ABSTRACT: Carcinomatous meningitis, specifically leptomeningeal metastases from solid tumors, has a dismal prognosis, with an overall median survival of 2 to 4 months. Lymphomatous meningitis has a better outlook, with a median survival of more than 6 months, but diagnosis may be delayed and treatment is not curative. Despite these poor statistics, there are subsets of patients who do relatively well. Moreover, there are a number of new approaches to the diagnosis and treatment of leptomeningeal metastases that promise to extend life and prevent disability. These include molecular techniques of diagnosis, expanding the repertoire of drugs available for intrathecal administration, using systemic chemotherapy to treat leptomeningeal disease, and applying strategies such as gene therapy and immunotoxins to the management of leptomeningeal metastases. These novel approaches offer the hope of liberating patients from a death sentence and providing clinicians with effective weapons in the fight against a dreaded neurologic complication of systemic cancer. [ONCOLOGY 16:237-250, 2002]
Leptomeningeal metastases consist of metastatic tumor cells growing either attached to the pia mater covering the brain and spinal cord or floating unattached in the cerebrospinal fluid (CSF). In either case, the tumor cells live in the subarachnoid space, which offers a hospitable environment for the growth of metastatic tumor cells. The rich vascular supply to the meninges provides hematogenously seeded metastatic tumor cells access to the subarachnoid space, and the CSF has a high content of oxygen and glucose to support tumor cells with high metabolic activity. Leptomeningeal metastases can, therefore, escape the need for angiogenesis, which limits the growth of parenchymal metastases. Lymphoma, breast cancer, melanoma, and lung cancer (especially small-cell lung cancer) are associated with the greatest predilection to metastasize to the subarachnoid space.
By spreading through the subarachnoid space, leptomeningeal metastases can produce neurologic signs and symptoms at multiple levels of the neuraxis (Table 1). Radiculopathies, cranial nerve palsies, seizures, and encephalopathy are typical. Symptoms of increased intracranial pressure, caused either by hydrocephalus or blockage of CSF absorption into the arachnoid granulations, occur frequently. Strokes may result from occlusion of arteries of the Circle of Willis or their penetrating branches.
Leptomeningeal metastases from solid tumors confer a poor overall prognosis. Mean survival from the time of diagnosis is 2 to 4 months. However, subsets of patients, specifically those with lymphoma and breast cancer, may survive for more than 1 year with a reasonably good quality of life. Based on experience with meningeal leukemia, the mainstay of treatment for leptomeningeal metastases has been intrathecal chemotherapy, supplemented by focal external-beam radiotherapy to sites of symptomatic bulk disease.
Because of the blood-brain barrier, chemotherapeutic agents delivered directly into the CSF may have greater access to tumor cells than systemically administered chemotherapy. However, for solid-tumor leptomeningeal metastases, this treatment approach is unsatisfactory, both in failing to markedly prolong survival and in failing to relieve neurologic symptoms. Therefore, better treatment and new treatment strategies are under investigation.
The clinical milieu presents a variety of opportunities for developing new methods of treating leptomeningeal metastases. For chemosensitive tumors, such as breast cancer and lymphoma, the development of more effective chemotherapy offers promise. In particular, the use of systemic chemotherapy with effective penetration into the CSF has not been adequately explored. Systemic chemotherapy combined with techniques to disrupt the blood-brain barrier is another promising approach. For chemoresistant tumors, such as melanoma and non-small-cell lung cancer, new strategies need to be devised. The intrathecal injection of novel therapeutic agents, including vectors for gene therapy and monoclonal antibodies complexed with radioisotopes or toxins, offers the best hope for progress.
There are three anatomic patterns of tumor spread in the subarachnoid space, and 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 CSF. 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 CSF. 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 CSF.
The first and third patterns are common in solid tumors; the second occurs most frequently with leukemia and lymphoma. The nodular pattern of solid tumor metastases may be one mechanism of resistance to intrathecal chemotherapy, since most chemotherapeutic agents, when administered into the CSF, only penetrate a few millimeters into adjacent tissues.
