Introduction
Background
Leptomeningeal carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases and was first reported in 1870 by Eberth, although the term was not used until the early 20th century. This type of spread occurs in an estimated 20% of patients diagnosed with cancer and is most commonly found in breast carcinoma, lung carcinoma, and melanoma in adults and hematogenous malignancies and primitive neuroectodermal tumor (PNET) in children. While less commonly seen in practice, prostate cancer can spread to the leptomeninges and is a grim finding in this often treatable neoplasm. The antemortem diagnosis is becoming more common, as newer therapies increase the life span of cancer patients and improvements in technology increase the sensitivity of imaging studies.
Patients typically present with symptoms caused by the effects of tumor emboli on subarachnoid nerve roots, direct invasion into the spinal cord or brain, or cerebrospinal fluid (CSF) obstruction. MR and CT demonstrate multiple masses within the subarachnoid space, hydrocephalus without a discernible cause, or diffuse leptomeningeal enhancement. The latter enhancement pattern has been referred to as cake icing or zuckerguss (German for sugar icing) and can be found in the brain, spine, or both (see Images 1-2).
Early diagnosis is important to begin therapy prior to neurologic deterioration. While there are clinical signs and radiologic findings that strongly suggest LC, most cases typically are diagnosed by CSF cytology or leptomeningeal biopsy. As the diagnostic accuracy of a single lumbar puncture (LP) is only 50-60% and 90% after 3 LPs, MR is considered complementary and can be invaluable, detecting up to 50% of cases with false-negative LPs.
Without appropriate therapy, the outlook is grim, and untreated patients are unlikely to survive more than 4-6 weeks. Intrathecal chemotherapy and/or radiation can increase survival to some extent, but most patients succumb to their disease within 6-8 months. Survival depends to some extent on the cell type of tumor involved, but the eventual outcome is invariably the same.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.
Pathophysiology
Primary tumors can spread to the leptomeninges in a variety of ways. Direct extension may occur from an intraparenchymal or periventricular primary brain tumor that forms in tissue near the CSF, and this is commonly found in medulloblastomas and other PNETs, ependymoma, and occasionally in glioblastoma multiforme. Arterial metastases can invade the CSF by pial rupture, ependymal invasion, or by extension along Virchow-Robin spaces.
Tumors also can extend in a perineural fashion along cranial nerves to eventually enter the subarachnoid space, and this pathway is particularly associated with squamous cell tumors of the head and neck. A similar method of spread along perineural spaces of the spinal nerves can occur with vertebral body or lymph node metastases.
Venous hematogenous access to the subarachnoid space can occur by a number of pathways, such as Batson plexus (internal vertebral venous plexus), the choroid plexus, or through the vessels of the arachnoid. Leukemia classically spreads hematogenously and has been shown to gain access to the CSF by invading the walls of arachnoid veins as well as through microinfarcts that break down the blood-brain barrier.
A less common route for CSF metastases is iatrogenic spread of tumor, which is becoming more frequent now that resection of solitary brain metastases has been shown to be beneficial to patients.
The choroid plexus forms approximately 500 mL of CSF per day, which circulates throughout the subarachnoid space surrounding the brain and spinal cord before being resorbed at the arachnoid granulations and superior sagittal sinus. CSF motion is caused by pulsations of the brain and spinal cord caused by the large amount of blood flowing through these tissues with each heartbeat, the constant formation and resorption of CSF, gravity, and the patient's body movements.
Tumor cells that enter the CSF flow freely throughout the subarachnoid space, often lodging a significant distance away from their entry point. Once the tumor cells have gained access to the subarachnoid space, they spread to other portions of the meningeal surface by direct extension or by shedding cells that are then carried to different parts of the neuraxis by CSF flow.
The pattern of growth of leptomeningeal tumor consists of either (1) a sheetlike extension along the pial surface from direct extension (see Image 3), occasionally with a secondary inflammatory reaction, or (2) as multiple nodules of various sizes studding the surface of the brain, spinal cord, and nerve roots (see Images 4-5). The latter appearance typically is seen within the cerebellar folia and the cerebral sulci and easily can be mistaken as intraparenchymal metastases on MR and CT if the association of the tumors with the deep sulci of the brain is not recognized.
