Leptomeningeal Carcinomatosis

Etiology

Most solid tumors are known to cause LC, 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), followed by melanoma.[5][6][7][8]

Epidemiology

About 110,000 new cases of LC are diagnosed each year in the United States. The true incidence of LC is difficult to determine, as this condition is usually underdiagnosed during a 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 incidence rates of 6% to 18% for melanomas. The incidence of LC is increasing due to improved survival rates secondary to the improved systemic control of the disease, better imaging, 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 LC after diagnosis of a solid tumor ranges between 1.2 and 2 years; this time is about 11 months in hematologic cancers.[9][10]

Pathophysiology

It is postulated that cancerous cells spread to leptomeninges via several different mechanisms, including direct seeding from brain parenchyma, dura mater (not protected by BBB), and bone, endoneurial/perineural invasion, and hematogenous seeding (especially via venous plexi). Some studies also indicate a correlation between neurosurgical interventions like cerebellar metastasis resection and the opening of ventricles with LC. 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 the upregulation of complement component 3 by cancer cells in cerebrospinal fluid (CSF), which in turn causes interruption of BBB and leads to penetration of plasma growth factors 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.

History and Physical

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 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 (CN) deficits, especially CN 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 lead to inflammatory reactions and disrupt CSF flow causing obstructive or communicating hydrocephalus and presenting as nausea, vomiting, positional headaches, and somnolence.

Evaluation

The diagnosis of LC 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, then diagnostic evaluation should be furthered by a lumbar puncture (LP). In the case of LC, 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 show elevated opening pressure (greater than 150 mm) as well. False-negative cytology results are common, and a study shows CSF cytology can have false-negative results 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 or the lumbar region or a site of known leptomeningeal involvement. In most cases, positive CSF studies and suggestive radiographic findings are enough to make a diagnosis, but a negative LP should be followed by at least one additional LP, especially if there is high clinical suspicion. The sensitivity of cytology is 50% to 60% after the first LP and approaches 85% to 90% with the second collection.

CSF tumor markers also have been evaluated as an aid in the diagnosis, but the relative lack of sensitivity and specificity limits this modality from 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.

Treatment / Management

The prognosis of LC remains poor despite advances in therapy. There is a lack of randomized clinical trials, and treatment methods are derived from lower evidence studies or clinical expert opinions. 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 IT chemotherapy. CSF flow obstruction is relieved by surgical interventions; however, surgery has a very marginal role in the management of LC. 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.

Differential Diagnosis

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 (IT) chemotherapy
• Cord compression
• Meningitis and encephalitis
• Sarcoidosis
• Steroid myopathy
• Stroke
• Toxic metabolic encephalopathy

Surgical Oncology

Indications and Techniques

Surgical procedures play a very minute role in the management of this disease. Ventriculoperitoneal (VP) shunt or intraventricular catheters can be placed for relieving symptomatic hydrocephalus and delivery of IT chemotherapy, respectively. In rare instances, resection of bulky CNS disease or biopsy of leptomeninges in the previously unknown primary may be done. However, there is no known survival benefit from surgical procedures.

Adverse Effects

Adverse effects include infection, shunt displacement, and catheter failure.

Radiation Oncology

Indications

Radiation is important for palliation of symptoms, especially in spinal involvement, as it may alleviate pain. Sometimes it may relieve hydrocephalus and associated symptoms and facilitate the administration of IT chemotherapy. However, a retrospective study has failed to show any survival benefit. Eradication of tumor craniospinal radiation is required, which carries very high systemic and CNS toxicities and risks 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 when combined with IV or IT chemotherapy.

Medical Oncology

IT Chemotherapy

IT chemotherapy has shown a survival benefit in retrospective studies. The agent used commonly includes 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 (commonly implicated organism is Staphylococcus epidermidis), seizure, myelosuppression, and leukoencephalopathy are some other complications encountered.

Systemic Chemotherapy

Numerous studies have shown that systemic chemotherapy has improved survival. It bypasses the administration issues of IT chemotherapy, treats the primary tumor, and also is effective in treating nodular type LC. BBB is disrupted in LC; hence systemic chemotherapy has been demonstrated to achieve therapeutic levels in CSF. 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 (VGEF inhibitor) and dabrafenib (BRAF inhibitor) have been reported to demonstrate a response in LC from melanoma. IT trastuzumab in LC from HER-2 positive breast cancer also has 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 LC from EGFR-mutant NSCLC that have shown promising results in terms of extended survival. Anaplastic lymphoma kinase (ALK) inhibitors are another class of drugs shown to be effective in LC from NSCLC with ALK rearrangements in ongoing trials.

Novel Therapeutics

Immunotherapy is another novel treatment approach to LC. 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.

Staging

Since leptomeningeal carcinomatosis is a late-stage, metastatic complication of various cancer types, it is classified as stage IV disease.

Prognosis

Prognosis remains grim in patients with LC. 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 CNS disease burden, extensive systemic disease with few treatment options, severe neurologic impairment, and encephalopathy are markers of poor prognosis.

Complications

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]