Dysembryoplastic neuroepithelial tumor
Dysembryoplastic neuroepithelial tumors are rare, indolent, low-grade tumors found in children and young adults. Most commonly affecting the temporal
Mar. 22, 2021
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The authors provide an updated summary of spinal ependymomas, highlighting new molecular features of the most common primary intraspinal tumor of adults as well as imaging characteristics. The update includes published epidemiological data, surgical treatment options, comments on the occurrence of these tumors in pregnancy, and updates in the evolving imaging modalities for diagnosis using diffusion tensor imaging.
In 1887, Horsley performed the first reported successful removal of an intradural, extramedullary tumor (46). With the help of Sir William Gowers, Horsley removed a "fibromyxoma" overlying the spinal cord at the T4 level. Postoperatively, the patient developed a debilitating pain syndrome but later experienced a full neurologic recovery. In the following 50 years, pioneering neurosurgeons such as Elsberg, Frazier, and Cushing took particular interest in extramedullary tumors, recognizing their frequently benign nature and often dramatic recovery from profound neurologic deficit (41; 31; 27). In 1911, Elsberg and Beer reported the first successful removal of an intramedullary spinal cord tumor (32). Frazier also commented on the potential for the removal of encapsulated intramedullary neoplasms (41). However, early attempts at removal of intrinsic intramedullary spinal cord tumors were associated with serious operative morbidity and mortality, such as complete paralysis.
For the next several decades, there was little impetus to modify the approach of biopsy, dural decompression, and radiation therapy, despite the recognition that after a relatively short remission, serious disability or death ensued. This "traditional" attitude was based on the assumption that it was not feasible to carry out extensive removal of tumors from within the center of the spinal cord without inflicting additional neurologic injury (26; 52). In 1954 Greenwood, with the aid of bipolar cautery and loupe magnification, reported 6 patients who underwent complete removal of intramedullary ependymomas (48). By 1963 Greenwood had treated 9 patients with surgery alone. There was no tumor recurrence in his surviving patients (7) with a mean follow-up of 9 years (49). With time, it has become clear that the majority of intramedullary spinal ependymomas can be radically excised with an acceptable morbidity and mortality, and a low incidence of recurrence (51; 83; 75; 119; 40; 52; 24; 23; 04; 78; 129; 39; 19; 34).
The clinical manifestations of intramedullary spinal cord tumors in general and ependymomas in particular are different in modern series (MRI era) compared with older series. Sensory complaints such as dysesthesia and back pain are the most common presenting symptoms. These symptoms are often nonspecific initially, and a high index of suspicion is necessary to allow early diagnosis of these lesions, especially without trauma history or prior complaints (108). Disease onset is usually insidious, and the duration of symptoms prior to diagnosis varies from several weeks up to 15 years (average of 14 months) (126). In a series of 38 patients with "true" intramedullary ependymomas, treated between 1985 to 1991 by Epstein and colleagues, only 5 presented primarily with motor dysfunction (34). Most of these patients (30) presented with only subjective sensory symptoms (dysesthesias), delaying the diagnosis. Patients with subtle motor signs may be evaluated for other conditions until neurologic deterioration occurs (89). The sensory symptoms may be in the hands or in the trunk as the tumors spread along the cervical and thoracic cord with an average span of 2 to 3 segments. Unusual and falsely localizing signs and symptoms may result from subarachnoid hemorrhage (02; 114), hydrocephalus due to raised cerebrospinal fluid pressure (98), and intramedullary cyst formation (120). Rarely, bleeding from spinal ependymomas may lead to secondary superficial siderosis of the nervous system and sensorineural hearing loss (71). Hemorrhagic presentations of ependymomas have been associated with anticoagulation, epidural anesthesia, pregnancy, and trauma (90).
