobulin
• beta-glucoronidase
• lactate dehydrogenase isoenzyme-5
• vascular endothelial growth factor

Treatment

There is currently no cure for leptomeningeal disease as the tumor is hard to eradicate.

Radiotherapy

Chemotherapy

Chemotherapy is injected directly into the cerebrospinal fluid, either by lumbar puncture (“spinal tap”) or through a surgically implanted device called an

The downside of a spinal tap diagnosis is that while it is highly accurate and reliable, it can also report false-negative results.[20] Chemotherapy is delivered intrathecally as it is hard for drugs to make it into the central nervous system. Intrathecal chemotherapy can only penetrate a few millimeters. If the tumor is any thicker, radiation is given to shrink it down.^[6]

The treatment is done to reduce pressure on the brain caused by any cerebrospinal fluid buildup and to reduce the number of cancer cells causing the pressure. For the best care, patients should see a physician who regularly treats leptomeningeal cancer and is most up-to-date on medicines that penetrate the blood-brain barrier, how to treat the symptoms, and clinical trials that might include patients with leptomeningeal cancer.^[25]

Risks of treatments

Both Chemotherapy and Radiotherapy are harmful to the body and most definitely the brain. Caution must be utilized in treating patients with NM. Another factor that makes treatment difficult is that there is no suitable method to evaluate the disease progression.^[26]

Prognosis

The prognosis is generally poor with survival typically measured in months.^[6] The median survival time of patients without treatment is four to six weeks. The best prognoses are seen from NM due to breast cancer with the median overall survival of no more than six months after diagnosis of NM.^[27] Death is generally due to progressive neurological dysfunction. Treatment is meant to stabilize neurological function and prolong survival. Neurological dysfunction usually cannot be fixed but progressive dysfunction can be halted and survival may be increased to four to six months.

It occurs in approximately 3-5% of cancer patients.^[8] The disease is usually terminal and if left untreated, the median survival is 4–6 weeks whereas if treated, the median survival can increase to 2–3 months.^[1] Treatment will be more effective if it is done on the primary tumor before it metastasizes to the brain or spinal cord.

Patients with leukaemia achieve better results compared to patients with solid tumours who have undergone treatment. It was found that 75% of patients stabilize or improve over several months as opposed to 25% of patients who do not respond and have progressive disease. But despite initial improvement, most patients survive only a few months. Breast cancer and small cell lung cancer are the two solid tumors that respond best to treatment^[28] Some patients do better than others, particularly those whose primary cancer is hematologic, bone marrow and lymph nodes.^[29]

Factors that lower survival

Much of prognosis can be determined from the damage due to primary cancer. Negative hormone receptor status, poor performance status, more than 3 chemotherapy regimes, and high Cyfra 21-1 level at diagnosis, all indicates lower survival period of patients with NM. Cyfra 21-1 is a fragment of the cytokeratin 19 and may reflect the tumor burden within the CSF.^{[citation needed]}

Epidemiology

In the United States, 1–8% of cancer patients are diagnosed with leptomeningeal disease, with approximately 110,000 cases per year.^[30] The exact incidence of leptomeningeal disease is difficult to determine, since gross examination at autopsy may overlook signs of leptomeningeal disease, and microscopic pathological inspection may be normal if the seeding is multifocal or if an unaffected area of the central nervous system (CNS) is examined.^{[citation needed]}

Current research

New treatments and clinical trial for breast cancer patients and non-small cell lung cancer patients with leptomeningeal disease are currently being explored.^[6]

People with leptomeningeal metastasis are generally excluded from clinical trials, thereby limiting the systematic assessment of novel therapies in this subgroup of patients with poor prognosis. More patients with leptomeningeal metastasis should be enrolled into trials investigating novel agents with the potential to penetrate the blood–brain barrier.^[31]

Novel approaches are being studied as currently available therapies are toxic and provide limited benefits.^[8]

History

Neoplastic Meningitis (NM) was first reported in the 1870s.^[32]

Gallery

• 
  Meningeal carcinomatosis in a patient with breast cancer (contrast-enhanced axial T1-weighted MRI)

References

Further reading

• Meningeal Carcinomatosis From Cervical Cancer:A Case Report and Review of the Literature

External links

 This article incorporates

U.S. National Cancer Institute

.

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