The multifocal dissemination of cancer cells from its primary site to subarachnoid, pia mater, and CSF in the brain and spinal cord is referred to as carcinomatous meningitis (CM). It is also termed as ‘leptomeningeal meningitis,’ ‘leptomeningeal carcinomatosis,’ ‘leptomeningeal metastasis,’ or ‘neoplastic meningitis.’ Beerman, in 1912, used the term ‘carcinomatous meningitis’ for a condition in which cancer cells metastasized to the meninges without involving brain parenchyma.
CM can occur in the advanced stage of many malignancies when cancer cells seed through CSF and deposit in the meninges. Involvement is usually multifocal and can cause a wide variety of symptoms. CSF analysis, along with imaging techniques, aid in the diagnosis. Treatment options include radiotherapy and chemotherapy. However, early diagnosis is challenging, and prognosis generally remains dismal. The development of newer techniques for diagnosis and novel therapeutic strategies may improve prognosis and limit morbidity.
Primary cancers that metastasize to the leptomeninges are intracranial or extracranial. The most common extracranial malignancies include breast cancer, lung cancer, and melanoma. Intracranial malignancies include cerebellar medulloblastoma, malignant ependymomas, neuromas, and gliomas.
The incidence of leptomeningeal metastasis from solid tumors is 5% to 8%, and from hematological malignancies is 5 to 15%. Among hematological malignancies, B-cell lymphoma is the most common etiology. However, the incidence may be as high as 20%, given the instances of undiagnosed cases, which are only reported at autopsies.
The most common solid organ tumors causing carcinomatous meningitis are lung cancer, melanoma, and breast cancer, with a varying incidence reported in several studies. Parenchymal brain malignancies causing carcinomatous meningitis include gliomas, ependymomas, and medulloblastomas. CM is usually associated with underlying parenchymal involvement in about 60% of the cases. In 1 to 7% of the cases, the primary site of the disease cannot be located despite extensive evaluation.
Cancer is an abnormal and uncontrolled proliferation of cells at a certain location that has the potential to spread to a distant site. These malignant cells develop vascularity, which in turn increases its ability to proliferate. About 14.1 million cases of cancers are registered every year, out of which about 8.8 million are eventually fatal, making cancer one of the leading causes of death. Though the preferential metastatic site is not definite, certain cancers are more likely to metastasize to specific locations.
The central nervous system (CNS) has three layers of meninges called the dura mater, the arachnoid, and the pia mater. The dura mater is known as the patchy-meningeal layer. The arachnoid and pia meningeal layers are called the leptomeninges. The cerebrospinal fluid (CSF) lies in the space between the arachnoid and pia mater, known as the subarachnoid space.
The CSF is the main route for the malignant cells to gain access to the leptomeninges. However, to do so, the cancer cells must cross the blood-brain barrier (BBB). The BBB is an anatomical structure that consists of brain microvascular endothelial cells (BMECs), which form tight intercellular junctions with astrocyte foot processes and regulate transport from blood to CSF. It is hypothesized that tumor cells bind to endothelial cells via receptors and confer changes in the endothelium. This exposes the vascular basement membrane to tumor cells, which then binds to specific components and enters the CSF. Certain genomic functions mediate this whole process of extravasation of cancer cells. This metastatic potential is acquired over time. The Massague’ group suggested that overlapped genes like COX-2, EGFR ligand, ANGPTL4, and LTBP1 are responsible for causing disruption of BBB and tumor proliferation in different parts of the brain.
Refer to figure 1: Schematic presentation of tumor cell penetration across BBB.
Routes of Spread
The routes of spread to BBB from primary tumor site includes:
CSF is known to be rich in high amounts of oxygen and glucose, enough to support the high metabolic demands of the rapidly multiplying malignant cells. Therefore, tumor proliferation in leptomeninges is not dependent upon angiogenesis, a limiting factor for tumors in other locations, including brain parenchymal metastasis.
The major risk factors associated with CM are:
Neurosurgical resection is the preferred treatment option for solitary brain metastasis. Many studies indicate that the risk of CM is 2.81 times more with piecemeal resection than in en-bloc resection.
Due to the selective permeability of BBB, conventional systemic therapy may not be effective in brain metastasis. Radiotherapy (RT) is a feasible option for radiosensitive tumors, especially if the primary site is unknown. Adjuvant RT is recommended after neurosurgical resection. Whole-brain radiation therapy (WBRT) reduces the risk of recurrence but is associated with increased adverse effects, and therefore stereotactic radiosurgery (SRS) is increasingly becoming the preferred option. Studies have shown that the risk of CM after prior neurosurgical resection is 6.5 times higher than SRS without previous surgery.