Patients with ependymomas arising in the cauda-equina and filum-terminale region usually present with longstanding symptoms associated with extradural cord compression include segmental, hemicord, and transverse dysfunction. Local or radicular pain is the most common symptom. Pain may be dull or sharp, constant or intermittent. Urinary dysfunction and motor weakness follow if the tumor is not diagnosed early. Less than 30% of patients with caudal ependymomas present with weakness. Early symptoms of extramedullary corticospinal tract compression or, rarely, intramedullary conus medullaris extension include stiffness, fatigue, and gait abnormalities. Severe loss of motor function is now uncommon.
A 45-year-old male presented with a 1-year history of sensory dysesthesias. Laboratory testing, including workup for diabetes and vitamin deficiency, was completely unremarkable. Neurologic exam was remarkable for sensory loss in the arms, trunk, and legs; however, there was no motor weakness. Patient described worsening gait. An MRI of the brain was unremarkable; however, an MRI of the C-spine showed an enhancing mass with a hemosiderin cap expanding the spinal cord at C6 and C7. He underwent a surgical procedure for resection of the intramedullary mass with laminoplasty. His sensory deficits worsened immediately postoperatively; he remained otherwise at his neurologic baseline. At his 3-months follow-up visit, the dysesthesia improved but persisted.
Ependymomas arise from ependymal cells forming the lining of the ventricles and the central. The etiology of ependymomas is unknown. Abnormalities characterized by gain on chromosomes 1q, 2, 5, 7, 9p, 12, 15, 18, 20, and X as well as losses on chromosome 6, 9, 13q and 22q have been described in spinal ependymomas, but their significance is unclear (12; 106; 97; 81; 57; 13; 58). Nearly all spinal cord ependymomas have gains on chromosome 7, whereas the most common chromosome loss is 22q, occurring in 60% of patients (57). In some adult tumors, there is involvement of the neurofibromatosis type 2 gene on chromosome 22q (101; 124), but in other patients, the neurofibromatosis type 2 gene is not involved, suggesting the involvement of another tumor suppressor gene on chromosome 22q (67). Familial autosomal dominant intramedullary ependymoma associated with the neurofibromatosis type 2 gene and without other features of neurofibromatosis type 2 has been described (130). Hagel and colleagues propose that most spinal gliomas associated with neurofibromatosis type 2 are likely spinal ependymomas based on immunohistochemistry and electron microscopy (53). Although rare, ependymomas have been reported in patients with neurofibromatosis type 1 as well (17). Loss of heterozygosity on 22q is inversely corrected with loss of heterozygosity of 11q. Loss of heterozygosity of 11q may be accompanied by mutations of the MEN1 gene, which is associated with malignant presentation (102). Preliminary gene expression profiling studies of spinal ependymomas suggest that they have increased expression of HOXb5, PLA2G, and CDKN2A and can be differentiated from intracranial tumors (66). Genes found to be hypermethylated include RASSF1A and TRAIL. HIC-1 was only hypermethylated in intracranial ependymoma. MGMT was rarely found to be hypermethylated. The stem cells for ependymoma have been proposed to be radial-glial (102).
The relative abundance of ependymomas of the spinal cord may be in proportion to the distribution of ependymal tissue throughout the CNS (82; 123; 78). About 50% of spinal ependymomas arise from the central canal of the cervical and thoracic spinal cord. They are the most common intramedullary spinal cord tumor in adults (34). The rest (approximately 50%) arise from the intradural portion of the filum terminale (109). Because of its neuroectodermal derivation, Slooff and Kernohan classified these tumors as intramedullary (116). From a surgical and clinical perspective, however, most of the ependymomas in the filum/cauda-equina region are extramedullary. A minority of these tumors may have their epicenter located within the tissue of the conus medullaris and, therefore, are "true" intramedullary neoplasms.
Ependymomas are unencapsulated but well circumscribed glial neoplasms (64).
