Browse the corpus

Leptomeningeal carcinomatosis is cancer involving the pia mater and arachnoid mater. Studies have shown that both solid tumors, including brain tumors and hematological cancers, can metastasize to involve the leptomeninges. Leptomeningeal carcinomatosis heralds a poor prognosis with limited treatment options. This activity describes the evaluation, diagnosis, and management of leptomeningeal carcinomatosis and stresses the role of team-based interprofessional care for affected patients. Objectives: Describe the etiology of leptomeningeal carcinomatosis. Describe the presentation of leptomeningeal carcinomatosis. Summarize the treatment options for leptomeningeal carcinomatosis. Review the importance of improving care coordination amongst interprofessional team members to improve patient outcomes affected by leptomeningeal carcinomatosis. Access free multiple choice questions on this topic.

Leptomeningeal carcinomatosis, also known as "leptomeningeal metastasis" or "carcinomatosis meningitis," is the involvement by cancer of the pia and arachnoid mater of the brain with the subarachnoid space in between. It was first described in the late 19th century, and many studies have been carried out on the subject in recent years. Studies have shown that both solid tumors, including brain tumors and hematological cancers, can metastasize to involve the leptomeninges. It is an uncommon and late complication seen in 5% to 8% of cases of solid tumors and 5% to 15% of cases of hematological cancers. Additionally, it implies a poor prognosis and limited treatment options.[1][2][3][4]

Most solid tumors are known to cause leptomeningeal carcinomatosis, but the most common solid tumors that involve the leptomeninges are breast, lung, and melanoma, gastrointestinal, and primary central nervous system tumors. Metastatic breast cancer is the most common etiology, followed by lung cancer (mainly small cell lung cancer), and melanoma.[5][6][7][8]

About 110,000 new cases of leptomeningeal carcinomatosis are diagnosed each year in the United States. The true incidence of leptomeningeal carcinomatosis is difficult to determine, as this condition is usually underdiagnosed during gross and microscopic examination at autopsy. The incidence varies among different cancer types. Among breast cancer patients, it ranges between 5% and 8%, up to 9% to 25% in lung cancer, and up to 30% in melanomas. Some authors have reported melanoma incidence rates of 6% to 18%. The incidence of leptomeningeal carcinomatosis is increasing due to improved survival rates, secondary to improved systemic control of the disease, better imaging and diagnostic modalities, and treatment with therapies that do not cross the blood-brain barrier (BBB). The longer patients live with systemic cancer, the higher the chances of tumor spread and seeding of the leptomeninges. The median time to diagnose leptomeningeal carcinomatosis after diagnosis of a solid tumor ranges between 1.2 and 2 years; this time is about 11 months in hematologic cancers.[9][10]

It is postulated that cancerous cells spread to the leptomeninges via several mechanisms, including direct seeding from the brain parenchyma, dura mater (not protected by the BBB), and bone, endoneurial/perineural invasion, and hematogenous seeding (especially via venous plexi). Some studies also indicate a correlation between neurosurgical interventions, such as cerebellar metastasis resection and ventricular opening, and the presence of leptomeningeal carcinomatosis. Another possible entry point is through the fenestrated endothelium of the choroid plexus, which allows selective solute transport in contrast to the BBB. One study suggests that cancer cells upregulate complement component 3 in cerebrospinal fluid (CSF), which in turn disrupts the BBB and allows plasma growth factors to penetrate into the CSF. One such plasma growth factor implicated in the process is vascular endothelial growth factor (VEGF), promoting tumor angiogenesis and endothelial cell proliferation. It is also an important drug target. There are different patterns of involvement of the leptomeninges, but typically, basal cisterns, posterior fossa, and cauda equina are affected.