Tumor foci may occur throughout the spine or brain surface, as well as within the ventricular system, but demonstrate a predisposition to forming larger tumor masses and thicker leptomeningeal coating in regions of relative CSF stasis, such as the basal cisterns and cerebellopontine angles of the brain and the cauda equina in the spine (see Images 1-2).
When the tumor mass in the basal cisterns grows large enough, obstructive hydrocephalus occurs. Nonobstructive hydrocephalus also is common in LC secondary to obstruction of CSF resorption at the arachnoid granulations by tumor cells, hemorrhage, and debris.
As the leptomeninges also cover the cranial nerves, tumor seeding of the cranial nerves is not uncommon and can be seen extending into the orbit and Meckel cave. These cranial nerve metastases frequently cause symptoms either from encasement of the nerve or by direct invasion with subsequent axonal destruction and demyelination.
A nodular appearance often is seen when LC involves the spinal nerves, with tumor foci appearing as a string of beads throughout the cauda equina and extending out of the nerves into the neural foramina (see Images 3-4). Extension along the spinal nerves or the paravertebral venous plexus into the subarachnoid space can occur from vertebral or lymph node metastases as well as direct extension from adjacent primary tumors, such as lung carcinoma. Along the spinal cord, leptomeningeal tumor typically presents as a thin coating along the pia mater, although nodularity and diffuse involvement of the arachnoid space also can occur.
Frequency
United States
Leptomeningeal carcinomatosis is found in 2-25% of patients with cancer, although in 2-4%, the primary tumor is never identified. A number of studies have estimated that LC occurs in breast cancer in 5-34%, small cell lung cancer in 9-26%, and melanoma in 17-25% of patients. Because of the prevalence of breast and lung cancers, most incidences of LC occur in patients with these tumor types.
Mortality/Morbidity
Mean survival time following diagnosis is 4 weeks without treatment and 6 months with appropriate therapy. Controversy exists in the medical literature regarding the appropriate therapy for patients with LC. Radiation of affected parts is standard therapy at most institutions, with or without intrathecal (direct infusion into the CSF) and/or systemic chemotherapy. Most studies report longer survival times in patients treated with intrathecal chemotherapy, although a recent study by Bokstein et al reported no improved survival and increased complication rates in patients treated with intrathecal and systemic chemotherapy compared to systemic chemotherapy alone. Intrathecal chemotherapy is perhaps the most common form of treatment and extends the life span of select patients, but currently is limited to methotrexate, Ara-C, and thiotepa, outside of experimental work.
Race
No race predilection is recognized.
Sex
LC is found more often in women, as breast cancer is one of the more common tumors to spread in this fashion. One small study found 36 of 41 cases of LC were female, although the results were skewed because of the relative absence of melanoma in the area. While females may represent a higher percentage of patients with LC, they also live longer following diagnosis.
Age
The average age at diagnosis is reported as 48.5 years, which is relatively young because of the prevalence of women with breast cancer and pediatric cases. A bimodal peak of sorts is seen, as tumors such as leukemia and medulloblastoma account for many LC cases in children, while breast, lung, and melanoma occur at a much later age. Because of the diverse nature of the tumors, an average age of presentation that is clinically useful does not exist.
Anatomy
Leptomeninges are formed from the pia mater and arachnoid mater and enclose the subarachnoid space. The pia mater is a thin membrane that covers the surface of the brain and spinal cord and extends into the sulci and around the proximal spinal and cranial nerves. The arachnoid mater forms the outer boundary of the subarachnoid space and is composed of a thin, vascular membrane connected to the pia mater by the arachnoid trabecula. The leptomeninges extend out of the cranial nerves to a certain extent, allowing easy access to these nerves by tumor cells within the CSF.
CSF is formed at the choroid plexus of the lateral, third, and fourth ventricles and is replaced approximately 5 times a day by resorption through the arachnoid granulations and superior sagittal sinus. CSF acts as a shock absorber for the brain, transports hormones, and carries waste materials to be absorbed into the blood stream for eventual excretion. Because of its continual motion, CSF is ideally suited as a mechanism for diffuse tumor seeding within the subarachnoid space.