Most appear as reddish, sausage-shaped growths with moderate vascularity. Shortly after Bailey and Cushing (06; 07) formally classified ependymomas as a distinct neoplastic entity, Kernohan and colleagues described 3 and later proposed 4 histological grades of ependymomas (62). Most spinal ependymomas exist in a histological benign form with little infiltrative potential and exhibit slow growth as evidenced by prolonged symptom duration preceding diagnosis, preservation of neurologic function in patients with extreme spinal cord compression, and characteristically long survival times following various forms of treatment (116). Cellular ependymomas, the most common histologic subtype, are characterized by areas of perivascular pseudorosettes and consist of fusiform cells arranged around small blood vessels. True ependymal rosettes, reproducing in miniature the lining of a normal ependymal cavity, are uncommon, especially in spinal ependymomas (81). Tanycytic ependymomas are a rare variant characterized by long spindle cells with eosinophilic cell processes and focal perivascular pseudorosettes (61). Anaplastic (malignant) ependymomas of the spinal cord are uncommon. In the series of 169 spinal ependymomas, only 5 tumors showed malignant change (116).
In the cauda equina region, the vast majority of ependymomas are myxopapillary (16; 117). Malignant variants of myxopapillary ependymomas have been reported (29; 100). This variant is not unique to the lumbar location (103; 76).
The histological appearance of myxopapillary ependymomas consists of a papillary arrangement of cuboidal or columnar tumor cells surrounding a vascularized core of hyalinized and purely cellular connective tissue (117; 118). These tumors have traditionally been considered the most benign form of ependymomas (116; 117). The benign clinical behavior is probably also closely related to tumor location in addition to any inherent biological characteristic.
Intracranial ependymomas tend to spread along the cerebrospinal fluid pathways and may lead to leptomeningeal seeding of the spinal cord. According to autopsy data, spinal seeding can be expected in 25% of cases subsequent to surgery of the primary intracranial tumor. This review will not address this entity (36).
Ependymomas are relatively rare tumors, accounting for only 4% to 6% of primary central nervous system neoplasms. Intracranial ependymomas generally occur in children and young adults and represent 1% to 8% of primary brain tumors. About one-third to one-half of all ependymomas arise within the spinal canal. They represent the most common intramedullary spinal neoplasm in the adult population and account for 40% to 60% of the 2700 primary spinal cord tumors diagnosed in the United States each year (126; 21; 107; 121; 50). Intramedullary ependymomas are seen most frequently in the fourth decade of life and are rare below the age of 10 years (50; 80). In children, older age and spinal location are predictive of improved 5-year survival (79).
Filum ependymomas may arise at any age but are more common in early and middle adult years (42; 21), with a peak occurrence in the third to fifth decade (87; 116; 38). Men are slightly more commonly affected than women (80). Familial cases have been reported (105).
Earlier series of intraspinal tumors tended to include more extramedullary lesions, whereas modern series probably overemphasize the relative number of intramedullary spinal cord tumors, being more oriented toward surgical "challenges." It is, therefore, difficult to quantify the real incidence of intramedullary versus extramedullary and extradural tumors (96).
There is an association between multiple spinal cord ependymomas and Neurofibromatosis type 2 (81). Based on SEER data, the incidence of ependymomas appears to have increased over the past 30 years in adults but not in children (80). However, spinal ependymomas associated with NF-2 seem to have an indolent course and may be observed or treated with surgery resection (03).
There is currently no prevention for spinal cord ependymomas.