Signs and symptoms may initially be nonspecific and may not prompt evaluation in a sick patient with metastatic cancer. Of note, a minority of patients may be diagnosed incidentally and may be asymptomatic at the time of diagnosis. However, some signs and symptoms may indicate the location of the involvement. A wide range of signs and symptoms have been reported, including but not limited to the following: Cerebral: headache, confusion, cognitive impairment, psychiatric disorders, seizures. Posterior fossa: cranial nerve deficits, especially cranial nerve VI, VII, and VIII (diplopia, facial weakness, hearing loss), ataxia. Vascular: ischemia and infarction. Spinal cord: limb weakness, dermatomal sensory loss, radicular pain, bladder, and bowel dysfunction. Inflammatory reactions: Tumor cells may elicit inflammatory responses and disrupt CSF flow, leading to obstructive or communicating hydrocephalus and presenting with nausea, vomiting, positional headaches, and somnolence.

The diagnosis of leptomeningeal carcinomatosis is often challenging due to the low sensitivity of different diagnostic modalities. The initial diagnostic evaluation includes at least a high-quality MRI of the brain and spine and CSF studies. MRI with gadolinium contrast has a sensitivity of 70% and specificity of 77% to 100%. It may detect leptomeningeal enhancement, hydrocephalus, subependymal nodules/deposits (which may also be seen on cerebral convexities), cisterns, and on the tentorium. Spinal cord involvement may show patchy enhancement of nerve roots and extramedullary nodules. If safe, a lumbar puncture should be performed to further the diagnostic evaluation. In the case of leptomeningeal carcinomatosis, CSF studies usually show mild pleocytosis, hypoglycorrhachia (usually less than 60 mg/dL), and elevated protein (greater than 45 mg/dL). If the glucose levels are very low, then infectious etiologies must be ruled out. In 50% to 70% of cases, it may also show elevated opening pressure (greater than 150 mm). False-negative cytology results are common, and a study shows that CSF cytology can yield false negatives of up to 36% when samples are refrigerated for 48 hours. These false-negative results can be minimized by securing a large volume (10 mL) of CSF for cytology, expediting sample processing without additional storage, and obtaining CSF from cisterns, the lumbar region, or a site of known leptomeningeal involvement. In most cases, positive CSF studies and suggestive radiographic findings are sufficient to make a diagnosis, but a negative lumbar puncture should be followed by at least 1 additional lumbar puncture, especially if clinical suspicion is high. The sensitivity of cytology is 50% to 60% after the first lumbar puncture and approaches 85% to 90% with the second collection.

If safe, a lumbar puncture should be performed to further the diagnostic evaluation. In the case of leptomeningeal carcinomatosis, CSF studies usually show mild pleocytosis, hypoglycorrhachia (usually less than 60 mg/dL), and elevated protein (greater than 45 mg/dL). If the glucose levels are very low, then infectious etiologies must be ruled out. In 50% to 70% of cases, it may also show elevated opening pressure (greater than 150 mm). False-negative cytology results are common, and a study shows that CSF cytology can yield false negatives of up to 36% when samples are refrigerated for 48 hours. These false-negative results can be minimized by securing a large volume (10 mL) of CSF for cytology, expediting sample processing without additional storage, and obtaining CSF from cisterns, the lumbar region, or a site of known leptomeningeal involvement. In most cases, positive CSF studies and suggestive radiographic findings are sufficient to make a diagnosis, but a negative lumbar puncture should be followed by at least 1 additional lumbar puncture, especially if clinical suspicion is high. The sensitivity of cytology is 50% to 60% after the first lumbar puncture and approaches 85% to 90% with the second collection. CSF tumor markers have also been evaluated as aids in diagnosis, but the relative lack of sensitivity and specificity limits their routine use. Nonetheless, this method is an option in certain tumors if all other workup is negative. Certain tumor markers that can be tested include CEA in adenocarcinomas, alpha-fetoprotein in hepatocellular and testicular carcinomas, and beta-human chorionic gonadotropin in choriocarcinomas and testicular carcinomas. There is also some data on determining VEGF levels in CSF, but further research is yet to be conducted on the topic. Recently, cell-free DNA in CSF has undergone evaluation to detect tumor-specific somatic mutations through next-generation sequencing, which may help detect certain tumors. Rarely, CSF flow studies/ventriculography using Indium 111-DTPA or Technetium-99m labeled albumin may be used to identify CSF flow. If there is no active systemic disease, then systemic restaging is advised to guide diagnosis and therapy.

