Epidemiology and Genetics

Primary tumors involving the spinal cord are uncommon¹ and tend to occur in young patients. In adults, they are outnumbered by primary brain tumors at a ratio of roughly 20 : 1; for children, a ratio of 5 : 1 is reported by most centers. Tumors arising from the spinal canal and vertebrae show a more heterogeneous age distribution. The rarity of primary spinal tumors makes it difficult to establish a clear-cut association with specific cytogenetic abnormalities. Some investigators have found an association between spinal and brain ependymomas and the loss of sequences in chromosome arm 22q, suggesting the presence of one or more ependymoma tumor suppressor genes in this location.^2–4 Pediatric ependymomas and astrocytomas have been associated with loss of chromosome arm 17p.^3,4 Some myxopapillary and papillary ependymomas have been associated with bcl-2 oncoprotein expression.⁵ Other ependymomas have been associated with mutations in the MEN1 gene and loss of heterozygosity in the chromosome arm 11q region.⁶

Prior exposure to therapeutic irradiation probably increases the risk for developing spinal canal meningiomas, soft tissue sarcomas, vertebral body sarcomas, and possibly spinal cord gliomas, although the magnitude of this risk is unclear. Neurofibromatosis is strongly associated with an increased incidence of spinal canal neurofibrosarcoma and has been associated with both intracranial and spinal cord ependymomas as well.² This latter association may be indirect, with the actual cause being the loss of a separate ependymoma tumor suppressor gene located near the NF2 gene.³

Anatomy

The spinal cord extends from the level of the foramen magnum to the L1-L2 vertebral level in most adults. Below the termination of the cord, the spinal canal contains the lumbar cistern, an enlargement of the subarachnoid space that surrounds the cauda equina. The spinal subarachnoid space terminates inferiorly at the S2-S3 level and does not extend laterally beyond the spinal canal. The subarachnoid space limits the volume at risk for harboring metastases borne by the cerebrospinal fluid (CSF). Below S2-S3, the spinal canal forms an extradural space, which continues inferiorly into the coccyx.

The cord proper lies within the spinal canal, with the dura intimately applied to the bony and ligamentous structures forming the periphery of the canal. In addition to the cord, the spinal canal includes the subarachnoid space, vessels, nerve roots, and meninges. The spinal canal is encased by the elements of the vertebrae and intervertebral ligaments, with the vertebral bodies located anteriorly; the pedicles, lamina, and transverse processes laterally; and the spinous processes posteriorly.

Tumors involving the spinal cord have often been classified by their anatomic relationship relative to the dura. The majority of extradural lesions are metastatic. Intradural, extramedullary tumors are roughly evenly divided between primary and metastatic tumors, while intradural, intramedullary tumors are most often primary gliomas.

Approximately 10% of all primary tumors involving the cord arise from the vertebrae, 65% from the spinal canal, and 25% from the cord proper. For purposes of treatment, it is useful to group primary tumors based on whether they arise from the cord, spinal canal, or vertebrae (Table 26-1). This system helps to predict whether radical surgery is feasible. It also suggests whether the normal spinal cord must be included within the high-dose irradiation volume or could instead be partially excluded from treatment with the use of sophisticated irradiation techniques.

Table 26-1 Common Primary Tumor Types Involving the Spinal Cord

Pathology

The histology of spinal tumors correlates strongly with location. Primary tumors of bone (osteogenic sarcoma, chondrosarcoma, and chordoma) comprise most primary vertebral tumors aside from myeloma or plasmacytoma. Chordomas in particular are concentrated in sacral locations. Soft tissue sarcomas (particularly nerve sheath tumors such as malignant schwannoma or neurofibrosarcoma) and meningiomas comprise most spinal canal tumors. Astrocytomas and ependymomas account for the majority of primary cord tumors, with oligodendrogliomas occurring rarely. Other histologies such as vertebral body hemangiomas, lipomas, and arteriovenous malformations (AVMs) are occasionally encountered. Cauda equina ependymomas account for 60% of all spinal ependymomas and are generally included with intramedullary ependymomas when radiotherapy results are reported. Although spinal ependymomas (cord and cauda) outnumber astrocytomas 2 : 1, intramedullary tumors are almost evenly divided between ependymomas and astrocytomas.

Grade is an important consideration for several tumor types. Low-grade spinal canal sarcomas appear to be at low risk for both local and distant recurrence if completely resected. High-grade, malignant meningiomas are probably at higher risk for recurrence than the more typical benign meningiomas. The importance of grade is uncertain for ependymomas, as some series have identified grade as a significant prognostic factor,^7–9 and others have not.¹⁰ The overall risk of subsequent intracranial failure for low-grade spinal ependymomas is low, on the order of 7%.¹¹ However, this value is probably higher for histologically malignant ependymomas.^12,13 Myxopapillary ependymomas reportedly have a particularly favorable prognosis.⁹

Grade is clearly the most important factor influencing outcome for spinal astrocytomas.^14,15 Although prolonged survival is generally the rule for patients with low-grade astrocytomas, malignant astrocytomas such as glioblastoma multiforme (GBM) and highly anaplastic (Grade 3) astrocytomas (HAAs) are aggressive tumors characterized by rapid local recurrence following treatment, craniospinal axis dissemination, and short survival.^13–17 The pilocytic astrocytoma subtype reportedly has a better prognosis than the diffuse fibrillary astrocytoma subtype.¹⁸

Clinical Presentation

Patients with primary spinal tumors generally present with local or distal neurologic symptoms produced by spinal cord dysfunction. Local symptoms often include focal pain, segmental or nerve root weakness, and sensory deficits corresponding to a dermatomal distribution. These symptoms and signs usually correspond closely to the level of the lesion within the cord. Distal symptoms are produced by involvement of the cord’s long tracts, creating paresis, sensory deficits, and autonomic dysfunction diffusely below the level of the cord lesion. Depending on the location of the lesion, long tract signs may be relatively lateralized (e.g., the Brown-Sécquard syndrome). Since the cord is substantially shorter than the spine in adults, an intrinsic cord lesion is generally located anatomically a few vertebral bodies above the clinical cord level (e.g., a T8 cord segment astrocytoma may lie at the level of the T6 vertebral body).

Routes of Spread

Primary cord tumors, particularly high-grade ependymomas and malignant astrocytomas, can spread via the subarachnoid CSF throughout the craniospinal axis. Low-grade astrocytomas and ependymomas generally remain localized. Primary tumors arising from the spinal canal and vertebrae occasionally spread hematogeneously, with the lungs being the most frequent metastatic site. Lymphatic metastases are rarely encountered with any primary spinal tumor.

Diagnostic and Staging Studies

The workup for primary cord tumors is chiefly radiographic. Magnetic resonance imaging (MRI) with gadolinium for contrast is the imaging study of choice.¹⁹ Standard or metrizamide-enhanced computed tomographic (CT) myelography is indicated for patients unable to undergo MRI (e.g., pacemaker-dependent patients). Intramedullary tumors usually extend for multiple segments of cord, and sagittal MRI is particularly useful for delineating the rostral and caudal extent of tumor. Imaging of the entire craniospinal axis is required for all ependymomas, because spinal axis metastases develop in 5% to 15% of intracranial ependymomas.²⁰ These spinal “drop metastases” can produce the initial symptoms of a disseminated, primary intracranial ependymoma.

The entire neuraxis should also be imaged for cord HAAs and GBMs. Low-grade spinal astrocytomas and oligodendrogliomas do not require imaging of the entire craniospinal axis. CT scanning of the chest to rule out pulmonary metastases should be performed for vertebral osteogenic sarcomas and chondrosarcomas, as well as for spinal canal neurofibrosarcomas. Other tests such as angiography may be of limited use for AVMs or meningiomas. CSF cytology may be informative, but its use in determining treatment or influencing outcome is controversial. No chemical markers appear to be clinically useful in the diagnosis or follow-up of spinal tumors. The role of the bromodeoxyuridine (BrdU) and Ki-67 labeling indices as prognostic indicators for spinal ependymomas is under investigation.^21,22 An elevated cyclin D1 labeling index, high MIB-1 proliferation index, and p53 immunolabeling might be indicative of high grade in ependymomas, although a correlation with clinical outcome is unclear.^5,23

Staging System

Presently there is no commonly accepted TNM-type staging system for primary cord tumors. Primary vertebral body tumors and spinal canal tumors should be staged using the American Joint Committee on Cancer (AJCC) staging systems for bone and soft tissues, respectively.²⁴

