Leptomeningeal cancer

Leptomeningeal cancer (also called leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, neoplastic meningitis, meningeal metastasis and meningeal carcinomatosis) is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord,^[1] causing them to become inflamed.^[2] The term leptomeningeal (from the Greek lepto, meaning “fine” or “slight”) describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located.^[3] The disorder was originally reported by Eberth in 1870.^[4]

It occurs with cancers that are most like to spread to the central nervous system.^[5] The most common cancers to include the leptomeninges are breast cancer, lung cancer, and melanomas because they can metastasize to the subarachnoid space^[6] in the brain which offers a hospitable environment for the growth of metastatic tumor cells.^[7][8] Individuals whose cancer has spread to an area of the brain known as the posterior fossa have a greater risk of developing a leptomeningeal cancer.^[9]

Leptomeningeal disease is becoming more evident because cancer patients are living longer and many chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells.^[10]

Epidemiology

In the United States, 1–8% of cancer patients are diagnosed with leptomeningeal disease, with approximately 110,000 cases per year.^[11] The exact incidence of leptomeningeal disease is difficult to determine, since gross examination at autopsy may overlook signs of leptomeningeal disease, and microscopic pathological inspection may be normal if the seeding is multifocal or if an unaffected area of the CNS is examined.^[12]

Causes

Leptomeningeal carcinomatosis occurs when the cancer cells invade and proliferate in the cerebrospinal fluid.^[13] and spread throughout the central nervous system.^[14] The metastatic tumor cells grows either attached to the pia mater covering the brain and spinal cord or floating unattached to the subarachnoid space.^[15] Tumors of diverse origins and hematologic cancers may spread to this space.^[16]

Some patients can develop a leptomeningeal tumor while receiving chemotherapy for their primary tumor.

Pathology

There are three anatomic patterns by which the tumor can spread in the subarachnoid space. More than one pattern may coexist in the same patient.

First, there may be plaque-like deposits of cells in the leptomeninges with invasion of Virchow-Robin spaces and, usually, the shedding of tumor cells into the cerebrospinal fluid.

Second, there may only be a thin coating of meninges, in some cases with only a single cell layer, but also with shedding of tumor cells into the cerebrospinal fluid. Third, there may be a pattern of nodular deposits of tumor on cranial and spinal nerve roots, frequently without tumor cells being shed into the cerebrospinal fluid.

The first and third patterns are common in solid tumors whereas the second occurs most frequently with leukemia and lymphoma.^[17]

Signs and Symptoms

The most common symptoms of leptomeningeal cancer is pain and seizures. The other symptoms may include headaches (usually associated with nausea, vomiting, light-headedness), gait difficulties from weakness or ataxia, memory problems, incontinence, sensory abnormalities.^[18][19] In some cases, symptoms may include double vision, numb chin,^[20] back pain, leg weakness, sphincter-related problems, hydrocephalus,^[21] loss of urine control, and difficulty walking. Depending on where the tumor cells settles, leptomeningeal cancer can cause almost any neurological problem.^[22]

Screening of involves an MRI scan to identify and diagnose tumors in the subarachnoid region of the brain. MRI can make a diagnosis even without an analysis of the cerebrospinal fluid but it can sometimes be difficult to detect because MRI scans cannot always pick up the problem.^[23]

Diagnosis

Diagnosis is most commonly made by lumbar puncture although the tests may be negative in roughly 10% of patients.^[24] Diagnosis often requires a high index of suspicion and is confirmed by neuroimaging and cerebrospinal fluid analysis.^[25] Physicians at Florida Hospital Cancer Institute may recommend a variety of tests and scans to help diagnoses which includes; a physical exam and medical history, a neurological exam and an MRI scan.^[26]

Treatment

There is currently no cure for leptomeningeal disease as the tumor is hard to eradicate.^[27] Current treatments for leptomeningeal tumors are palliative. The goals for treatment include prolonging survival and stabilizing neurological symptoms.

A combination of surgery, radiation, and chemotherapy treatment can be used to help improve the prognosis of the disease. The identification of malignant cells in the cerebrospinal fluid should be confirmed and if there is any doubt about the diagnosis, potential treatments should not be initiated as they can be toxic.

Chemotherapy is injected directly into the cerebrospinal fluid, either by lumbar puncture (“spinal tap”) or through a surgically implanted device called an Ommaya.^[28] The downside of diagnosis, which is performed via spinal tap is that while it is highly accurate and reliable, it can also report false-negative results.^[29] 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.^[30]

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.^[31]

Prognosis

The prognosis is generally poor with survival typically measured in months.^[32] It occurs in approximately 3-5% of cancer patients.^[33] The disease is usually terminal and if left untreated, the median survival is 4–6 weeks whereas if treated, the median survival can increase to 2–3 months.^[34] Treatment will be more effective if it is done on the primary tumor before it metastasizes to the brain or spinal cord.

Patients with leukaemia achieve better results compared to patients with solid tumours who have undergone treatment. It was found that 75% of patients stabilize or improve over several months as opposed to 25% of patients who do not respond and have progressive disease. But despite initial improvement, most patients survive only a few months. Breast cancer and small cell lung cancer are the two solid tumors that respond best to treatment^[35] Some patients do better than others, particularly those whose primary cancer is hematologic, bone marrow and lymph nodes.^[36]

Current Research

New treatments and clinical trial for breast cancer patients and non-small cell lung cancer patients with leptomeningeal disease are currently being explored.^[37] Diagnostics that improve early detection and chemotherapeutics tailored to the primary malignancy will likely be the most significant advances in improving survival.^[38]

Patients with leptomeningeal metastasis are generally excluded from clinical trials, thereby limiting the systematic assessment of novel therapies in this subgroup of patients with poor prognosis. More patients with leptomeningeal metastasis should be enrolled into trials investigating novel agents with the potential to penetrate the blood–brain barrier.^[39]

Novel approaches are being studied as currently available therapies are toxic and provide limited benefits.^[40]

References

External links

 This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms".