Neuro-Oncology
Choroid plexus tumors of childhood
Aug. 23, 2023
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Spinal cord astrocytomas are uncommon tumors that present unique diagnostic and therapeutic challenges. Surgical intervention carries significant risk, but has the potential to offer both diagnostic and therapeutic benefit. Tumor-related morbidity and mortality remains high, despite continued research into the field.
• Clinical symptoms are often insidious and nonspecific. | |
• Spinal astrocytomas are rare entities, but carry high associated morbidity and mortality. | |
• Treatment options are limited, but surgical intervention can offer diagnostic and therapeutic benefit. | |
• Better understanding of the etiology and molecular biology will hopefully lead to safer and more effective therapies. |
In 1888, William Gowers and Victor Horsley described the first diagnosis and removal of an intradural spinal tumor. However, it was not until over 20 years later that Elsberg and Beer described the first removal of an intramedullary tumor utilizing both a laminectomy and midline myelotomy (22). Progress remained limited in subsequent years, however, due to the rarity of cases, the limits in diagnostic technology, and the high morbidity of intervention. Greenwood reported on 6 patients who underwent complete removal of intramedullary ependymomas (29), but half developed significant neurologic disability.
Significant advances have been made in subsequent years. The advent and dispersion of MRI technology has greatly aided in detecting these tumors early on in their course. In addition, advances in neurooncology have aided in classification and genetic profiling. Moreover, improvements in surgical tools and microsurgical technique have allowed for safer and more complete resection, leading Epstein and colleagues in the 1980s to report apparent cures in low-grade tumors, especially in children (23; 20; 24; 18).
Despite these advances, however, many of the key points outlined in the initial reports about intramedullary spinal tumors remain true to this day. As Greenwood recommended in 1954, when attempting complete removal of the tumor, the important factors are: “surgery [should] be carried out before paralysis is too far advanced; [… the tumor] should be of such consistency that it can be handled without damage to the cord; […] a good plane of cleavage between the spinal cord and the tumor; […] gentleness that does not exceed the elastic limit of cord tissue” (29). For infiltrating astrocytomas of the cord surgical resection is often not feasible (and may not be of value) and only a biopsy for diagnostic purposes is performed.
Symptoms usually develop insidiously over months to years, especially with low-grade tumors, and can often be nonspecific. In malignant astrocytomas, symptoms are similar, but with a shorter duration and increased intensity. In children and adults, the most common early symptom is focal back pain. Seventy percent of patients experience pain along the spinal axis, usually worst in the segments directly over the tumor. Characteristically, the pain is worse in the recumbent position, as venous congestion further distends the dura and results in typical night pains. Radicular pain occurs in about 10% of cases and is usually limited to 1 or 2 dermatomes.
After pain, the next most common presentations are sensory deficits (65%) followed by motor deficit (50%) (56). Mild spasticity, increased reflexes, and extensor plantar signs consistent with myelopathy occur relatively early in the neurologic course with cervical and thoracic tumors. Sphincter disturbance is a relatively late sign, except for tumors that originate in the conus medullaris and cauda equina. Symptoms of syringomyelia/hydromelia may also be present if a secondary associated syrinx is present.
Spinal astrocytomas can occur at any age, including in young children. Symptoms and signs in children and infants can be subtle and depend on the developmental stage of the child. Usually, weakness of the lower extremities first manifests in children as an alteration of a previously normal gait. This is often subtle and may only be apparent to a parent who notes a tendency in the child to fall frequently or walk on the heels or toes. In young children, a history of being a "late walker" is common, and in the youngest children (under 2 years of age), a history of motor regression (ie, starting to crawl again instead of walking or refusing to stand) is common.
Changing of handedness can also be a sign of weakness. In very young children and infants with congenital astrocytomas of the cord, presenting symptoms can be vague and nonlocalizing, such as irritability, fever, or vomiting. Occasionally, the infant will have a head tilt or torticollis with cervical tumors (39). Likewise, kyphoscoliosis can develop with thoracic tumors (33). Mild scoliosis is the most common early sign of an intramedullary thoracic cord astrocytoma.