Standard Therapeutic Approaches

Surgical exploration combining maximal resection (preferably en bloc) with minimal risk of iatrogenic injury is the preferred initial treatment procedure. In addition to decompressing the cord, essential histologic information is obtained. There is no role for preoperative irradiation or irradiation without a prior attempt at histologic diagnosis. As many as 4% of radiographically diagnosed “cord gliomas” have proven to be benign upon pathologic examination, with infarcts, demyelinating processes, amyloidosis, and sarcoidosis comprising some of the disease processes which mimic gliomas.²⁵

The anatomic location and histology of the tumor have important implications for treatment. Complete resection of primary vertebral body tumors is infrequent; the radiation oncologist must generally deal with residual macroscopic tumor requiring radiation doses greatly exceeding normal spinal cord tolerance. Charged particle beams are generally employed in this setting. Completely resected, low-grade spinal canal sarcomas and meningiomas generally do not require postoperative irradiation. Subtotally resected meningiomas may be managed with observation, conventional megavoltage irradiation, or charged particle beams. Charged particle beams are preferred to irradiate subtotally resected or high-grade sarcomas of the spinal canal.

The extent of resection is variable for primary cord gliomas. Using modern microsurgical techniques with intraoperative monitoring, complete resection of low-grade gliomas has become more common, and outcome has been successful without the use of adjuvant radiotherapy.^26,27,97 Postoperative megavoltage irradiation provides favorable long-term results following subtotal resection. Craniospinal irradiation is employed in the management of malignant as well as benign, multifocal ependymomas.

The favorable location of ependymomas of the cauda equina usually permits complete resection. Intramedullary ependymomas frequently have tissue planes separating the tumor and cord that facilitate complete resection, as well. Low-grade astrocytomas and oligodendrogliomas are infiltrative and generally lack tissue planes separating the tumor from normal cord. Aggressive resection in this situation can result in substantial neurologic injury, so subtotal resection or biopsy is often performed. However, aggressive resection has been performed successfully in some expert hands.²⁸ If frozen sections suggest HAA or GBM, resection is usually abandoned after biopsy is performed.

The treatment approach for primary spinal canal and vertebral tumors differs from that for primary cord tumors because a small distance (often on the order of millimeters) physically separates the tumor from the cord. This distance often allows aggressive surgery without an unacceptably high risk of cord injury.

Chemotherapy is not indicated in the management of low-grade cord gliomas, although concurrent treatment with carmustine (bis-chloroethyl-nitrosourea [BCNU]) or temozolomide might be useful with HAAs or GBMs. Osteogenic sarcomas arising from the vertebrae should be treated with aggressive chemotherapy, as performed in other osseous sites. The role of adjuvant chemotherapy for other soft tissue and bone sarcomas is less clear, but in view of the high risk of systemic recurrence, might be considered for high-grade lesions. Adjuvant chemotherapy with procarbazine, lomustine (chloroethyl-cyclohexyl-nitrosourea [CCNU]), and vincristine (PCV) may be considered for malignant (but not benign) meningiomas.

Role of Radiation Therapy

The radiation oncologist faces four basic clinical situations when evaluating a patient with a primary cord glioma:

The radiotherapeutic approach is different for each situation (Table 26-2). Postoperative irradiation is not indicated for completely resected low-grade gliomas.^26,29,30 Incompletely resected low-grade astrocytomas and ependymomas are generally treated with postoperative focal irradiation. High-grade (malignant) astrocytomas are palliatively irradiated with focal fields. Malignant ependymoma and multifocal, benign ependymomas are treated with curative-intent, craniospinal irradiation.

Table 26-2 Radiotherapeutic Management of Primary Spinal Tumors

HAA, Highly anaplastic (Grade 3) astrocytoma; GBM, glioblastoma multiforme; XRT, x-ray therapy.

* Total dose prescribed using standard (1.8-Gy) once-daily fractions with megavoltage photons unless otherwise specified.

† Includes astrocytoma, ependymoma, and oligodendroglioma.

‡ Megavoltage photon irradiation.

§ Protons or helium ions.

Completely resected spinal canal meningiomas require no additional therapy, since the risk of recurrence is only on the order of 6%.³¹ However, subtotally resected meningiomas have a higher risk of local recurrence, making postoperative irradiation a reasonable consideration.