Intramedullary ependymomas are a group of spinal cord tumors with a well-defined clinical presentation and MRI appearance. The differential diagnosis includes astrocytomas, gangliogliomas, oligodendrogliomas, subependymomas, hemangioblastomas, metastases, and benign lesions such a lipomas (108). Clinically, the sensory phenomena, manifested by dysesthesias, are present in the great majority of patients with intramedullary ependymomas. It may be related to the common location of the tumor around the central canal. It is different from patients with spinal cord astrocytomas and gangliogliomas in whom the presenting problem is usually back pain followed by progressive motor dysfunction. When sensory phenomena are part of the initial symptomatology in patients with astrocytomas, they are usually manifested as loss of sensation rather than dysesthesias. Unlike astrocytomas, gadolinium-enhanced MRI in patients with ependymomas often shows clear demarcation of the rostral and caudal poles of the tumor. When viewed on cross-sectional images, the cord is expanded uniformly, unlike the astrocytomas in which the cord is usually "lumpy." In a comparative MRI analysis of 43 patients, the presence of syringohydromyelia appeared to be a significant factor in distinguishing ependymoma from astrocytomas (63). Furthermore, inflammatory lesions (multiple sclerosis, neuromyelitis optica, lupus, etc.) may also mimic spinal cord ependymomas.
Subependymoma is a distinct tumor entity characterized by slow growth and usually noninvasive behavior (50). MRI, even with enhancement, is often not distinguished between a subependymoma and the more common ependymoma (77; 85; 91). Spinal cord subependymomas follow a benign course. The surgical treatment is identical to that for ependymomas.
Plain films are insensitive in evaluating patients with suspected intradural pathology. Even secondary bony changes such as erosion or foraminal widening are better demonstrated with computed tomography (127). Plain films are better, however, for diagnosis of instability and quantification of scoliosis and kyphosis.
MRI is the diagnostic procedure of choice for primary and recurrent intramedullary spinal ependymomas (125; 08; 86; 65; 74). Following gadolinium injection, more than 90% of lesions enhance homogeneously and brightly, and have sharply defined rostral and caudal margins. Ependymomas originate from the region of the central canal, expand symmetrically within the spinal cord, and typically squeeze the surrounding neural tissue to only a few millimeters of thickness. About 30% of intramedullary ependymomas are associated with a rostral or caudal cyst, similar to that noted for spinal cord astrocytomas. Myxopapillary ependymomas of the conus medullaris also exhibit contrast enhancement, although not always as intensely as those within the cord parenchyma. The presence of syringohydromyelia on MRI favors the diagnosis of ependymoma and can help to differentiate it from astrocytoma (63).
These tumors may appear hyperintense on T1-weighted images as a result of the accumulation of mucin (60).
Presurgical MRI with diffuse tensor imaging to evaluate the relationship between neoplasm and white matter fiber tracts has helped in differentiating noninfiltrating neoplasms, such as spinal ependymomas, from other infiltrative and more aggressive neoplasms, which are considered not resectable. This allows an understanding of the neoplasm that is not appreciated with conventional MRI and may facilitate in preserving neurologic function after surgery (47).
Because of their rarity, the management of spinal ependymomas has evolved empirically over the years based on case series and retrospective studies (126; 69). There are no prospective randomized studies available to guide the management of these patients.
Surgery. With advances in neurosurgical techniques, the "traditional" approach of biopsy, dural decompression, and radiation therapy for intramedullary gliomas is no longer recommended. This course of treatment was based on the assumption that it is not feasible to carry out extensive removal of tumors from within the center of the spinal cord without a great likelihood of inflicting additional neurologic injury (26; 52; 93). This guideline, however, has been revised because the majority of these neoplasms are low-grade neoplasms that are surgically curable (73). Modern neurosurgical aids such as the operating microscope, the intraoperative ultrasound (35), the CO2 laser (28), and especially ultrasonic aspiration (33; 22) have dramatically improved the results and the operative morbidity of spinal ependymomas (34; 73).
Ependymomas of the cauda equina can usually be seen immediately following dural opening.
The nerve roots are displaced laterally but may lie posteriorly and obscure the tumor in patients with a ventrally located tumor. In these cases, it is relatively simple to remove the tumor en bloc by dividing the distal filum terminale caudal to the tumor and then displacing the entire mass out of the cauda equina and incising the remainder of the tumor just below the conus medullaris. The relationship of the tumor to the conus medullaris is variable. In many cases, the entire mass is within the filum, and it is not necessary to pursue tumor fragments rostrally into the conus medullaris. Occasionally, however, this pursuit may be mandatory in an effort to obtain a surgical cure. It is essential that neural tissue in the conus medullaris not be manipulated in any way and that tumor fragments be "extracted" from below.
