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Intracranial ependymomas: prognostic aspects.

According to the grading of brain tumors as proposed by the WHO in 1976, out of 128 ependymomas 83 tumors could be classified as grade II and 38 as grade III Only seven subependymomas were benign and could be assigned to grade I. In contrast to most series known from the literature, 73 ependymomas were located above the tentorium and only 55 in the posterior cranial fossa. The grade of malignancy rised with an increased distance from the ventricular level. Macroscopically complete exstirpations were usually possible in hemispheric ependymomas, whereas tumors arising from the floor of the fourth ventricle often allowed only a partial removal. The operative mortality in the infratentorial group was more than twice as that in the supratentorial group. Postoperative survival was predominantly dependent on the histologic grade of malignancy. The five year survival rate without recurrence was 57.4% in grade II ependymomas as compared to 24.1% in grade III ependymomas. It could be improved by postoperative radiation therapy in both groups of malignancy. The almost identical longterm results indicate that even in less malignant ependymomas new tumor growth will occur later on.

Ependymoma↗

Genetic abnormalities and CNS tumors: report of two cases of ependymoma associated with Klinefelter's Syndrome (KS).

OBJECTS: Genetic syndromes associated with ependymoma are uncommon, with the exception of NF2. We describe two cases of ependymoma presenting with Klinefelter's Syndrome (KS) as co-morbid condition. MATERIALS AND METHODS: The first patient was diagnosed for KS during pregnancy; he also presented a thyroid agenesis and a deficit of methyltetrahydrofolate reductase (MTHFR); at 30 months of age he was operated on for a grade II ependymoma of IV ventricle; after a multiple-stage surgery, he underwent oral chemotherapy and stereotactic radiotherapy, but after 15 months he presented a local recurrence and died. The second patient was diagnosed for KS at the age of 16 months; at 10 years of age, due to back pain, he underwent an MRI, which showed a cauda equine tumor. He underwent surgery and radiotherapy. Histology was of mixopapillary ependymoma. CONCLUSION: In a review of literature, various neoplasms have been described in association with KS. To our knowledge, these are the first two cases reported of ependymoma associated to KS. A retrospective study of 44 monoinstitutional ependymoma cases demonstrated association with genetic syndromes in 22%.

Central Nervous System Neoplasms↗

p14ARF protein (FL-132) immunoreactivity in intracranial ependymomas and its prognostic significance: an analysis of 103 cases.

Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been described in a few studies and a strong prognostic value of p53 aberrant expression has been established. Recently, p53 regulation has found to be dependent on the function of the pl4ARF gene product, which has been shown to be critically involved in human carcinogenesis. In this study we have examined patients with intracranial ependymomas (n=103) for immunoexpression of the novel antibody FL-132 to human pl4ARF protein. We found that: (1) the polyclonal FL-132 antibody seems to be suitable for studying pl4ARF protein status in routinely processed and paraffin-embedded specimens; (2) decreasing pl4ARF protein expression is associated with patterns of ependymoma biological aggressiveness, i.e., increasing tumor grade, elevated growth fraction and p53 protein accumulation; however, there was no any association between p14 and MDM2 immunoexpression in ependymomas; (3) although the biological events underlying pl4ARF inactivation in ependymal neoplasms are still unclear, FL-132 immunohistochemistry appears to be useful for assessing an individual prognosis in these tumors; when the p14 score was considered as "high" versus "low" (cut-off p14 labeling index at 10%), it represented an independent prognostic factor in both univariate and multivariate analyses (hazard ratio -3.56; P=0.0003); and (4) most beneficial information for evaluation of malignant ependymoma outcome should be elicited from simultaneous immunohistochemical investigation of p14 ARF and p53 in tumor specimen.

Adolescent↗

Analysis of chromosome 7 in adult and pediatric ependymomas using chromogenic in situ hybridization.