The prognosis of leptomeningeal carcinomatosis remains poor despite advances in therapy. There is a lack of randomized clinical trials, and treatment methods are derived from lower-quality studies or clinical expert opinion. Treatment focuses on improving neurologic deficits, quality of life, and prolonging survival while minimizing toxicity. Commonly, radiation is applied to bulky or symptomatic anatomical lesions followed by intrathecal chemotherapy. CSF flow obstruction is relieved by surgical interventions; however, surgery has a very marginal role in the management of leptomeningeal carcinomatosis. Systemic therapy can be added to the regimen to treat the primary tumor and potentially prolong survival. Palliative and supportive treatment are provided as needed with anti-depressants, anxiolytics, and opioid and non-opioid agents. Psychostimulants should always be provided in addition to pursuing the treatment of the disease/cancer.

As patients can present with a wide variety of clinical features, it is crucial to consider alternative diagnoses like infectious etiologies, autoimmune and vascular disorders, adverse effects from chemoradiation, paraneoplastic syndromes, and toxic-metabolic encephalopathy (especially in a sick patient). The list may include, but is not limited to, the following: Brain abscess Brain metastasis Chemical meningitis due to intrathecal chemotherapy Cord compression Meningitis and encephalitis Sarcoidosis Steroid myopathy Stroke Toxic metabolic encephalopathy

Indications and Techniques Surgical procedures play a very minor role in the management of this disease. Ventriculoperitoneal shunts or intraventricular catheters can be placed to relieve symptomatic hydrocephalus and to deliver intrathecal chemotherapy, respectively. In rare instances, resection of bulky central nervous system disease or biopsy of the leptomeninges to identify the previously unknown primary may be performed. However, there is no known survival benefit from surgical procedures. Adverse Effects Adverse effects include infection, shunt displacement, and catheter failure.

Indications Radiation is important for symptom palliation, especially in spinal involvement, as it may alleviate pain. Sometimes it may relieve hydrocephalus and associated symptoms and facilitate the administration of intrathecal chemotherapy. However, a retrospective study has failed to show any survival benefit. Eradication of the tumor requires craniospinal radiation, which carries very high systemic and central nervous system toxicities and risks of myelosuppression and other complications. Given the poor prognosis, it is considered technically impractical. Dosage Whole-brain radiotherapy (WBRT) is usually given at a dose of 30 to 40 grays (Gy) in 2 to 3 Gy fractions. Focal radiotherapy is done for spinal lesions. Adverse effects Cognitive impairment, somnolence, and late leukoencephalopathy occur when combined with intravenous or intrathecal chemotherapy.

IT Chemotherapy IT chemotherapy has shown a survival benefit in retrospective studies. The agents commonly used include methotrexate (MTX), cytarabine, thiotepa, and sustained-release liposomal cytarabine. Studies have shown superior efficacy of sustained-release cytarabine compared to MTX. Aseptic/chemical meningitis is a common complication that is manageable with steroids. Infectious meningitis (the commonly implicated organism is Staphylococcus epidermidis), seizures, myelosuppression, and leukoencephalopathy are other complications encountered. Systemic Chemotherapy Numerous studies have shown that systemic chemotherapy has improved survival. It bypasses the administration issues of intrathecal chemotherapy, treats the primary tumor, and is also effective in treating nodular-type leptomeningeal carcinomatosis. BBB disruption in leptomeningeal carcinomatosis; hence, systemic chemotherapy has been shown to achieve therapeutic CSF concentrations. Agents used include high-dose MTX, high-dose cytarabine, capecitabine (particularly for breast cancer), thiotepa, and temozolomide. There seems to be some promise in using etoposide in small-cell lung cancer. Targeted Therapy Bevacizumab (VEGF inhibitor) and dabrafenib (BRAF inhibitor) have been reported to demonstrate a response in leptomeningeal carcinomatosis from melanoma. Intrathecal trastuzumab in leptomeningeal carcinomatosis from HER-2-positive breast cancer has also shown some promise and a favorable adverse effect profile. There are several ongoing phase II trials on the subject. EGFR-mutant non-small cell lung cancer (NSCLC) has shown a response to erlotinib and gefitinib, but at higher doses, as they do not cross the BBB easily. There are ongoing trials of other tyrosine kinase inhibitors (TKIs) in leptomeningeal carcinomatosis from EGFR-mutant NSCLC that have shown promising results, including extended survival. Anaplastic lymphoma kinase (ALK) inhibitors are another class of drugs shown to be effective in leptomeningeal carcinomatosis arising from NSCLC with ALK rearrangements, as demonstrated in ongoing trials. Novel Therapeutics