Leptomeningeal metastases can produce a wide variety of signs and symptoms (Table 1). Although the textbook picture of leptomeningeal metastases involves the presence of signs and symptoms at multiple levels of the neuraxis,[1-3] the goal should be to diagnose the condition and begin treatment at an earlier stage, before disseminated fixed neurologic deficits have developed.
In the supratentorial compartment, leptomeningeal metastases can produce encephalopathy associated with widespread depression of cortical metabolism. Patients have decreased attentiveness, cognitive deficits, and, eventually, somnolence. Seizures can occur either from the simultaneous presence of parenchymal metastases or from invasion of the cerebral cortex by extension of leptomeningeal tumor along the perivascular spaces.
Patients may also present with symptoms of increased intracranial pressure, such as headache, nausea, and "false localizing" cranial nerve palsies with diplopia or vertigo. Increased intracranial pressure develops from three mechanisms of obstruction of CSF flow:
(1) A block of CSF outflow from the ventricles leading to noncommunicating hydrocephalus,
(2) A block of CSF flow at the incisura or over the convexities, producing communicating hydrocephalus, or
(3) A block of CSF absorption in the arachnoid granulations, producing increased intracranial pressure without hydrocephalus, a condition similar to pseudotumor cerebri (benign intracranial hypertension).
Tumor metastases to the subarachnoid space tend to localize to cranial and spinal nerve roots, leading to cranial neuropathy and spinal radiculopathy. In lymphoma patients, this may be difficult to distinguish from multiple mononeuropathy produced either by immune mechanisms or by lymphoma infiltration into peripheral nerves. An electromyogram may be helpful in this circumstance, by distinguishing radiculopathy from peripheral neuropathy.
Leptomeningeal metastases frequently coexist with intraparenchymal brain metastases. The signs and symptoms of the intraparenchymal metastases, including seizures, hemiparesis, and aphasias, may add to the symptoms and signs of leptomeningeal disease and present a confusing picture. In addition, leptomeningeal metastases may narrow pial arteries and lead to stroke or focal hemispheric or brain stem deficits on a vascular basis. Leptomeningeal metastases may produce clinical and arteriographic findings similar to central nervous system (CNS) vasculitis (Figure 1).
Case Report 1
A 47-year-old woman was diagnosed with bilateral invasive lobular carcinoma of the breast in February 1997. She had ovarian and bone marrow metastases. She underwent a bilateral mastectomy followed by chemotherapy with doxorubicin(Drug information on doxorubicin) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) but failed to respond. Bony metastases developed subsequently.
In May 1998, the patient underwent chemotherapy with high-dose cyclophosphamide, carboplatin(Drug information on carboplatin) (Paraplatin), and thiotepa(Drug information on thiotepa) (Thioplex), accompanied by autologous peripheral stem cell rescue, and was started on tamoxifen(Drug information on tamoxifen) (Nolvadex). She presented with neurologic symptoms in March 1999, with attacks of headache, nausea, and vertigo. The attacks could begin spontaneously or be precipitated by changes in position; the vertigo would last 3 to 5 minutes, but the headache would persist for about 30 minutes. Some attacks were accompanied by diplopia or graying out of vision. At this point, the presence of bone and bone marrow metastases had been established.
The woman’s CSF examination revealed an opening pressure of 390 mm H2O, protein of 67 mg/dL, glucose of 40 mg/dL, and no white blood cells but a positive cytology for adenocarcinoma cells consistent with a primary breast tumor. Magnetic resonance imaging (MRI) of the brain and spine were initially normal. She received a ventriculo-peritoneal shunt with an on-off valve. This relieved her headaches and vertigo. She was initially treated with intrathecal methotrexate(Drug information on methotrexate) at 12 mg weekly; she could tolerate having the shunt valve turned off for only 60 to 90 minutes. Immediately after her fourth dose of intrathecal methotrexate, she developed acute headache, nausea, and fever. These symptoms cleared over 24 hours, and she was subsequently treated with thiotepa at 10 mg weekly.