Location of brain metastasis and tumor volume has not been found to increase the possibility of occurrence of CM. It is the chance of CSF exposure for the spilling of the tumor cells that is rather significant. In patients receiving SRS for brain metastases, certain independent factors that influence the risk of CM are the type of primary tumor, number of intracranial metastases, young age, and distant brain failure (defined as development of new metastatic lesion outside of the treated radiation field).
Clinical features of carcinomatous meningitis are pleomorphic because of the extensive involvement of neuraxis. Different pathophysiological mechanisms include:
The most common presenting symptom is a headache and is found in about 39% of patients. Headache is caused by either meningeal irritation or by raised ICP. In meningeal irritation, headaches are associated with nuchal rigidity worsened by leg flexion (Kernig sign). In raised ICP, headaches are accompanied by nausea, which is worse in the morning. Confusion is the second most common presentation and occurs because of the metabolic depression of the cortex by active malignant cells. This results in an altered state of consciousness or cognitive impairment. It can also cause temporal lobe seizures presenting as deja vu, stereotypical movements, euphoria, hallucinations, and amnesia.
Posterior fossa involvement causes both cerebellar signs and cranial neuropathies. These are observed in 65% of the cases and incorporate nausea, vomiting, dizziness, ataxia, and diplopia. Cranial neuropathies present as diplopia, visual loss, facial weakness, hearing loss, balance disturbances, dysphagia, dysarthria, and hoarseness. Among cranial nerves, CN 6, 7, and 8 are more frequently impacted.
CM may also involve the spinal cord and its exiting nerve roots. The spinal nerve roots that are affected produce symptoms in the anatomically associated regions. Symptoms may include segmental numbness, dysesthesia, pain, and lower motor neuron pattern limb weakness. The involvement of sacral nerve roots may cause bowel and bladder dysfunction. Cauda equina and conus medullaris syndromes can be the only presentation in CM patients. Leg weakness (28%) and back pain/paralysis (18%) are the initial presenting symptoms of leptomeningeal metastases of the spinal cord.
CM can be asymptomatic in 2% of the patients.
The first and foremost step in the evaluation of carcinomatous meningitis is obtaining a comprehensive history and physical exam. An accurate neurological exam helps determine whether the involvement is focal or multifocal and leads the clinician to suspect leptomeningeal involvement. CSF evaluation and neuroimaging study is the next step in the diagnosis. A pragmatic approach for both diagnosis and prognosis may require testing of tumor markers as well.
Cerebral Spinal Fluid
CSF findings typically include the following:
The standardization of the method for CSF collection is an indispensable requirement. An appropriate site (producing symptoms preferably) and sufficient volume (minimum 10 ml) are the prerequisites for the spinal tap. Analysis of CSF via lumbar puncture (LP) and CSF tested from an indwelling catheter produces varying results.
Although CSF cytology is the gold standard for diagnosis, immunohistochemical staining of the cells is recommended, particularly if the primary site of the tumor remains unknown. Flow cytometry is a rapid, quantifiable measure of a specific type of cell with certain characteristics such as cancer cells that are associated with specific antigens. It provides a highly sensitive method for the detection of hematological malignancies. FISH (fluorescent in situ hybridization) is a cytogenetic technique for localizing particular DNA sequences or genes and may yield information on metastatic lesions but with a lower sensitivity. PCR (polymerase chain reaction) is used to identify immunoglobulin gene arrangements in malignant cells, specifically for lymphoma. Hence the study of cytological, morphological, molecular, and cytogenetic characteristics is vital for identification of the tumor type and, at times, the prognosis.
Tumor markers have a role in making an early diagnosis and monitoring response to treatment. However, it may also be imperative in determining the prognosis. The nonspecific markers include LDH (lactate dehydrogenase), beta-2 microglobulin, and specific markers include AFP (alpha-fetoprotein), BHCG (beta-human chorionic gonadotropin), and CEA (carcinoembryonic antigen). CSF value of more than 1% of the serum level of these markers is diagnostic. A study done at Memorial Sloan-Kettering Cancer Center demonstrated that patients with CM from breast cancer, lung cancer, and melanoma have abnormal levels of at least one tumor marker in CSF in 74-90% of the cases. CEA is helpful in adenocarcinoma of the lung, AFP in germ cell tumors, and Beta-2 microglobulin in hematological malignancies. The pro-angiogenic factor VEGF (vascular endothelial growth factor) in CSF also has a diagnostic significance. The VEGF index, defined as the ratio of CSF/serum VEGF concentration to CSF/serum albumin levels, is found to be higher in CM and is a promising reliable diagnostic tool. Moreover, the detection of several tumor markers in CSF can increase sensitivity, specificity, and predictive value.