Independent predictors for patient survival, morbidity, progression of tumor, or recurrence include functional level at time of diagnosis (72), age (47; 45), and tumor/grade histologic subtype–with pilocytic features and lower grades conferring a more favorable prognosis (42; 49; 37; 03). Due to the infiltrative nature of astrocytomas, however, overall recurrence rates remain high. Karikari and colleagues in a 2011 single-institution series reported a recurrence rate of 48% among partially- and completely resected spinal astrocytomas (38). Sandler and colleagues reported a 57%, 5-year survival rate, after limited resection and postoperative radiation (61). Data for lower-grade lesions tends to be more favorable – series have demonstrated that with a combination of postoperative radiation and limited resection for low-grade astrocytomas, 5-year survival rates can be as high as 60% to 90% (35). High-grade astrocytomas, on the other hand, continue to have a poor prognosis, with an average survival of 6 months for adults and 13 months for children (32). For malignant spinal astrocytomas, Adams and colleagues have reported survival rates of 52%, 32%, and 19% at 1-, 2-, and 5-years, respectively (03).
Multiple sources have reported a correlation between the presence of a surgical plane and improved progression-free survival, as a well-defined plane aids in extent of resection (56; 28; 38; 45). But the data on extent of resection and its impact on survival remains mixed. In one 2013 study, researchers performed a retrospective case series analysis of 83 patients with a histologically confirmed diagnosis of spinal astrocytoma (26). Higher WHO grade among all patients was associated with worse PFS and overall survival. However, among patients with infiltrative tumors, neither extent of resection of tumor nor radiotherapy were associated with a difference in outcomes in multivariate analysis. Similarly, in an older series, radical resection of malignant astrocytomas did not result in any neurologic improvement after surgery and median survival was only 6 months postoperatively (14). The likelihood that previous case series include a mixture of histologically similar but molecularly distinct tumors likely explains the variability in outcomes reported.
A previously healthy 40-year-old, right-handed man presented with bilateral lower extremity tingling that spontaneously resolved after 4 to 5 months. During the prior year, he had developed some discoordination of gait, resulting in occasional falls. He also complained of urinary urgency and decreased bladder emptying. His neurologic examination revealed sensory loss to pinprick from T4 to L1 bilaterally, normal gait with good lower extremity motor strength, hyperreflexia in the lower extremities, and upgoing toes. Proprioception was intact. MRI revealed a 3 x 1.2 cm mildly enhancing lesion at the T3-T4 level of a slightly swollen spinal cord.
He was followed clinically and radiologically until 1 year later, when symptomatic lower extremity weakness became greater. At that time, he underwent a T1 through T4 laminectomy with ultrasound-guided biopsy of the spinal cord tumor and dural patch. His postoperative course was complicated by a transient dural leak, worsening of his lower extremity weakness, and transient urinary retention. The pathology was a grade 2 astrocytoma. He was treated with a total of 48.6 Gray of radiotherapy between C1 and T1 over 6 weeks. Lower extremity strength improved with rehabilitation, and he eventually recovered ambulation, though with a mildly ataxic gait.
Two years after his initial surgery, he represented with increasing lower extremity weakness. As a result of continued tumor progression documented on MRI, he was treated with 4 cycles of lomustine and procarbazine, but without noticeable neurologic improvement. After another 2 years, he experienced further clinical progression, and sustained an ankle fracture, followed by deep venous thrombosis. He was treated with 4 cycles of temozolomide chemotherapy, and though on subsequent follow-up he had radiographic stability of his tumor, he continued to progress.
The etiology of glial tumors, and specifically astrocytomas, remains unknown. Although chromosome rearrangements and overexpression of oncogenes have been described in spinal astrocytomas, the exact mechanism of oncogenesis remains uncertain (73; 57; 69). Much of the genetics and processes in spinal astrocytomas are inferred to be similar to those in intracranial astrocytomas, but distinct analysis of spinal gliomas is difficult due to the relative paucity of cases.