Her ventricular CSF contained normal protein and glucose concentrations but was never free of malignant cells. She did well clinically, however, continuing to work and travel. Her neurologic examination was normal aside from distal sensory loss in the lower extremities consistent with a mild peripheral neuropathy. However, in September 1999, she developed persistent diarrhea, nausea, and vomiting and was found to have an obstructed bile duct caused by peritoneal seeding of her carcinoma. Her brain MRI now demonstrated diffuse and nodular leptomeningeal contrast enhancement (Figure 2). She was lost to follow-up and presumably died shortly thereafter.
• Discussion—This case illustrates several points. First, it demonstrates the presentation of leptomeningeal metastases with symptoms of increased intracranial pressure, without focal neurologic signs or hydrocephalus. Her attacks of headache, nausea, and vertigo presumably represented plateau waves of high CSF pressure. These symptoms were relieved entirely by a ventriculo-peritoneal shunt. Second, it is unclear whether the patient achieved any benefit from intrathecal chemotherapy, as her CSF cytology was persistently positive and imaging studies showed disease progression. Third, she developed peritoneal seeding, presumably as a result of shunting cells from her subarachnoid space to her peritoneal cavity. Nevertheless, aggressive management of her disease achieved 6 months of productive life.
Case Report 2
A 74-year-old man was diagnosed with folliculotrophic cutaneous T-cell lymphoma and leukemia in March 2000. He was treated with interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) and achieved only a partial response. In August 2000, he presented to the neurology service with the recent onset of headache and diplopia. He had a right cranial nerve VI palsy and gait imbalance, but otherwise had a normal neurologic examination. Neuroimaging studies, including MRI of the brain with and without gadolinium, were normal. His CSF contained normal protein and glucose concentrations but an elevated white blood cell count of 58 × 106/L with 37% eosinophils and abnormal lymphocytes, consistent with lymphoma.
He had an Ommaya reservoir implanted and has begun treatment with intrathecal methotrexate at 12 mg weekly. Systemic treatment with denileukin diftitox (Ontak), a monoclonal antibody to the CD25 antigen, is planned. His subjective diplopia and gait imbalance have improved, but his nerve VI palsy persists.
• Discussion—This case illustrates the point that early in the course of leptomeningeal metastases, patients have only isolated neurologic signs and symptoms—in this case, a single cranial nerve palsy. Moreover, neuroimaging studies may be normal. One must have a high index of suspicion to make the diagnosis in this circumstance. The other point is that CSF eosinophilia, without another cause (such as treatment with nonsteroidal anti-inflammatory drugs), is highly suggestive of leptomeningeal lymphoma.
Case Report 3
A 72-year-old man was admitted to the neurology service in December 1998, with progressive polyradiculopathy of 4 months’ duration. His neurologic symptoms began with asymmetric weakness of the lower extremities, followed by left facial nerve palsy and left-sided tinnitus. His presentation was complicated by a history of Lyme disease. Initial CSF assay showed 1 × 106 lymphocytes/L, protein of 80 mg/dL, glucose of 44 mg/dL, and a negative cytology.
Two subsequent CSF examinations were nondiagnostic, and the patient’s weakness progressed. An MRI of the lumbosacral spine found enhancing lesions of the filum terminale and left L4 nerve root. A biopsy performed in March 1999 revealed diffuse large B-cell lymphoma involving the nerve root. He subsequently developed axillary adenopathy and lung lesions.
The plan was to treat him with intrathecal methotrexate, but an Ommaya reservoir became infected and had to be removed. He was therefore treated with M-BACOP (high-dose systemic methotrexate, bleomycin(Drug information on bleomycin) [Blenoxane], doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], prednisone(Drug information on prednisone)), with response of his peripheral lymphoma and stabilization of his neurologic disease. Although neurologically disabled, he has survived almost 2 years since presentation.
• Discussion—This case illustrates the difficulty of diagnosing leptomeningeal metastases when the CSF is nondiagnostic. In this man’s case, there were too few lymphocytes in the CSF to perform reliable flow cytometric analysis. Polymerase chain reaction (PCR) analysis looking for clonal immunoglobin gene rearrangement might have been useful but was not performed. Despite the problems with diagnosis and treatment, he has survived for 2 years with reasonably good quality of life.