carcinomatosis (LC) is a serious complication of cancer that carries substantial rates of
morbidity and mortality. It may occur at any stage in the neoplastic disease, either as
the presenting sign or as a late complication, though it is associated frequently with
relapse of cancer elsewhere in the body.
First recognized by Eberth
in 1870, LC remains underdiagnosed even today. Nevertheless, it has been recognized more
frequently in the last 3 decades than before because of improved diagnostic tools,
therapy, and awareness.
LC occurs with invasion to
and subsequent proliferation of neoplastic cells in the subarachnoid space. Malignancies
of diverse origins may spread to this space, which is bound by the leptomeninges. Spread
of hematologic cancers to this space and direct CSF seeding of intraparenchymal intraaxial
CNS tumors are also well recognized.
The leptomeninges consist of
the arachnoid and the pia mater; the space between the 2 contains the CSF. When tumor
cells enter the CSF (either by direct extension, as in primary brain tumors, or by
hematogenous dissemination, as in leukemia), they are transported throughout the nervous
system by CSF flow, causing either multifocal or diffuse infiltration of the leptomeninges
in a sheetlike fashion along the surface of the brain and spinal cord. This multifocal
seeding of the leptomeninges by malignant cells is called LC if the primary is a solid
tumor, and lymphomatous meningitis or leukemic meningitis if the primary is not a solid
Lymphomatous meningitis or
leukemic meningitis is somewhat of a misnomer, as meningitis implies an inflammatory
response that may or may not be present. It is not a single entity pathologically; it can
occur concurrently with CNS invasion or wide dissemination in the intraventricular spaces,
or in association with CNS metastases, with the clinical picture differing somewhat in
seeding of the leptomeninges may be explained by the following 5 postulated mechanisms:
(1) hematogenous spread to choroid plexus and then to leptomeninges, (2) primary
hematogenous metastases through the leptomeningeal vessels, (3) metastasis via the Batson
venous plexus, (4) retrograde dissemination along perineural lymphatics and sheaths, and
(5) centripetal extension along perivascular and perineural lymphatics from axial
lymphatic nodes and vessels through the intervertebral and possibly form the cranial
foramina to the leptomeninges.
Signs and symptoms usually
are attributable to obstruction of CSF flow that leads to increased intracranial pressure
(ICP) or hydrocephalus, local tumor infiltration in the brain or spinal cord that causes
cranial-nerve palsies or radiculopathies, alterations in the metabolism of nervous tissue
that causes seizures, and encephalopathy or focal deficits or occlusion of blood vessels
as they cross the subarachnoid that lead to infarcts.
- In the US: Approximately
1-8% of patients with cancer develop LC. However, the exact incidence is difficult to
determine as gross inspection at autopsy may miss LC, and microscopic pathologic
examination findings may be normal if the seeding is multifocal or if an unaffected area
of the CNS is examined. The most frequent origin of such neoplasms is the lungs (30-70%),
followed by breast (10-30%), GI tract (2-20%), and malignant melanomas (2-15%).
Adenocarcinomas are the most common tumors to metastasize to the leptomeninges, though any
systemic cancer can do so. Small-cell lung cancers spread to the leptomeninges in 9-25% of
cases; melanomas, in 23%; and breast cancers, in 5%. However, because of the different
relative frequencies of these cancers, most patients with LC have breast cancer.
Uncommon neoplasms, such as embryonal
rhabdomyosarcoma and retinoblastoma, also tend to spread to leptomeninges, but sarcomas
rarely do. Medulloblastomas are among those tumors that spread to the CSF, as do
ependymomas and glioblastomas on occasion. Squamous cell carcinomas of head and neck can
spread to the meninges along cranial-nerve paths. Although LC is uncommon in children, it
can be seen in those with acute lymphocytic leukemia (ALL) and primary brain tumors,
particularly ependymomas, medulloblastomas, and germ-cell tumors.
The incidence of LC
increases the longer a patient has the primary cancer; LC is accompanied by other
intracranial metastases in 98% of patients with a nonleukemic primary cancer.
The median survival is 7 months for patients with LCs from breast cancers, 4
months for patients with LCs from small-cell lung carcinomas, and 3.6 months for patients
LCs from melanomas.
- Spinal-root involvement is caused
by either meningeal irritation, presenting with nuchal rigidity and neck and back pain
(rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy
(usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted
in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes,
paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord
compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal
rigidity, positive results on the straight-leg raising test, and decreased rectal tone are
- Over the course of the disease,
cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although
these are seldom the presenting complaint (30% of patients), mild cranial-nerve
abnormalities are usually present on physical examination; the abnormalities typically
include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not
have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve,
cerebral, and spinal signs.
- Biochemical markers in CSF have
poor sensitivity and specificity, but levels decline with successful therapy. Therefore,
their reelevation can signal a relapse before any other findings become apparent. Useful
markers include carcinoembryonic antigen (CEA) from adenocarcinomas, alpha-fetoprotein and
beta-human chorionic gonadotropin from testicular cancers, 5-hydroxyindoleacetic acid
(5-HIAA) from carcinoid tumors, and immunoglobulins from multiple myeloma; their presence
in CSF is virtually diagnostic.