Bevacizumab (VEGF inhibitor) and dabrafenib (BRAF inhibitor) have been reported to demonstrate a response in leptomeningeal carcinomatosis from melanoma. Intrathecal trastuzumab in leptomeningeal carcinomatosis from HER-2-positive breast cancer has also shown some promise and a favorable adverse effect profile. There are several ongoing phase II trials on the subject. EGFR-mutant non-small cell lung cancer (NSCLC) has shown a response to erlotinib and gefitinib, but at higher doses, as they do not cross the BBB easily. There are ongoing trials of other tyrosine kinase inhibitors (TKIs) in leptomeningeal carcinomatosis from EGFR-mutant NSCLC that have shown promising results, including extended survival. Anaplastic lymphoma kinase (ALK) inhibitors are another class of drugs shown to be effective in leptomeningeal carcinomatosis arising from NSCLC with ALK rearrangements, as demonstrated in ongoing trials. Novel Therapeutics Immunotherapy is another novel treatment approach to leptomeningeal carcinomatosis. Agents like nivolumab, ipilimumab, and pembrolizumab have been studied and have shown some positive results. Intrathecal Interleukin-2 (IL-2) and intrathecal tumor-infiltrating lymphocyte (TIL) therapies also have been studied, but the data on these therapies is scant so far, and further trials are needed before these regimens can be considered in routine treatment.

Prognosis remains grim in patients with leptomeningeal carcinomatosis. The time from diagnosis to death is about 4 to 6 weeks if left untreated. With treatment, overall survival is approximately 2 to 4 months. Patients with breast cancer have shown better prognosis and response to therapy, with a median survival of 5 to 7 months, compared to other solid tumors like melanoma and lung cancer, with a median survival of approximately 4 months. Favorable prognostic factors include KPS greater than 70, normal CSF flow, absence of major neurologic deficits, active treatment, chemosensitivity of primary cancer, and CSF protein less than 50 mg/dL at the time of diagnosis. According to the US National Comprehensive Cancer Network, KPS less than 60, high central nervous system disease burden, extensive systemic disease with few treatment options, severe neurologic impairment, and encephalopathy are markers of poor prognosis.

Leptomeningeal carcinomatosis is itself a complication of metastatic disease, and complications resulting from it are often related to interventions. These can include aseptic/chemical meningitis, myelosuppression secondary to intraventricular chemotherapy, catheter-related infections, intraventricular catheter malpositioning, unidirectional catheter obstruction, leukoencephalopathy, Ommaya reservoir exposure, and chemotherapy-related myelopathy.[11]

Patients need to see an oncologist who specializes in leptomeningeal metastatic disease. The healthcare team can educate patients about the available (albeit limited) treatment options and prepare patients and families for unfavorable outcomes.

Leptomeningeal carcinomatosis remains a diagnostic challenge due to the limited and variable sensitivities of diagnostic modalities. Symptoms may be ignored initially in sick patients with metastatic disease, leading to a delay in diagnosis. Prognosis remains poor despite advances in therapies due to limited evidence from studies and variable/limited response to treatment, which is limited by toxicity. Understanding the molecular mechanisms of brain metastasis may help identify and evaluate more effective, targeted therapies targeting tumor-specific molecular markers across different tumor types.

Leptomeningeal carcinomatosis is best managed by an interprofessional healthcare team that should include clinicians, oncology specialists, oncology specialty nurses, pharmacists, and hospice and palliative care nurses. The prognosis for most patients is poor; thus, efforts should focus on improving quality of life. Pain control and support measures should be provided. No aggressive studies or treatments are warranted for most patients, as death is usually imminent.[12] The use of newer biological agents should be used with good judgment as they only prolong life by a few weeks or months; on the other hand, they burden the family with enormous costs of the medications.