A few ependymomas of the cauda equina seem to have grown from the region of the conus medullaris and have erupted out of the filum, with tumor tissue filling the entire thecal sac below the conus medullaris. In these cases, the normal neural elements of the cauda equina are not displaced circumferentially around the mass but rather run through the tumor tissue. In these cases, it is necessary to remove the tumor bit by bit by working between and around the neural elements until all of the neoplastic tissue is removed. In such an occurrence, it is frequently necessary to extract remaining tumor fragments from within the conus medullaris. However, it is again important to leave the neural tissue undisturbed and remove tumor fragments by working through that area from which the tumor has grown into the thecal sac. Rarely, ependymomas may grow caudally into the sacrum with the tumor being mostly or entirely extradural and may reach gigantic size (18; 30; 25; 45).
True intramedullary ependymomas almost invariably have a "true" cleavage plane between the tumor and adjacent neural tissue (34). Although this contributes to "total" excision of these neoplasms, it is also a potential hazard, because it encourages the surgeon to attempt an en bloc resection and to remove the entire mass in 1 or 2 large pieces. If this is attempted, there will be excessive and unnecessary manipulation of normal neural tissue. To avoid these complications, the ependymoma should be centrally "debulked" as with an astrocytoma, and only when the core of the tumor has been removed should the surgeon develop the plane of cleavage between the tumor and adjacent tissues. This may be accomplished by retracting the remaining tumor tissue into the residual cavity and not by retracting the spinal cord from the tumor. Some authors, however, favor en bloc excision of these tumors (56; 68).
The decision to perform an instrumented fusion in addition to the laminectomy is a difficult decision. A study by Sciubba and colleagues involving 32 patients who underwent cervical laminectomy without fusion for resection of an intradural tumor (18 intramedullary and 14 extramedullary) were followed to assess for kyphotic deformity that subsequently resulted in the need for a subsequent fusion surgery (110). Each increasing number of laminectomies performed was associated with a 3.1-fold increase in the likelihood of subsequent vertebral instability. At a mean follow-up interval of 25.2 months, 33% (4 of 12) of the patients who had undergone a 3 or more level laminectomy required subsequent fusion compared with 5% (1 of 20) who had undergone a 2 level or less laminectomy (p = 0.03). Four (36%) of 11 patients initially presenting with myelopathic motor disturbance required subsequent fusion compared with 1 (5%) of 21 presenting initially with myelopathic sensory or radicular symptoms (p = 0.02). Age, the presence of a syrinx, intramedullary tumor, C-2 laminectomy, C-7 laminectomy, and laminoplasty were not associated with subsequent symptomatic instability requiring fusion (110).
Radiation therapy. The efficacy and the need for adjuvant radiation therapy following surgery of spinal ependymomas is still unclear (44; 95; 24; 43; 113; 78; 128; 129; 126; 115; 112; 107; 59; 94). Generally, radiation therapy is withheld following "complete" tumor resection, except for patients with high-grade tumors (126; 115; 72). Controversy exists mainly regarding incompletely resected tumors (111). Most authors recommend postoperative radiation therapy in all patients with residual tumor (126; 115; 84; Gomez et al 2005; 05). There is increasing evidence that adjuvant radiation therapy increases the time-to-tumor progression. Others recommend careful monitoring (with MRI) of patients with minimal residual disease and reoperation in those with substantial residual tumor. For these authors, radiation therapy is reserved for the rare occasion of patients with documented rapid tumor growth or in the occasion that the tumor could not be radically removed (20). In general, ependymomas receive approximately 5040 cGy in 180 cGy fractions, whereas malignant ependymomas and multifocal ependymomas receive between 5040 cGy and 5400 cGy, respectively (59). There are studies suggesting the feasibility and safety of stereotactic radiosurgery in patients with spinal cord tumors (104; 10). Additional studies will be necessary to determine the long-term toxicity of this technique and its precise role.