CSF Flow Studies
In CM, obstructions in CSF flow are common because of the adhesion of tumor cells in the subarachnoid space and occur in 30 to 70% of the cases. Obstruction to CSF flow is hazardous as it decreases treatment efficacy and increases toxicity and mortality by hindering chemotherapy drug distribution. Hence, it is essential to ensure appropriate CSF flow during chemotherapy. CSF dynamics are monitored by 111Indium-DPTA ventriculography or Technetium-99m-DPTA flow studies before starting intrathecal therapy. Furthermore, it will decrease treatment-related mortality and improve survival by reducing tumor progression, neurological, and systemic toxicity.
Gadolinium-enhanced MRI scan is a pertinent test for the diagnosis of CM. Radiographic findings may include hydrocephalus and leptomeningeal enhancement of the brain in the T1 weighted image with contrast. T2/FLAIR hyperintensities may be seen in the subarachnoid space. The cerebral convexities, cerebellar folia, basal cisterns, and ventricular ependymal regions are the common areas that display enhancement or nodular deposits in CM. In the spinal cord, linear and nodular leptomeningeal enhancements may occur along the nerve roots, particularly in the cauda equina.
For solid tumors, the sensitivity of MRI is 76%, and it increases to 95% for spinal MRI in patients presenting with cauda equina syndrome.
MRI shows enhancement in both inflammatory and carcinomatous meningitis. Hence, it is imperative to pair it with CSF cytology. False-positive leptomeningeal enhancement may be seen in patients undergoing treatment due to therapy-induced inflammatory reaction, as seen with radiotherapy and immunotherapy. The prevalence is low (<1%) but still should be considered as a possibility in patients.
Refer to Figure 2: MRI T1 weighted images showing leptomeningeal enhancement, and
Figure 3:  MRI T1 weighted images showing leptomeningeal enhancement in lower portions of the spinal cord and post-treatment images.
The management of carcinomatous meningitis is complex and involves a combination of multiple treatment modalities. The goal of treatment is to improve the quality of life, prolong survival, and stabilize neurological deterioration while minimizing iatrogenic toxicity. The therapeutic options depend on ‘good risk’ versus ‘poor risk’ disease and are determined by the patient’s KPS score, tumor grade, systemic disease burden, and neurological status.
The KPS (Karnofsky performance score) and ECOG (Eastern Cooperative Oncology Group) are the two common performance status scoring systems to document the functional status of patients with cancer. Palliative care is recommended for patients with low KPS and high ECOG scores, as the risks associated with treatment outweigh potential benefits. Evaluation of treatment response and toxicity is also essential during every stage of treatment.
Guidelines on the management of patients with CM have been formulated by NCCN and ESMO. The three primary therapeutic modalities are:
Radiation therapy of CM includes focal radiation to nodular plaque-like deposits of malignant cells in meninges or diffuse radiation therapy to linear leptomeningeal contrast-enhancement lesions. It is usually targeted to sites of symptomatic or bulky disease.
Cranial irradiation is helpful in isolated cranial neuropathies and obstructive hydrocephalus. Focal spinal irradiation is helpful for lower extremity weakness and bladder or bowel involvement. Even though the neurological deficits may not improve, it decreases radicular pain. The dose used for cranial and spinal irradiation is typically 30 Gy in 10 daily fractions. For patients with poor prognosis, 20 Gy in 5 daily fractions can be used.
Whole-brain radiation therapy (WBRT) is helpful in patients with hydrocephalus secondary to CM. It decreases the ICP by breaking down adhesions caused by tumor cells and minimize the requirement of ventriculoperitoneal (VP) shunt. It enables intrathecal chemotherapy to work effectively by restoring CSF flow. WBRT is also helpful in bulky tumors and can be used in patients with low KPS scores, multiple metastatic lesions, severe systemic illness, and reduced survival. The dose is 30 Gy in 10 daily fractions.
Radiosensitive tumors include hematological malignancies, gynecological tumors, pediatric gliomas, and rhabdomyosarcomas. Focal radiation therapy rarely causes adverse effects. Alopecia, seizures, encephalopathy, mucositis, myelopathy, and myelosuppression can occur with more extensive fields. In patients with good-risk disease (Karnofsky performance status ≥60, no major neurologic deficits, minimal systemic disease), a multimodal approach comprising of both chemotherapy and radiation therapy is preferred.
