The spread of malignancies to the central nervous system may either result in a single leptomeningeal metastasis, multiple secondary tumors or parenchymal brain lesions. The former are located in the subarachnoid space and primarily affect pia mater and arachnoid mater, but may exert local mass effects and provoke severe neurological deficits and death.
The most common symptom of LM is headaches. The majority of affected individuals also claims nausea and vomiting. Furthermore, patients may experience neurological symptoms consistent with cranial nerve palsies, cerebellar dysfunction, and spinal neuropathies. In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. Because most affected individuals suffer from multiple LM, they may show neurological symptoms seemingly unrelated to each other. For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status. Additionally, focal or generalized seizures, as well as meningism, may be reported. Neither of the aforementioned symptoms is specific for LM .
LM are typically associated with high tumor grades and other metastases. Thus, in patients previously diagnosed with advanced-stage cancer, clinical findings may prompt a suspicion of parenchymal brain tumors or neoplastic meningitis. Rarely, symptoms related to LM constitute the first manifestation of cancer. Diagnosis of LM is based on gadolinium-enhanced magnetic resonance imaging and cytological analyses of CSF specimens, and the former technique may also be employed to visualize parenchymal brain lesions . Neuroimaging is preferentially performed before lumbar puncture to obtain CSF samples since the latter procedure may provoke misleading meningeal enhancement.
Indeed, enhancement of the outer meninges is a very common, yet unspecific finding in LM patients. Enhancement of the pia mater and nodular lesions are less frequently observed, but are considered to be more specific for neoplastic meningitis. Imaging procedures should encompass the entire neuroaxis because the majority of individuals who develop LM present with multiple metastases unevenly distributed throughout the subarachnoidal space. Besides LM, affected individuals may present parenchymal brain tumors and hydrocephalus. While hydrocephalus is readily observed in computed tomography scans, this technique does often yield unaltered images with regards to the meninges.
At least 10 ml of CSF should be examined for tumor cells to avoid false-negative results. Furthermore, a second sample may be obtained and analyzed in the case of the first specimen yields negative results. Morphological features of tumor cells largely depend on the origin of the primary tumor and it may be a challenge to distinguish malignant cells from merely atypical ones, particularly in the case of lymphoma or leukemia. Here, flow cytometric analyses may be necessary to identify a monoclonal population of immune cells. Immunohistochemical and molecular analyses may also aid to relate LM with a determined solid primary tumor and set the basis for target-oriented therapy. Finally, it has to be noted that LM is frequently associated with pleocytosis, enhanced protein levels, and low glucose concentrations in CSF.
A thorough workup including an analysis for further metastases, an association of LM with a primary tumor, and a pathohistological classification of both is the basis of therapy. Determined molecular properties, e.g., hormone receptor expression and enzymatic activity, may render neoplasms susceptible to certain therapeutics, but they may differ between the primary tumor and LM . While systemic chemotherapy is generally indicated to treat malignancies and metastases in peripheral tissues, an alternative route of administration has to be chosen to deliver drugs to the subarachnoid space. Intrathecal drug application via an intraventricular reservoir is preferred, but mechanical obstruction of the subarachnoid space by metastases may prevent compounds from reaching the entire neuroaxis. Lumbar punctures may be required to deliver active agents to the leptomeninges surrounding the inferior segments of the central nervous system. Of note, certain chemotherapeutics are neurotoxic and cannot be applied as described above. This is the case for vincristine; methotrexate, cytarabine, liposomal ara-C, and thiotepa, and are rather well-tolerated, though, and are most commonly used in LM patients. Pharmacodynamic and pharmacokinetic properties of those drugs have been reviewed elsewhere .
In patients with a high-performance status, craniospinal axis irradiation is recommended to target the entire neuroaxis. In contrast, a low-performance status indicates irradiation of symptomatic sites or sole palliative care.
Additional measures may be taken to relieve symptoms, e.g., the positioning of a ventriculoperitoneal shunt to lower intracranial pressure and application of corticosteroids to reduce spinal cord compression.
Despite diagnostic advances that allow for an earlier recognition of LM, they are still associated with a poor prognosis. In general, patients suffering from hematological malignancies that spread to the leptomeninges have a better outcome than those diagnosed with solid primary tumors. Median survival times of few months and two months have been reported, respectively .