Nerve sheath sarcomas are approached in a similar manner: postoperative irradiation is generally withheld if the tumor has been completely resected. Particle beam irradiation is given if macroscopic tumor remains. Incompletely removed vertebral chondrosarcomas and chordomas are likewise irradiated with charged particles (see Table 26-2). Osteogenic sarcomas are treated with a combination of chemotherapy, surgery, and postoperative particle beam irradiation if complete resection is not achieved.

Simulation

CT-based simulation (with or without MRI fusion) is presently the preferred technique. When possible, intensity modulated radiation therapy (IMRT) should be used to treat spinal tumors with curative intent, due to the advantages obtained by delivering a more homogeneous dose distribution across the high-dose target volume, and reducing the dose delivered to nearby critical structures, including the heart, lung, kidneys, gastrointestinal tract, and liver. Where IMRT is unavailable conventional treatment techniques are employed, beginning with a 2D or CT-based simulation before the start of irradiation.

Low-grade cord gliomas are treated with megavoltage photon fields encompassing the radiographically apparent lesion (gross target volume [GTV]) with a 3- to 5-cm margin of normal spinal cord (or brainstem for high cervical lesions) both rostrally and caudally (clinical target volume [CTV]). The preoperative sagittal MRI is the most useful study for determining the size and location of the GTV. Field width for non-IMRT cases rarely needs to exceed 7 to 8 cm, since only the cord requires irradiation. Sophisticated immobilization devices are useful when treating with IMRT, and thermoplastic face masks are useful for conventionally-treated tumors located in the cervical spine. A typical clinical, non-IMRT setup for a patient with a thoracic cord glioma is shown in Fig. 26-1.

FIGURE 26-1 • Clinical setup showing cephalad and caudal field borders for a localized low-grade thoracic spinal cord glioma.

Whether to include an associated syrinx (a dilated, fluid-filled intramedullary cavity) in the treatment volume is controversial. At times, the syrinx results from local mass effect causing obstruction and dilation of the central canal of the spinal cord; in this situation, the syrinx is not actually part of the neoplastic process, but instead represents a reaction of normal tissue. At other times, the tumor itself may be from a cystic cavity or syrinx as part of the neoplastic process, and in this situation the syrinx must be included in the GTV treatment volume. Clinically distinguishing these situations from one another is often difficult; consultation with the neurosurgeon regarding his or her impression at the time of surgery is often beneficial. In general, a small syrinx can easily be included in the treatment volume. An extensive syrinx extending for virtually the entire length of the cord can be technically difficult to encompass with conventional treatment fields. IMRT can be particularly beneficial in this situation (Fig. 26-2).

FIGURE 26-2 • A, Beam’s eye view achieved using three-dimensional conformal reconstruction of a thoracic cord glioma target volume and adjacent lungs with a posterior oblique wedged-pair irradiation technique. Custom low melting point alloy blocking or multileaf collimation is designed using the beam’s eye view of the target volume. B, Transverse section showing dosimetry from the treatment plan developed using the target volume derived from A. Note the substantial portion of lung included in the beam’s exit path at this level. C, Dose-volume histogram derived from the treatment plan shown in B using dosimetry information for the entire treatment volume. Virtually the entire target volume receives 100% of the total dose of 50.4 Gy at 1.8 Gy per fraction. Despite the impressive amount of lung included in the exit beam shown in B, the histogram shows that only 10% to 15% of each lung actually receives more than 25 Gy (50% of the total dose) under this plan. Nonetheless, 40% of the left lung and 60% of the right lung receives a dose greater than 15 Gy (30% of the total dose). See also Fig. 26-2. D, Verification simulator film taken with the beam’s eye view geometry based on the treatment plan developed in A, B, and C. E, Port film taken during treatment on the linear accelerator using the treatment field shown in D confirms the accuracy of the daily patient setup.