Risk factors associated with other tumors, such as smoking, diet, and exposure to common carcinogens (eg, asbestos), have not been correlated with primary spinal cord tumors to date. However, similar to cranial gliomas, spinal astrocytomas are thought to be related to radiation of the spinal cord (50). Moreover, genetic predisposition to intramedullary astrocytomas is seen in patients with neurofibromatosis type 1. And though intramedullary tumors in patients with neurofibromatosis type 2 are usually ependymomas and schwannomas, astrocytomas can also be seen (53; 54).
Genetics. As with many brain tumors, genetic studies have demonstrated the importance of mutations involved in the pathogenesis of spinal cord astrocytomas. Gene mutations that have been seen in association with spinal cord astrocytomas include IDH, H3K27M, TP53, CDKN2A, CDKN2B, PTEN, NF1, NF2, NTRK1, NTRK3, PDG-FRA, BRAF, and EGFR (63; 67). Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have been found in malignant spinal astrocytomas, with distinct patterns of DNA methylation when compared to that of their cranial counterparts (66).
The lysine27-to-methionine mutation in the histone H3 genes (H3K27M), commonly associated with diffuse brainstem gliomas, has been found in many midline astrocytomas throughout the neuraxis, including the spinal cord. When present in spinal cord astrocytomas, this mutation has been associated with a worse prognosis when compared to patients with histone H3 wild-type tumors (71).
When classifying by WHO grade, high-grade (WHO grade 3 or 4) spinal cord astrocytomas were commonly found to contain the H3K27M mutation (63; 05). Additionally, TERT promoter, TP53, PPM1D, NF1, ATRX, and P1K3CA mutations have also been described in high-grade spinal cord astrocytomas (05). Low-grade (WHO grade 1 or 2) spinal cord astrocytomas were commonly associated with either a BRAF-K1AA1549 translocation, BRAF copy number gain, or BRAF amplification (63). Additionally, WHO grade 1 spinal cord astrocytomas were found to have mutations in NF2, NTRK1, NTRK3, PDG-FRA, and TP53 (63).
In addition to genetic mutations, the role of specific microRNA (miR) has been explored as a way to better predict clinical prognosis as it relates to spinal cord astrocytomas. To date, miR-126, miR-106a, miR-130a, miR-181d, and miR-326 have been associated with a more favorable prognosis when present (67). On the other hand, miR-21, miR-22, miR-155, miR-182, miR-210, miR-215, miR-637, and hTERT have been associated with a poorer prognosis (51; 67). Although the role of many of these microRNA have not been fully elucidated, miR-22 has been found to upregulate the invasion capacity of spinal cord astrocytoma cells by inhibiting the enzyme tissue inhibitor of matrix metalloproteinase-2 (TIMP2) (51).
Cell biology and immunology. Some studies have indicated the cell surface marker CD133, previously seen in intracranial astrocytomas to denote self-renewal and resistance to chemotherapy and radiotherapy, is also important in spinal cord astrocytomas (34). In fact, patients with spinal cord astrocytomas expressing CD133 are more likely to have intracranial dissemination from the primary spinal cord site corresponding with a worsening prognosis (34).
Pathology and pathophysiology. Spinal cord astrocytomas can be divided into the 2 histologic subtypes of infiltrating (WHO grade II-IV) and pilocytic (circumscribed WHO grade I lesions) (60).
Historically, there have been attempts to subclassify these tumors. Minehan and colleagues described 3 typical subtypes in their series: (1) diffuse fibrillary astrocytoma (32%); (2) pilocytic astrocytoma with calcification, cysts, and Rosenthal fibers (43%); and (3) "not otherwise specified astrocytoma," which clinically acted as a low-grade astrocytoma (14%) (49). An entity known as “dysplastic astrocytoma” has also been described, with a similarity to hamartomas and a course similar to that of pilocytic astrocytomas (36). Occasionally, in lower-grade lesions and/or with limited biopsy samples, relatively low cellularity areas of tumor can be conflated with the diagnosis with spinal cord gliosis. About 30% of pediatric (17), and 15% to 25% of adult (24; 49) spinal astrocytomas have anaplastic features (14).