Few studies have yielded reliable data that distinguish between ependymal neoplasms based on molecular genetic attributes. The present study utilizes chromogenic in situ hybridization (CISH), a relatively recent hybridization technique, to retrospectively examine chromosome 7-copy number in pediatric and adult ependymomas. Of the 27 hybridizations, polysomy of chromosome 7 was detected in 10 out of 15 (66%) adult ependymomas, and in only three out of 12 (25%) pediatric lesions. All myxopapillary ependymomas showed polysomy. The remaining tumors were diploid. The authors conclude that (1) there are distinct genetic subsets of ependymoma, in particular, increases in copy number of chromosome 7 are almost exclusively found in myxopapillary ependymoma, and that (2) CISH is a rapid and sensitive method of stratifying morphological variants of ependymoma and potentially other central nervous system (CNS) tumors. These results encourage further investigations with CISH on a larger scale to determine its merit as an ancillary diagnostic and prognostic tool.

Adult↗

Secondary ependymoma presenting as a presacral mass.

Ependymomas are common types of tumors occurring within the brain and usually derive from the ependymal lining, especially of the ventricles. Ependymomas also occur, usually within the spinal canal, as primary intramedullary lesions or as late "drop" metastases from intracranial ependymomas. Extradural ependymomas are rare. They could occur as intraspinal or extraspinal lesions. We hereby report a case of an extradural (intraspinal) lesion with extraspinal extension, the extraspinal lesion being presacral in position, which presented with urinary and colonic symptoms. The lesions were secondary ependymoma subsequent to an intracranial ependymoma previously treated by combined surgery, radiotherapy, and chemotherapy 4 years earlier. The extradural and extraspinal site of the secondary lesion as well as its mode of presentation are noteworthy.

Adult↗

Chromosome aberrations in four ependymomas.

Cytogenetic analysis of short-term cultures from three untreated and one recurrent ependymoma revealed clonal aberrations in three of the four tumors. A posterior fossa ependymoma from a 3-year-old male patient showed trisomy 11 as the sole clonal chromosome aberration. A recurrent spinal ependymoma from a 35-year-old male showed hypertriploid clones with abnormalities involving chromosomes 1p11,7q21, and 10p13. A 62-year-old male patient with a cerebellar ependymoma showed a hypodiploid stem-cell line with clonal structural aberrations of both the long and short arms of chromosome 1, an interstitial deletion of 2q, trisomy 7, and monosomy for chromosomes 11, 13, and 16. A 3-year-old female patient with posterior fossa ependymoma showed a normal 46,XX karyotype. Chromosome 1 aberrations appear to be the most consistent finding in this small series of tumors, with the net loss or rearrangement of chromosome 1 pter-->p22 material from two of the four tumors. These findings, in addition to a previously published case [1], suggest a possible role for genes on the short arm of chromosome 1 in the cytogenetic evaluation of ependymomas.

Adult↗

Intracranial ependymomas: results of treatment with partial or whole brain irradiation without spinal irradiation.

Twenty patients with intracranial ependymoma (16) or anaplastic ependymoma (4) received post-operative radiation therapy at the University of California, San Francisco from 1959 through 1981. No patient received prophylactic spinal irradiation. The actuarial survival at 5, 10, and 15 years for 15 patients with ependymoma who received greater than 45 Gy was 67, 57, and 46%, respectively. Only one patient (7%) developed clinically recognized spinal metastases; this patient was eventually shown to have tumor at the primary site, within the irradiated volume. Six of 11 patients treated with partial brain irradiation had an intracranial recurrence, versus 1 of 4 patients treated with whole brain irradiation. Three patients were autopsied after failing partial brain irradiation for an ependymoma and the site of failure was within the irradiated volume of each patient. Partial brain irradiation was used to treat 4 patients with anaplastic ependymoma. One developed a local recurrence within the irradiated volume. The other three survived longer than 10 years. At UCSF, most patients with low grade ependymomas are presently treated with partial brain irradiation, but whole brain plus spinal irradiation is used for anaplastic tumors.

Adolescent↗

Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients.

