Leptomeningeal cancer

• 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 sensorineural hearing loss caused by complications with the 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]

Neoplastic meningitis (NM) shows diffuse infiltration of tumor cells into the subarachnoid space which may be associated with increased intracranial pressure, signs of meningeal irritation, and damage to the cranial and spinal nerve roots. Pathological feature include:

• 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 axonal swelling. In areas of tumor cells, infiltration of 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.

NM is a secondary cancer meaning that it is the result of neoplastic cells that have metastasized from a primary cancer site. These cancers develop an enzyme that is able to break down blood vessels at a microscopic level. These cells enter the blood vessels and travel across the body. Once the brain is reached, they break down the blood–brain barrier to enter the Cerebrospinal Fluid (CSF). There the cancerous cells seed and disseminate into the leptomeninges which are composed of the arachnoid and the pia. The CSF continues to carry neoplastic cells through the brain tracts and spreads the cancerous cells.

Lung cancer, breast cancer, and malignant melanoma comprise the majority of solid tumors spreading to the leptomeninges. Although rare, meningeal carcinomatosis can arise from cervical cancer.[16] Only eight cases of MC arising from squamous cell carcinoma of the uterine cervix are previously reported in the literature.[16]

Since NM is a result of primary cancer metastasis and can develop from primary brain tumors or parenchymal metastasis when tumor cells are lodged in small central nervous system (CNS) vasculature, causing local ischemia and vessel damage which result in tumor spillage into the Virchow-Robin spaces and providing access to the subarachnoid space.

• Hematogenous spread, or spread through blood vessels, 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 appear with spinal arteries where leakage of tumor cells is into 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 thoracic pressure increases and venous flow is retrograde which then allows 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.[17] Malignant cells can migrate along spinal or cranial nerve epineurium-perineurium, invade the subpial space, and travel along blood vessels into the 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 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 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]

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.

• 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.

Criteria for CSF abnormalities include:

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

These markers can be good indirect indicator of NM but most are not sensitive enough to improve cytogical diagnosis:

• 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

Radiotherapy is used mostly for focal type of NM due to the nature of damage and success rate associated with the treatment. Radiotherapy targets the tumor and destroys the collective tissues of cancerous cells.

Chemotherapy is injected directly into the cerebrospinal fluid, either by lumbar puncture (“spinal tap”) or through a surgically implanted device called an Ommaya reservoir.[12] Intrathecal Therapy is preferred since intravenous chemotherapy do not penetrate the BBB.[24] The most common chemicals used are liposomal cytarabine (DepoCyte) and intrathecal methotrexate (MTX).

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]

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]

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.