The value of histological subtyping will likely diminish as that of molecular subtyping grows.
Spinal gliomas are relatively rare lesions, accounting for 8% to 10% of all primary spinal tumors, which in turn only account for 2% to 4% of all CNS tumors. Spinal astrocytomas represent an even smaller subset of these still, with 30% to 40% of gliomas classified as astrocytomas, and the remaining classified as ependymomas (47; 06). Oligodendrogliomas of the spinal cord are exceedingly rare. Average age at presentation has been estimated to be between 35 and 59 years, with a slightly higher incidence in males (48; 47). These tumors can be found in patients of all ages, however, and congenital spinal astrocytomas have been reported. In the pediatric population, astrocytomas have previously been observed to have a higher incidence in children under 10 years of age, whereas ependymomas are more frequent in the older age groups (15; 16).
Overall, there does not appear to be a section of the spinal cord that is preferentially involved, with cervical, thoracic, and even lumbar lesions all being reported (56; 01). In young children, holocord lesions are also present, but occur much more rarely (32). Interestingly, intracranial and spinal astrocytomas do not tend to occur concurrently.
Unfortunately, there is no known risk factor for spinal cord astrocytoma and therefore there are no known prevention strategies.
As the presenting symptoms of these lesions is often nonspecific and slowly-progressive, the differential diagnosis is broad, including syringomyelia, multiple sclerosis/transverse myelitis, Guillain-Barré syndrome, vitamin B12 deficiency, spondylosis, herniated disc, spinal stenosis, amyotrophic lateral sclerosis, metastatic cord compression, congestive myelopathy (dural AV fistula), and infections such as syphilis, HIV myelopathy, etc. Many patients are initially suspected to have an orthopedic problem, and children may be mistakenly diagnosed with cerebral palsy or some other congenital disorders (50).
Once imaging is obtained (MRI with and without gadolinium), the differential diagnosis narrows and includes astrocytoma, ependymoma, hemangioblastoma, and intramedullary metastasis. However, even in the presence of an expansile intramedullary mass on MRI, other nontumor diagnoses can still present similarly, such as transverse myelitis, multiple sclerosis, and abscess (48).
X-rays are insensitive in evaluating patients with suspected intradural, especially intramedullary, pathology. However, they can be useful in the quantification of any associated scoliosis and kyphosis.
CT, although also limited as a primary diagnostic tool, can demonstrate some bony changes such as pedicle erosion or foraminal widening, and can be demonstrated with CT (70). It can, however, play an important role in surgical planning, especially if extensive decompression and subsequent fusion are intended. In cases when an MRI cannot be obtained, moreover, CT myelography can also help identify any expansile lesions of the spinal cord.
MRI imaging is the imaging modality of choice. The T1-weighted images help delineate the location of the tumor within the spinal cord, as well as the presence of any associated cysts. Gadolinium enhancement will furthermore reveal any areas of suspected higher grade and help demarcate of the tumor boundaries in high-grade lesions. The T2-weighted images will demonstrate high signal intensity and reveal the extent of associated edema.
Unlike ependymomas, which enhance brightly, astrocytomas often have inhomogeneous patches of enhancement within a more extensive abnormal area evident on T2-weighted images (32). Characteristics that differentiate astrocytomas from ependymomas are ill-defined borders, patchy irregular enhancement, and eccentric location in the spinal cord. Also, astrocytomas tend to have less edema and hemorrhage than ependymomas or hemangioblastomas (10; 07; 41).