In 33 patients undergoing operation and postoperative irradiation for intracranial ependymomas between January 1963 and December 1983, the tumor was grade 1 or 2 in 26 (79%) patients and grade 3 or 4 in 7 (21%). Operation consisted of only biopsy in 1 (3%), subtotal removal of tumor in 28 (85%), and gross total resection in 4 (12%). All patients received brain irradiation with a median dose of 4800 cGy. Seventeen (52%) patients also received spinal axis irradiation (median dose, 3000 cGy) which included 5 with high-grade tumors and 12 with low-grade infratentorial tumors. The relapse-free and overall survival rates at 5 years were 61% and 62%, respectively. Prognostic factors analyzed for statistically significant survival differences included age, sex, hydrocephalus, site, grade, extent of operation, extent of brain field, spinal axis irradiation, and brain dose. Grade was the only significant factor found: the 5-year survival of patients with low-grade ependymomas, 71%, was significantly better (p less than 0.04) than that of patients with high-grade ependymomas, 29%. Among the 31 patients evaluable for patterns of failure, treatment failed in 12 (39%) (10 only in the brain, 1 in the brain and spinal cord, and 1 only in the spine). All but one of the brain failures were at the site of the original primary lesion. Treatment failed in 4 of the 6 (67%) patients with high-grade tumor but in only 8 of the 25 (32%) with low grade tumor. Among the 7 low-grade infratentorial ependymomas treated with brain irradiation only, there was 1 treatment failure (in the spine; salvaged with further irradiation). Among the 12 patients with low-grade infratentorial tumors who received spinal axis irradiation, treatment failed in 1 (8%) (in the spine and also in the brain; patient subsequently died of disease). Nineteen (58%) patients remain alive; all but 2 of the patients who had recurrence died of their disease. This retrospective study suggests that: (a) patients with high-grade tumors have significantly poorer survival compared with those with low-grade tumors; (b) the main cause of death in ependymoma patients is intracranial failure at the primary site; and (c) craniospinal axis irradiation may not be necessary for patients with low-grade infratentorial ependymoma (localized irradiation alone may be adequate).

Adolescent↗

APC and CTNNB1 mutations are rare in sporadic ependymomas.

The ependymoma is the second most common malignant brain tumor of childhood; however, its molecular basis is poorly understood. The formation of multiple ependymomas has been reported as an occasional feature of Turcot syndrome type 2 (TS2), a familial cancer syndrome caused by inherited mutations of the APC tumor suppressor gene, and characterised by the concurrence of a primary CNS tumor (predominantly medulloblastoma) and multiple colorectal adenomas. APC is a critical component of the Wnt/Wingless signaling pathway, which is disrupted in sporadic cancers (e.g., colorectal adenomas, hepatocellular carcinomas, and medulloblastomas) by somatic mutations affecting multiple genes encoding alternative pathway components, including APC and CTNNB1 (encoding beta-catenin). To investigate any role for genetic disruption of the Wnt/Wingless pathway in sporadic ependymomas, we performed mutation analysis of APC and CTNNB1 in 77 primary tumors. Two synonymous APC polymorphisms (PRO1442PRO; THR1493THR) were identified, which were detected at equivalent rates in ependymomas and control nonneoplastic DNA samples (n =50); however, no further APC or CTNNB1 sequence variations were found. In summary, although inherited APC mutations may be associated with ependymoma development in certain TS2 cases, these data indicate that somatic mutations affecting APC and CTNNB1 do not play a major role in the pathogenesis of sporadic ependymomas.

Adenomatous Polyposis Coli Protein↗

The results of radiotherapy for ependymomas: the Mayo Clinic experience.

PURPOSE: This analysis was performed to examine the outcome of patients with histologically confirmed ependymomas of the brain or spinal cord who received postoperative radiotherapy. METHODS AND MATERIALS: Eighty patients with histologically confirmed ependymomas were evaluated retrospectively. All were treated with various combinations of surgery, radiotherapy (RT), and chemotherapy. Follow-up ranged from 5 to 30 years (median 10.4 years). RESULTS: The 5- and 10-year survival rates for the entire study group were 79% and 73%, respectively. Patients with low-grade (1 and 2 of 4) tumors had a 5-year survival rate of 87% as compared to 27% for those with high-grade (3 and 4 of 4) tumors (p < 0.0001). Patients with tumors of the spine had a 5-year survival rate of 97% as compared to 68% for those with infratentorial tumors, and 62% for those with supratentorial tumors (p = 0.03). Patients with myxopapillary ependymomas of the spine had a 5-year survival rate of 100% as compared with 76% for patients with other histological subtypes of ependymoma (p = 0.02). Multivariate analysis revealed that the survival rate was independently associated with tumor grade (p = 0.0007) and histological subtype (p = 0.02). Twenty-eight patients (35%) experienced local failure and 10 patients (13%) developed leptomeningeal seeding. The 5-year leptomeningeal failure rate was 10% in patients with low-grade tumors as compared to 41% for patients with high grade tumors (p = 0.01). CONCLUSION: Patients with low-grade tumors, especially those with myxopapillary subtypes, have high 5-year survival rates when treated with post-operative radiotherapy. High grade ependymomas are associated with a much poorer outcome. New forms of therapy are required to improve the outcome of patients with high-grade ependymomas.