- Epithelial-associated glycoprotein
(HMFGI antigen) is present in 90% of LCs.
- Neither CEA nor beta-glucuronidase
is helpful in detecting solid tumors or metastases, nor are they useful in detecting
leptomeningeal lymphomatosis. However, if their levels are elevated, a return to normal
levels of both markers signifies successful treatment.
- CSF fibronectin values are elevated
in LC but also in bacterial meningitis and tick-borne encephalitis.
- Myelin basic protein can indicate
disease activity, particularly if values are measured longitudinally.
- Elevated CSF CEA is specific,
unless serum levels are unusually high (ie, >100 ng/mL).
- CSF beta-glucuronidase values are
frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations
also occur with bacterial, viral, fungal, or tubercular meningitis. In association with
elevated lactate dehydrogenase (LDH), however, high CSF beta-glucuronidase levels can
indicate LC from a breast primary tumor with a high sensitivity and specificity.
Histologic Findings: Leptomeningeal
biopsy may be necessary if the patient has no evidence of a primary tumor. The findings
can be diagnostic if results of all other tests are negative. Macroscopic pathology shows
diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve
roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells
covering the blood vessels and nerves, either as a single layer or as aggregates.
varies by primary cancer, but metastatic disease is stage IV by definition.
Medical Care: Treatment
goals include improvement or stabilization of the patient's neurologic status and
prolongation of survival. Patients most likely to benefit from therapy are those with
indolent systemic cancers that are likely to respond to therapy and those with minimal or
absent systemic disease and no fixed neurologic deficits. Some clinicians are hesitant to
even treat LC, given the short duration of survival and risk of neurotoxicity, but a high
index of suspicion and prompt treatment can prevent serious and irreversible neurologic
- For patients who respond well to
treatment, start treatment with radiation to bulky tumors and symptomatic sites, and place
a ventricular catheter if possible. Scan CSF flow, and follow this with intrathecal
chemotherapy if CSF flow is not obstructed. Also, optimally manage any systemic cancers.
- For patients with a fair
response to treatment, local radiation therapy and intrathecal chemotherapy delivered by
means of LP may be appropriate.
- Patients who are classified as
poor risk may be offered radiation therapy to symptomatic sites or supportive measures
only (eg, analgesics, anticonvulsants, steroids). Treatment is difficult and primarily
palliative, and results are generally poor because of the presence of many metastases.
- A number of other therapies are
- Mafosfamide is a form of
cyclophosphamide that is active intrathecally and has little neurotoxicity aside from
headaches, but only phase II trials have been conducted.
- Diaziquone is effective in
hematologic tumors. Adverse effects include headaches and immunosuppression. It can be
given at a dosage of 2 mg twice weekly.
- Another drug,
4-hydroperoxycyclophosphamide (4-HC) is in phase I trials and is apparently effective in
- Topotecan, a topoisomerase I
inhibitor, is in phase I trials.
- A drug available for high-dose
systemic administration, 6-mercaptopurine (6-MP), has shown efficacy in some patients.
- Intrathecal busulfan, currently
in phase I trials, may be active against cyclophosphamide-resistant neoplasms and other
- Another drug,
3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea hydrochloride
(ACNU) is modestly effective in animal studies; however, it is neurotoxic and not yet
available for use in humans.
- Immunotoxins, such as monoclonal
antibodies coupled with a protein toxin or radioisotope, seem effective and are being
- Gene therapy based on the herpes
simplex virus thymidine kinase gene combined with ganciclovir is under study but not yet
- Catheter placement causes
perioperative complications (1% of patients), and after placement, the catheter tip can
migrate into the brain tissue, obstruct the shunt, or, more commonly, cause infection
(usually Staphylococcus epidermidis, in 5% of patients).
- MTX administration can cause
acute arachnoiditis (nausea, vomiting, mental status changes), seizures, mucositis, or
myelosuppression (avoidable with folic acid coadministration).
- Meningeal irritation,
characterized by headache, fever, stiff neck (sometimes), confusion, and disorientation,
sometimes develops several hours following intrathecal MTX administration but is
self-limiting and resolves within 24-72 hours; no specific treatment is available.
- Transverse myelitis is a rare
idiosyncratic reaction to MTX that begins 30 min to 48 h after intrathecal treatment and
presents with paraplegia, leg pains, and development of a sensory level and bladder
dysfunction; it should be distinguished from traumatic spinal subdural hematoma. Again, no
specific treatment is available but some improvement can occur over days to months.
- Leukoencephalopathy is the most
serious complication; it appears a year after treatment and is more likely in those who
have also undergone cranial radiation. It presents as a progressive encephalopathy, often
with ataxia, dysarthria, and focal findings.