Chemotherapy. Chemotherapy has no role for the majority of patients with low-grade or myxopapillary ependymomas. For patients with tumors that recur after surgery and radiation therapy, a variety of chemotherapeutic agents, including platinum agents, procarbazine, temozolomide, and etoposide have been tried with only limited success (113; 128; 09; 15). There are also anecdotal data suggesting that irinotecan (122) and imatinib (37) may have activity in ependymomas.
The results of surgery for caudal ependymomas are excellent. Complications are generally related to wound healing and perioperative fistulas. A joint neurologic and plastic surgery approach was developed to reduce the morbidity of wound closure following extensive and complicated laminectomy (132; 131). The fascia requires particular attention because this is usually the only watertight layer. The fascia and muscle are released both superficially from the subcutaneous tissues and deeply from the bony elements. If this is not enough to achieve closure with no tension, relaxing incisions are performed. The musculofascial layer is closed with "figure-of-8" Novafil or Prolene sutures that are tightly knotted. If there is any doubt regarding the watertightness of the closure, it is tested with injection of fluid under pressure. Improvement of the perioperative deficit is often dramatic and depends mainly on the severity and duration of the existing deficit. Filum ependymomas generally do not recur following en bloc resection. There is about a 20% recurrence rate if tumor is left behind (117). It appears that gross-total resection seems to be particularly beneficial for WHO grade II spinal ependymomas (88).
In a series by Epstein and colleagues of adult intramedullary spinal cord ependymomas treated surgically, 37 out of 38 patients had gross total removal of their tumor, as confirmed by a postoperative MRI (34). There has been no clinical or radiographic evidence of recurrence after a mean follow-up period of 24 months in any patient in whom total removal was accomplished. The morbidity of the surgical procedure was directly related to the preoperative neurologic status. Patients with little or no disability preoperatively are at little risk to sustain an injury, whereas patients with more significant neurologic dysfunction have a greater likelihood of being impaired by surgery. In one study, spontaneous regression of residual tumor after surgical resection was noted in 37% of patients (54).
For patients treated with surgery and radiation therapy, the overall 5-year survival ranges from 83% to 97%, and 10-year survival from 68% to 95% (126; 107). Patients with myxopapillary ependymomas generally have a better prognosis than other types of low-grade ependymomas (100% 5 year survival) (107). Local recurrence is the predominant pattern of failure (129; 126). Rarely, cerebrospinal fluid dissemination, spread to extravertebral soft tissues, and distant metastases may occur (81). The majority of patients who develop recurrent disease generally do so within 3 years of diagnosis, although there are numerous reports of recurrent disease developing over 10 years after treatment (126).
Nonmodifiable risk factors including age, tumor location (eg, spinal vs. intracranial), and associated mutations substantially influence the natural history of ependymomas. Poor prognostic factors for ependymomas include incomplete resection (128; 14; 01; 11), impaired preoperative neurologic function (54), age less than 20 years, the presence of 3 to 4 anaplastic features (necrosis, mitosis, vascular proliferation, cellular pleomorphism, or overlapping nuclei), and a MIB-1 proliferation index of greater than 20% (99). In children with ependymoma, older age and spinal location are correlated with improved survival (79).
There are reports in the literature of pregnant women who are discovered to have spinal ependymoma. The management of these patients presents unique surgical and anesthetic challenges (70; 55; 92). Intratumoral or subarachnoid hemorrhagic presentations of ependymoma are associated with pregnancy (90).
Reza Yassari MD MS
Dr. Yassari of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Jonathan Nakhla MD
Dr. Nakhla of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Rafael De la Garza MD
Dr. De la Garza of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure for advisory board membership, and research support from BMS.See Profile
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