Adolescent↗

Prognostic value of immunoexpression of the chemoresistance-related proteins in ependymomas: an analysis of 76 cases.

Intracranial ependymomas are the third most common primary brain tumor in children. A variety of chemotherapy protocols have been introduced for the treatment of ependymoma although overall these have not contributed to patients outcome. To our knowledge, data on the prognostic value of immunoexpression of the chemoresistance-related proteins (ChRPs) in ependymomas are absent. Seventy-six patients with intracranial ependymomas who received combined treatment were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to metallothioneins (MT), glutathione S-transferase pi (GST pi) and P-glycoprotein (P-GP). The results demonstrated significant preponderance of expression of all the above-mentioned ChRPs for the low-grade tumors. The progression-free survival time was found to be significantly shorter for immunonegative tumors in both tumor grades. Multivariate analysis using a Cox hazard model revealed that recurrence-free survival time is significantly associated with tumor grade, and MT and P-GP expression. Risk of recurrence increased for the high-grade ependymomas (hazard ratio 2.85; P = 0.004), and decreased for the MT-positive tumors (hazard ratio -2.72; P = 0.005) and for the P-GP-positive tumors (hazard ratio -2.02; P = 0.02). The obtained results allow one to conclude that ChRPs expression is closely associated with low-grade ependymomas and immunohistochemical findings may be estimated as a predictor for local tumor progression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Genetic abnormalities detected in ependymomas by comparative genomic hybridisation.

Using comparative genomic hybridisation, we have analysed genetic imbalance in a series of 86 ependymomas from children and adults. Tumours were derived from intracranial and spinal sites, and classified histologically as classic, anaplastic or myxopapillary. Ependymomas showing a balanced profile were significantly (P<0.0005) more frequent in children than adults. Profiles suggesting intermediate ploidy were common (44% of all tumours), and found more often (P<0.0005) in tumours from adults and the spinal region. Loss of 22q was the most common specific abnormality, occurring in 50% of spinal (medullary) ependymomas and 26% of tumours overall. Genetic profiles combining loss of 22q with other specific abnormalities--gain of 1q, loss of 6q, loss of 10q/10, loss of 13, loss of 14q/14--varied according to site and histology. In particular, we showed that classic ependymomas from within the cranium and spine have distinct genetic profiles. Classic and anaplastic ependymomas with gain of 1q tended to occur in the posterior fossa of children and to behave aggressively. Our extensive data on ependymomas demonstrate significant associations between genetic aberrations and clinicopathological variables, and represent a starting point for further biological and clinical studies.

Adolescent↗

Giant cell ependymoma of the filum terminale. A report of two cases.

We describe two histologically unusual cases of ependymoma of the filum terminale. Both tumors occurred in 14-year-old boys. An intradural encapsulated mass attached to the filum terminale was demonstrated radiologically in both cases and totally resected at surgery. In case 1 the neoplasm was uniformly composed of pleomorphic giant cells and was without perivascular pseudorosettes or myxopapillary changes. Case 2 was a myxopapillary ependymoma with multiple foci of pleomorphic giant cells. Neither tumor had prominent mitotic activity, necrosis, or endothelial proliferation. Both tumors were immunopositive for cytokeratin and glial fibrillary acidic protein. Ultrastructural features included basal laminae, interdigitating cell processes, microvilli, cilia, intercellular junctions, and cytoplasmic intermediate filaments. Cytogenetic analysis in case 1 showed a hypodiploid karyotype with monosomy of chromosomes 1, 10, 14, 16, 20, and 22. We interpret both tumors as most consistent with a variant of ependymoma. Because of the unique gigantocellular light microscopic appearance of the entire tumor in case 1, we propose classifying this tumor as a new morphologic subtype: giant cell ependymoma of the filum terminale. The combination of gigantocellular and myxopapillary features in case 2 supports a histogenetic relationship between giant cell ependymoma and myxopapillary ependymoma.