There is no clear consensus on the best treatment for spinal astrocytomas. Surgery with an experienced spine surgeon, however, remains a mainstay of therapy, even if only to establish a diagnosis. Modern neurosurgical aids, such as the operating microscope, intraoperative ultrasound (25), and ultrasonic aspiration (15), have improved the results and operative morbidity (24). Based on this increased safety, early surgical intervention has been advocated by some (74), but remains controversial due to the high associated morbidity and mortality (18; 48). Moreover, the consideration for surgery must be weighed in the context that oftentimes a diagnosis has not yet been established. For asymptomatic and suspected low-grade lesions, observation with serial imaging may be appropriate. However, for others, a laminectomy, expansile duraplasty, and maximal safe resection given the constraints of the tumor planes is typically pursued.
In terms of operative approach, a standard laminectomy is typically employed. Preoperative MRI and transdural ultrasonography are both helpful in localizing the tumor and in guiding the levels of laminectomy. Afterwards, a midline durotomy is performed, and the cord exposed. Lesions that are encountered close to the surface of the cord may sometimes be entered at this point; otherwise, a myelotomy site must be chosen to minimize the chance of neural deficit.
Spinal cord astrocytomas are relatively firm, occasionally contain microscopic foci of calcium, and only rarely have a cleavage plane to facilitate an "en bloc" resection. As a result, in the overwhelming majority of cases, it is necessary to remove the tumor from inside-out until the glia-tumor interface is recognized. Intraoperative use of 5-aminolevulinic acid for fluorescence guidance has been attempted to improve visualization of the tumor, but remains experimental (21).
Somatosensory and motor evoked potentials are critical in identifying the extent of tumor and for early detection of impending deficits in motor and sensory pathways. Intraoperative monitoring can assess for intraoperative damage and guide the operative dissection (15; 46), though it may not prevent a neurologic deficit.
Radiation therapy for spinal astrocytomas is often considered for the treatment of spinal cord astrocytomas. The length of the field usually is the length of the tumor as delineated by MRI, with 1 to 2 vertebral levels caudal and cephalad (3 to 5 cm). Upper cervical tumors are treated with parallel opposed lateral fields to avoid the laryngeal airway and pharyngeal mucosa. Thoracic tumors are typically treated with direct posterior or posterior wedged fields to minimize dose to the lungs, esophagus, heart, liver, and kidneys. Lumbar and cauda equina tumors are treated with full opposed anterior-posterior and posterior-anterior fields because of the lordosis in this region. Lateral fields can be used to avoid radiating the pelvis contents (ovaries and uterus) (35; 59).
Evidence for limited series has suggested that radiation may not be indicated in the initial treatment of totally resected low-grade lesions (23; 52; 27). However, the nature of spinal astrocytomas often makes it difficult for a surgeon to obtain a total resection in all cases. Radiation therapy after partial resection, with doses of 40 to 50 Gy, is thought to improve survival and reduce recurrence rate when compared to historical controls (49; 64; 59). In children radiotherapy has higher risks, and evidence has suggested that radiotherapy is associated with decreased survival (45). Some authors suggest radiotherapy should be reserved for higher grade tumors (30). Patients with high-grade astrocytic tumors have also had improved survival rates, although still with a high mortality rate (64). Radiation therapy at these doses has been shown to be well tolerated and below the limit associated with substantial risk for radiation myelopathy (12; 64). The dose response relationship suggests that results are no better with higher doses than 50.4 Gy.
The role of systemic therapy for spinal cord astrocytomas is not well defined due to the paucity of clinical trials for this subset of patients. Common agents used are similar to those used for intracranial astrocytomas (44) including: temozolomide, bevacizumab, nitrosoureas, procarbazine, vincristine, etoposide, cyclophosphamide, and carboplatin. In 1 study by Allen and colleagues, 13 children with high-grade astrocytomas who were given "8 in 1" aggressive chemotherapy had no improvement in survival rates compared with patients receiving conventional chemotherapy consisting of lomustine and vincristine (04). In contrast, several other reports exist of patient response to chemotherapy using regimens of carboplatin and vincristine, or PCV chemotherapy regimen of procarbazine, lomustine, and vincristine (09; 08; 31). Although temozolomide is somewhat effective for astrocytomas of the brain, data for spinal cord astrocytomas are limited. A small series suggested the possibility of benefit which would need to be clarified in larger studies (40). Bevacizumab, an antiangiogenic therapy approved for recurrent intracranial glioblastoma, has similarly been explored in a limited number of patients with recurrent spinal glioblastoma (11). In patients with progressive/recurrent disease systemic therapies are often utilized in an attempt to shrink tumor or at least stabilize disease.