Chemotherapy options in CM include both intrathecal and systemic chemotherapy.
Intrathecal chemotherapy (IT) is the mainstay of treatment for CM due to the selective BBB that limits the therapeutic efficacy of most systemic chemotherapy agents. It cannot be used with a VP shunt in place as it leads to toxic drugs entering the peritoneal cavity. IT is done either by injecting the drug into the subarachnoid space after performing an LP or by using an Ommaya catheter. Ommaya catheter is a small circular device placed beneath the scalp and drains into the lateral ventricle by a tube, thereby facilitating access to the CSF in the ventricles for the introduction of chemotherapy agents.
Lumbar puncture (LP) is easy to perform but has certain limitations. The requirement of frequent LPs increases the risk of bleeding with severe thrombocytopenia, and an unpredictable path of drug distribution in the brain after the spinal tap. As compared to LP, the Ommaya reservoir offers several merits. Drug administration is relatively painless and can be performed frequently. It ensures a uniform drug distribution in the subarachnoid space. However, it can be a source of infection that can prove dangerous in an already immunocompromised patient and requires surgery, which may not be possible in some patients. The intraventricular approach has been noted to have a better response than the intralumbar method and also offers a survival benefit. A randomized controlled trial done by Glantz et al. showed an increase in progression-free survival with the intraventricular route for methotrexate compared to intrathecal (43 vs. 19 days, p=0.048).
Conventional drugs for the intrathecal route (IT) include methotrexate, cytarabine, and less commonly, thiotepa. Methotrexate is the most common agent and can cause myelosuppression and neurological complications, including aseptic meningitis. Hematological malignancies are more responsive to IT. Early studies have described therapeutic efficacy with intrathecal administration of monoclonal antibodies, including trastuzumab in human epidermal growth factor receptor 2 (HER2) positive breast cancer and rituximab in lymphoma.
Systemic chemotherapy helps treat leptomeningeal disease as well as a systemic disease. As the BBB may only be partially disrupted in CM, agents used must be safe at high doses or lipid-soluble, so that therapeutic levels can be attained in CSF. Methotrexate and cytarabine require higher doses due to their low permeability.
It is convenient for high-risk surgical patients as it does not require Ommaya reservoir placement, and practical in cases of CSF flow obstruction. It may also provide uniform drug distribution in CSF. Several agents can be used, and the choice depends on the primary tumor. High dose systemic methotrexate along with leucovorin rescue, is used as an alternative to IT. Capecitabine, an oral 5-fluorouracil drug, is effective in breast cancers with CM. Several newer molecularly targeted therapies also have efficacy in CM.
Some examples of targeted therapy effective in CM include:
A combined multimodality approach may improve clinical outcomes. In breast cancer, a combination of intrathecal liposomal cytarabine and intravenous high dose methotrexate has shown promising results. A retrospective study done on patients with non-small cell lung cancer showed that the use of IT, WBRT, and EGFR-TKI were predictors for improved survival.
Refer to Figure 4: Management of Carcinomatous Meningitis
Numerous conditions can present with similar symptomatology as carcinomatous meningitis and should be taken into consideration whenever patients present with indistinguishable signs and symptoms.
Carcinomatous meningitis represents advanced-stage disease and usually has a dismal prognosis. The median time of survival is 2 to 4 months, even with treatment. Early diagnosis, normal CSF protein levels, and low disease burden are factors associated with a better prognosis. Patients with KPS score >60, minimal systemic disease, minimal neurological deficits, and options for effective systemic therapy are considered to have a good-risk disease. In these patients, systemic therapy combined with IT or RT may be beneficial. In poor-risk patients, palliative care is the best option. CM, due to lymphomas and leukemias, has a better prognosis compared to solid tumors.
Several future directions may help improve survival in patients with carcinomatous meningitis. This includes early diagnosis by analyzing circulating tumor DNA in CSF (CSF-ctDNA). These are shed from the cancer cells as a result of apoptosis and necrosis. Identification can help avoid subjecting the patient to high-risk surgeries or biopsies. The amount of CSF-ct DNA can provide information about tumor burden, recurrence, and treatment response. The identification of novel mutations in CSF-ctDNA can also provide newer therapeutic targets. There is a need for discovery of non-invasive methods like ultrasonography or CT scan guided drug delivery. Novel biological agents and immunomodulatory drugs may help in achieving better survival and improved quality of life.
The multidisciplinary team comprising of neurologists, neurosurgeons, medical oncologists, radiation oncologists, psychiatrists, and nurses must manage the biological, psychological, and social aspects of this disease.
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