Presentation
The initial presentation of patients with LC can vary, but more than one half of patients have the simultaneous appearance of symptoms and signs at more than one level of the neuraxis. Although the patient initially may complain of a single symptom, careful clinical examination usually reveals numerous distinct neurologic abnormalities. Wasserstrom described a series of 90 patients with LC of which only 17 had a single neurologic deficit upon examination. Multiple level cranial nerve and spinal nerve palsies are seen commonly and are the result of direct tumor involvement, but LC should be considered even in the presence of a single cranial nerve deficit.
Headache is the most common symptom at presentation, affecting approximately 50% of patients, while pain, nausea and/or vomiting, weakness, and sensory disturbances are each seen in approximately one third. Seizures occur in approximately 20% of patients, and strokelike syndromes and diffuse encephalopathy occasionally are seen. Frequent clinical signs include altered mental status in approximately 25%, cauda equina syndrome in 20%, and polyradiculopathy in 15%.
Preferred Examination
Contrast-enhanced MR of the brain and spine is the imaging modality of choice because of its safety, excellent contrast resolution, and multiplanar abilities. A wide range of the sensitivity of MR in detecting LC has been reported. Some of this discrepancy is from the difference in sensitivity between solid tumors and hematologic malignancies, with one study reporting a sensitivity of 90% in patients with solid tumors but only 55% in patients with lymphoma and leukemia.
Recent studies have tended to show higher sensitivity rates due to advancements in MR technology, particularly better T1-weighted images as well as the advent of 3-dimensional T1-weighted sequences and postcontrast fluid attenuated inversion recovery (FLAIR). Collie et al recently reported a 100% sensitivity for intracranial LC in 25 patients evaluated with gadolinium-enhanced MR. No large recent study has looked at MR sensitivity, although it likely is in the 70-90% range in detecting intracranial LC.
When the patient has a contraindication to MR, CT myelography is the next best test to evaluate the spine and has the added benefit of allowing CSF sampling at the same time as the diagnostic test is performed. The physician must exclude obstructive hydrocephalus prior to beginning the procedure, as removal of CSF below the obstruction may result in downward herniation and death.
Plain myelography demonstrates the thickened nerve roots, subarachnoid masses, and blockage of the subarachnoid space, but has not been used as a primary diagnostic tool since the increased availability of good quality CT and MR. Plain myelography is still used to provide additional imaging during a CT myelogram.
It is important to remember that CSF cytology will detect some cases that are not visible on MR, and vice versa. Both tests should be performed if LC is clinically suspected and the initial test is negative.
Limitations of Techniques
CT continues to be used as a screening tool in the metastatic workup of many cancer patients but is relatively insensitive compared to MR, particularly in the detection of LC. Contrast-enhanced CT may miss tumor in up to one third of cases and mischaracterize leptomeningeal tumor deposits as intraparenchymal in another third. CT may be necessary when a contraindication to MR exists, such as a pacemaker or certain aneurysm clips, or when the patient is unable to hold still long enough for an MR. With the advent of newer and faster techniques and MR scanners as well as MR-compatible aneurysm clips, these situations have become less frequent.
MR depicts leptomeningeal tumor well, particularly when magnetization transfer or postcontrast FLAIR techniques are used. MR is much better at depicting metastases from solid tumors than those from hematologic malignancies.
Myelography and CT myelography have been used to evaluate LC and have the advantage of allowing CSF sampling at the time of the study. However, the test is invasive, has the risk of contrast reaction and downward herniation in patients with CSF obstruction, and has not been shown to be as sensitive as MR in detecting focal tumor deposits on the cord or nerve roots, although it is more accurate in identifying cord enlargement.
Differential Diagnoses
Meningitis, Bacterial
Tuberculosis, CNS
Other Problems to Be Considered
Meningitis, Fungal
Neurosarcoid (can easily mimic LC, as it may appear as basal cistern enhancement or multiple enhancing masses throughout the leptomeninges)
Postsurgical changes (often can lead to leptomeningeal and dural enhancement)
More on Leptomeningeal Carcinomatosis |
 Overview: Leptomeningeal Carcinomatosis |
| Imaging: Leptomeningeal Carcinomatosis |
| Follow-up: Leptomeningeal Carcinomatosis |
| Multimedia: Leptomeningeal Carcinomatosis |
| References |
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Further Reading
Keywords
leptomeningeal carcinomatosis, leptomeningeal metastases, arachnoid metastases, zuckerguss, LC