Some experiments have suggested that the use of demethylation inhibitors may be a novel therapy for high-grade spinal cord astrocytomas expressing H3K27M mutations (02). Furthermore, animal models utilizing the injection of neural stem cells expressing both cytosine deaminase and thymidine kinase into the epicenter of a spinal cord astrocytoma epicenter revealed prolonged survival after treatment (02).
Overall, the incidence of these lesions is low, and more studies with collaborative and multidisciplinary approaches are needed to find consensus in their treatment.
The most common complication of surgery is worsened neurologic deficit. Data on how common this is, however, remains highly variable between series. In Epstein’s adult series of 17 patients with low-grade astrocytomas who underwent gross surgical resection, no clinical evidence presented of tumor recurrence after follow-up of 50.2 months. After surgery, 12 of the 17 patients maintained the same functional grade, 3 improved, and 2 deteriorated (24).
In contrast, in another small series of 18 patients, Przybylski and colleagues reported a weak trend toward neurologic deterioration in patients who underwent complete resection (55). In Karikari and associates’ adult series of 21 astrocytoma patients, however, 1 improved, 10 remained the same, and 10 deteriorated (38). As has been noted in a prior section, better long-term outcomes have been associated with lower-grade tumors and better preoperative functional status. Though it remains somewhat controversial, most series also point to improved outcomes with a higher extent of resection (47; 38; 45).
Other complications of surgery include postoperative pseudomeningocele and CSF leak, poor wound healing, wound infection, meningitis, spinal cord tethering, spinal arachnoiditis/arachnoid cyst, and pulmonary complications such as pneumonia and pulmonary embolus (20; 58). As a result of the midline dorsal approach commonly used, posterior column deficits resulting in significant proprioceptive loss are possible after surgery. Orthopedic complications of kyphosis and scoliosis, especially in children, may mandate spinal fusion or other measures for stabilization of the spine (65). Leahu and colleagues demonstrated less postoperative kyphoscoliosis in patients who underwent an osteoplastic laminotomy versus a simple laminotomy in children (43). In 1 small retrospective study, surgical treatment of intramedullary spinal cord tumors does not appear to adversely affect quality of life in children (62).
The most important complication of radiation therapy is radiation myelopathy. Radiation myelopathy was not reported in the studies reviewed, with mean follow up times of 38 to 44 months (19; 61; 64), but this may be difficult to recognize and distinguish from tumor progression. In 1 series of patients treated with greater than 55 Gy, there was a 6% incidence of myelitis (35). Children may have a lower tolerance to radiation of the cord than adults. Myelopathy has occurred in cases where the dose was as low as 40 Gy given in 2 Gy fractions (35). Side effects from the involvement of lungs and esophagus in the radiation field can include cough, dysphagia, and odynophagia. In young children, radiation alters bone development, resulting in reduced stature.
Tumor progression is the main cause of death in patients with high-grade astrocytomas or in incompletely resected tumors that recur after radiation therapy. Subarachnoid and intracranial metastases occur more commonly in high-grade astrocytomas. Patients with cervical and cervicomedullary tumors often die of respiratory paralysis. Patients also may die of pulmonary embolus and other complications of paraplegia or quadriplegia (19; 68; 13).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Kristopher A Lyon MD
Dr. Lyon of Baylor Scott and White Health has no relevant financial relationships to disclose.
See ProfileEkokobe Fonkem DO
Dr. Fonkem of Baylor Scott and White Health received research support from Abbvie, Novocure, and Nativis and an honorarium from Monteris.
See ProfileRimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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