LM may arise after the spread of malignant cells originating from solid tumors, lymphoma or leukemia . While the possibility of spread to the leptomeninges cannot be ruled out in any cancer, most cases of LM are associated with the following primary tumors :
Although reported incidences of LM are increasing, this complication of cancer is still assumed to be largely underdiagnosed. Epidemiological data provided should thus be interpreted with care.
As has been indicated in the previous section, certain malignancies are associated with an increased risk of LM. According to current knowledge, the individual risk of cancer patients for developing LM is as follows :
Infiltration of the subarachnoid space allows for an extensive distribution of tumor cells along the entire neuroaxis. Considerable research efforts have been undertaken to clarify how degenerated cells reach this privileged area, and the following routes of metastatic spread have been identified :
Predilection sites of tumor cell accumulation and metastatic growth are determined by CSF flow and gravity and comprise basal cisterns, cerebellopontine angle, posterior fossa and lumbar cistern. Here, LM exert local mass effects and interfere with the brain, spinal cord, and nerve function. At the same time, tumor cells may form mechanical obstacles that hinder CSF drainage, and this condition may result in hydrocephalus.
General measures to reduce carcinogen exposure may lower the individual risk of developing malignancies; detection of cancer during early stages may prevent metastatic spread. In this context, patients should be advised to refrain from tobacco consumption, to put safety measures into practice, and to regularly undergo preventive medical check-ups. Treatment of certain subtypes of cancer (e.g., T-cell lymphoblastic lymphoma) comprises prophylactic brain irradiation or intrathecal application of chemotherapeutics.
Brain and spinal cord are surrounded by the meninges, namely by pia mater, arachnoid mater and dura mater. The former two are also referred to as leptomeninges. The subarachnoid space, i.e., the more or less extensive space between pia mater and arachnoid mater, is filled with cerebrospinal fluid (CSF). Tumor cells may infiltrate this space by crossing the boundaries of vessels or adjacent tissues and may then be distributed within the CSF. Accordingly, patients may develop a single leptomeningeal metastasis (LM) or present with multiple secondary tumors to be encountered in pia mater and arachnoid mater.
For a long time, LM have been considered uncommon. Most types of cancer are expected to spread through hematogenous route or through lymphogenic route, and metastases most frequently form in regional lymph nodes, lungs, liver, and spleen. However, the incidence of LM is increasing , possibly due to prolonged survival times and improvements of therapeutic regimens directed against neoplasms in the aforementioned tissues. Chemotherapeutic drugs differ with regards to their pharmacokinetic properties and may or may not reach certain compartments. To date, most chemotherapeutics are unable to penetrate into privileged areas because they cannot overcome physiological and functional barriers like the blood-brain barrier and the blood-CSF barrier . Consequently, tumors may proliferate in these regions despite otherwise effective systemic chemotherapy. Tumor growth may be associated with secondary inflammation and this fact that has lead to using the terms carcinomatous and neoplastic meningitis to refer to LM.
Although those barriers may display increased permeability in close proximity to tumors, they do pose a major obstacle to LM treatment. In general, chemotherapeutics have to be administered intrathecally. Furthermore, affected individuals may be subjected to radiotherapy. Despite all efforts, LM are associated with a poor prognosis and median survival times of less than half a year.
The brain and the spinal cord are enveloped by distinct tissues referred to as meninges. The inner meninges, pia mater and arachnoid mater, may also be designated leptomeninges. They enclose the subarachnoid space, which is filled with cerebrospinal fluid (CSF). If tumor cells reach the leptomeninges and the CSF, they may easily spread to multiple sites along the neuroaxis. Consequently, few patients present with a single leptomeningeal metastasis (LM) - the majority of affected individuals suffer from several metastases that interfere with brain and spinal cord function. Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.
Tumor cells that spread to the leptomeninges may originate from any type of cancer but are most commonly detected in patients previously diagnosed with carcinoma of the breast or lung, malignant melanoma, malignancies of the gastrointestinal tract and adenocarcinoma of unknown origin. These are aggressive neoplasms, and LM generally develop during advanced stages of these diseases. At this time, metastases may already affect other tissues, too. Thus, any therapeutic regimen should target the primary tumor as well as leptomeningeal and other metastases. In most cases, only palliative care can be offered. Patients may be administered chemotherapeutics, may undergo radiotherapy and additional measures to relieve symptoms in order to maintain life quality during the following months. To date, there is no cure for LM.