When IMRT is not utilized, tumors in the upper cervical spine are generally treated with opposed lateral fields to avoid unnecessary irradiation of the aerodigestive mucosa. Tumors located more caudally are often treated with differentially weighted anterior-posterior–posterior-anterior (AP-PA) fields using compensators. Use of beam-split abutting opposed lateral and AP-PA fields to treat tumors at the cervicothoracic junction is discouraged; the risk of overdosing the normal cord and underdosing the tumor owing to setup variation or error far outweighs any advantage in reducing acute morbidity. Again, IMRT is of particular benefit for tumors located in this region, eliminating the problems of possible overlap/underdosing inherent in the use of abutting fields (Fig. 26-3). When the use of abutting fields is unavoidable, a matching beam-split technique using independent jaws is required. The match line should be shifted 1 cm after every 10 Gy to minimize the risk of inadvertent overlap. A medulloblastoma-type “gap” technique should only be used when treating the craniospinal axis, and the gap should never be located over a site of macroscopic disease.

FIGURE 26-3 • The advantages of intensity modulated radiation therapy (IMRT) are highlighted by this difficult low-grade astrocytoma involving the thoracic cord, associated with a neoplastic syrinx extending cephalad through the cervicothoracic junction into the cervical cord. These three images demonstrate the superior dose-homogeneity IMRT provides within the high-dose treatment volume and the substantially greater sparing of adjacent normal structures throughout the treatment volume (compare the isodose curves involving the lung with the discussion in Fig. 26-2). Conventional treatment techniques are not able to provide this level of precise dose-localization, although, theoretically, stereotaxic body radiosurgery would provide similar advantages. A, Transverse image. B, Coronal image. C, Sagittal image. The 5040 cGy isodose line is shown in dark blue.

Wedged pair, posterior, oblique fields offer the theoretical advantage of decreased morbidity by minimizing exit dose in any given location; however, the planning and setup are technically more difficult, and scrupulous verification is necessary to ensure adequate coverage during treatment. Care must also be taken with this technique to ensure that the kidneys, liver, or substantial portions of the lungs are not irradiated beyond tolerance. The use of three-dimensional (3D) conformal treatment planning with dose-volume histograms has greatly improved the reliability and safety of this technique (see Fig. 26-2).

Caudal ependymomas have historically been treated with generous fields extended inferiorly to encompass the entire thecal sac and laterally as far as the sacroiliac joints to encompass the sacral nerve roots. The traditional justification for using such extended fields has been to comprehensively irradiate the subarachnoid space, which many incorrectly believe extends laterally along the sacral nerve roots. However, the subarachnoid space terminates inferiorly at the S2-S3 level and does not extend laterally beyond the confines of the spinal canal. Enlarging the fields laterally beyond the bony canal only serves to unnecessarily irradiate a larger volume of normal tissue. Similarly, CSF-borne metastases from the cauda would be expected to spread from the primary tumor in a cephalad direction as well as caudally. It is logically inconsistent to extend fields caudally well beyond the termination of the subarachnoid space, while arbitrarily stopping fields only a few vertebral bodies cephalad to the primary tumor, where no similar barrier to spread exists.

It is worth noting that a series from Iowa with small numbers of cauda ependymomas found that adjuvant thecal sac irradiation was beneficial when piecemeal rather than en bloc resection was performed.³² However, several other series found no advantage to the use of traditional extended fields over focal fields.^8,33 Following an uncomplicated resection, the use of fields extended inferiorly and laterally to encompass the entire sacrum appear unnecessary from both a clinical and theoretical standpoint.

Craniospinal axis irradiation using a medulloblastoma-type technique is advised for malignant ependymomas, as well as for multifocal, benign ependymomas. Care should be taken to ensure that the matchline does not cut through macroscopic disease, and that the matchline is moved 1 to 2 cm every 10 Gy to minimize inadvertent setup overlap causing overdosage of the normal cord. Focal boost fields with 3- to 5-cm craniocaudal margins should be applied to macroscopic disease sites after the entire neuraxis is treated. Prophylactic craniospinal irradiation is not advised for GBMs or HAAs despite their propensity for CSF dissemination. Since local failure is inevitable, the increased morbidity of neuraxis irradiation to control microscopic, asymptomatic disease is inappropriate. Focal fields encompassing the symptomatic, macroscopic disease with a 3- to 5-cm margin are used instead.

Spinal canal meningiomas are treated with focal fields encompassing the preoperative tumor volume with a 3- to 5-cm margin in cephalocaudal dimension, usually using megavoltage beams. Once again, IMRT is extremely useful in this situation due to improved dose homogeneity across the CTV.