Adolescent↗

Clear cell ependymoma: a mimic of oligodendroglioma: clinicopathologic and ultrastructural considerations.

Although clear cells resembling oligodendrocytes are known to occur in ependymomas, tumors composed primarily of such cells, i.e., clear cell ependymoma (CCE), are rare. Herein we characterize the clinicopathologic features of eight examples of CCE encountered at Mayo Clinic from 1983 to 1996. The tumors occurred in patients 3-31 years of age and presented as well-demarcated, deeply situated, contrast-enhancing masses, all of which were supratentorial. All but one case lacked classic light microscopic features of ependymoma. Although nearly all were immunoreactive for glial fibrillary acidic protein, it was electron microscopy that showed the diagnostic hallmarks of ependymoma, including complex intercellular junctions, surface microvilli and cilia, and microrosette formation, thus underscoring the importance of electron microscopy in the diagnosis of clear cell ependymomas. The differential diagnosis of CCE includes not only oligodendroglioma, but central neurocytoma and glioneurocytoma. Unlike oligodendrogliomas, CCEs are characterized by their sharp circumscription, hypervascularity as reflected in contrast enhancement on computed tomography and magnetic resonance imaging, their noninfiltrative pattern of growth that displaces parenchyma, and the occasional formation of vague perivascular pseudorosettes. Unlike central neurocytomas and glioneurocytomas, CCE lack secretory granules, vesicles, and synapses by electron microscopy and neuroendocrine markers by immunocytochemistry. In summary, the diagnosis of CCE requires neuroimaging, histologic, and ultrastructural correlation. The latter is essential in a limited biopsy. Ultrastructural studies also play a role in identifying glioneurocytomas. CCEs behave like more ordinary ependymomas. The importance of their recognition is the avoidance of alternative diagnoses and inappropriate therapies.

Adolescent↗

Immunohistochemical detection of schwannomin and neurofibromin in vestibular schwannomas, ependymomas and meningiomas.

In addition to schwannomas, patients with neurofibromatosis type 2 (NF2) frequently develop meningiomas and occasionally, ependymomas. Using DNA and protein analyses, we have shown NF2 gene mutations and lack of the gene product schwannomin in 29 schwannomas, 10 meningiomas, and in 7 ependymomas. We have raised antibodies (ABs) to peptides from the C-terminal (5990-AB) and N-terminal (5991-AB) domains of schwannomin. The ABs specifically detected a 65 kDa protein in a Schwann cell line and recognized schwannomin in the cytoplasm of Schwann cells (SCH), perineurial cells, and vestibular ganglion neurons. None of the 29 schwannomas were stained by the 5990-AB. Only 4 schwannomas were stained by the 5991-AB, indicating that most truncated schwannomins were unstable or not expressed in schwannomas. Seven of 10 meningiomas, including 3 tumors from NF2 patients, were not stained by either 5990-AB or 5991-AB. Only 2 of 7 ependymomas lacked schwannomin. Complete lack of schwannomin in these tumors supports a tumor suppressor function for schwannomin in some meningiomas and ependymomas. All tumors showed staining with an antibody to a C-terminal peptide of neurofibromin, confirming that full-length neurofibromin is present in these vestibular schwannomas, meningiomas, and ependymomas. The presence of schwannomin in some meningiomas and in the majority of ependymomas indicates that additional genes are likely to play a role in tumorigenesis of these tumors.

Brain Neoplasms↗

Supratentorial ependymomas in adult patients.

OBJECTIVE: Ependymomas arise from different areas in the neuraxis and have variable outcomes that depend on tumor location and patient age at the time of presentation. The predictive value of histology for these tumors is unresolved. We report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery, histology, ploidy, and proliferation index in tumor control. METHODS: Fourteen of the 23 supratentorial ependymomas were in the region of the third ventricle and the remainder were located in the hemispheres. Resections were gross total in 12 patients, subtotal in 8, and biopsy in 3. A single pathologist reviewed all slides and quantitated the deoxyribonucleic acid. The mean follow-up duration was 95 months (+/-75 mo). RESULTS: All of the malignant ependymomas were hemispheric (n = 4). Mortality occurred only in patients with third ventricular tumors; two patients died as a result of surgical complications and three as a result of tumor progression. Kaplan-Meier estimates of 5- and 10-year survival rates were 100% for hemispheric and 72.5% for third ventricular tumors (62.5% including the two perioperative deaths). The median time to recurrence was 53 months, with a 10-year progression-free survival rate of 27%. Univariate analysis revealed that recurrence was associated with malignant histology, including mitoses, cellularity, and aneuploidy. For nonmalignant ependymomas, recurrence was associated with subtotal resection and metastases. S-phase fraction did not correlate with recurrence. Only malignant histology correlated with recurrence on multivariate analysis. CONCLUSION: Although the numbers are too small to draw any definite conclusions, treatment of ependymomas that arise in the supratentorial compartment in adult patients results in excellent outcomes despite frequent recurrences. Association with the third ventricle and metastases seem to have a negative impact on survival, whereas malignant histology, subtotal resection, and metastases may be predictors of recurrence.

Adolescent↗

Intradural extramedullary spinal ependymoma: a benign pathology?

STUDY DESIGN: Spinal ependymoma is a benign central nervous system tumor described as an intramedullary lesion more frequently located at the conus medullaris. It has been described exceptionally in the literature as an intradural extramedullary tumor. OBJECTIVE: Presentation of an extremelly rare location and evolution of extremedullary ependymoma and discussion of its probable origin, differential diagnosis, treatment options, and follow-up. SUMMARY OF BACKGROUND DATA: This case demonstrates an unusual location of a benign ependymal tumor in the extramedullary space with a total resection, which recurred in a lower level with a malignant transformation with the same extramedullary location. METHODS: The authors present the case of a 47-year-old woman with a subacute spinal cord dysfunction and an intradural extramedullary D2-D3 tumor mimicking meningioma or neurinoma. At surgery, an encapsulated intradural extramedullary mass was found, but neither dural attachment nor medullary infiltration was present. RESULTS: After complete resection, anatomic-pathologic studies confirmed that the lesion was a benign classic ependymoma. Good neurologic outcome was achieved, and no residual tumor was present at magnetic resonance imaging (MRI) control performed at 3 and 9 months later. One year after surgery, a new intradural extramedullary tumor was found at the D4 level without recurrence at D2. The patient was operated on again, but at this time the histologic study showed an anaplastic ependymoma with a proliferation index of 25% measured by Ki-67. Whole central nervous system radiotherapy was performed. CONCLUSION: All of the previously reported cases of spinal intradural extramedullary ependymomas carried out a benign course. The case we are reporting is the first one in which malignant transformation occurred. This tumor should be taken into account in the differential diagnosis of intradural extramedullary lesions. Moreover, close follow-up is recommended for this unusual location of ependymomas.

Cell Transformation, Neoplastic↗

An immunohistological study of 66 ependymomas.

Sixty-six ependymomas were examined immunohistologically to determine their distribution of glial fibrillary acidic proteins, S-100 protein and vimentin. The neoplasms were subdivided into four groups: (1) ependymomas from the cauda equina, predominantly of the myxopapillary type; (2) benign ependymomas; (3) malignant ependymomas; and (4) ependymoblastomas. Marked differences in antigen reactivity were observed between each group. The intensity of the reaction with the three antibodies was strongest in malignant ependymomas. Ependymomas from the cauda equina showed a patchy distribution of positivity for the three antigens in cells surrounding blood vessels but there was no staining of collagenous septa or the myxoid areas. In ependymoblastomas, the cells of the rosettes were negative for glial fibrillary acidic protein, but there was focal positivity for vimentin and S-100. Other areas showed tumour cells containing moderate amounts of vimentin and small amounts of S-100, and a few bands of filaments positive for glial fibrillary acidic protein. The cytogenetic and biological implications of these findings are discussed.

Cauda Equina↗