Prognostic value of Ki-67 (MIB-1) and p53 in ependymomas

To determine whether Ki-67 (MIB-1) and p53 have prognostic value in ependymomas, clinicopathologic study was undertaken in 29 patients with this tumor. The clinical course correlated well with the histological grade according to the World Health Organization (WHO) grading system, and it was the worst in patients with anaplastic ependymoma. The percent expression of MIB-1 and p53 correlated with the histological grade of malignancy. With regard to the subtypes of benign ependymoma, the clinical course was the worst in clear-cell ependymoma, which had a significantly higher expression of MIB-1 and p53 than the other subtypes. Tanycytic ependymoma showed the most benign clinical course and the lowest expression of MIB-1 and p53. Although the WHO grading generally tended to correlate with the clinical course of ependymomas, these two subtypes-clear-cell ependymoma and tanycytic ependymoma-exhibited biological properties different from those of other grade II ependymomas.     

A case of tanycytic ependymoma arising from the cerebral hemisphere

We report a rare case of tanycytic ependymoma arising from the cerebral hemisphere. A 59-year-old man was admitted to our hospital because of the incidental detection by MRI of a tumor lesion in the right temporooccipital paratrigonal region. The mass showed low-to iso-intensity on T₁-weighted images and high intensity on T₂/proton-weighted images. Partial resection was performed using a transsulcal approach to avoid compromising the visual field. Most of the tumor cells showed elongated spindle shapes arranged in dense fascicles. A few true ependymal rosettes and perivascular pseudorosettes were visible. The tumor cells were positive for GFAP, S-100, and vimentin, but negative for synaptophysin, EMA, and keratin. The MIB-1 labeling index was approximately 1%. Ultrastructurally, the tumor cells had ependymal cell features, such as microvilli and cilia. From these findings, a pathological diagnosis of tanycytic ependymoma was made.     

Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas

BACKGROUND: The results of attempts to identify histopathologic parameters that contribute to the clinical outcome of patients with ependymomas have been controversial. This may be due to the relative rareness of ependymomas. Furthermore, in many investigations, myxopapillary ependymomas and subependymomas were included and may have confounded results, because those tumors should be considered clinicopathologic entities distinct from the other ependymomas. METHODS: In this retrospective study, the influence of the histologic subtype of ependymoma and of individual histologic features on the outcome of 69 patients with ependymomas was investigated. Myxopapillary ependymomas, subependymomas, and ependymomas with spinal localizations were excluded from the analysis. The ependymomas were subdivided into cellular, papillary, clear cell, and tanycytic subtypes. The study extended over a period of 30 years. RESULTS: No differences in clinical outcome between the four histologic subtypes of ependymomas were revealed. Neither tumor localization (either infratentorial or supratentorial), patient age, nor gender affected survival. The survival of patients who underwent complete tumor resection differed significantly from that of patients who underwent partial resection. In univariate analysis, the features of nuclear atypia, the mitotic index, and the MIB-1 labeling index (LI) significantly influenced survival. With regard to survival, the presence of microcysts, blood vessel density, and the feature of vascular hyalinization demonstrated a trend but did not reach significance. In multivariate analysis, only the mitotic index and the MIB-1 LI were identified as factors with independent prognostic significance (P = 0.027 and P = 0.023, respectively). Both proliferation indices were correlated strongly with each other. CONCLUSIONS: The results of the univariate analysis indicated that, for patients with intracranial ependymoma, nuclear atypia, the mitotic index, and the MIB-1 LI significantly influenced survival. In the multivariate analysis, the mitotic index and the MIB-1 LI were the only features that had independent prognostic significance. Because both showed strong correlations, only one of them should be included in a grading scheme for intracranial ependymomas.     

A case of angioglioma composed of astrocytoma with a papillary growth pattern: Immunohistochemical and ultrastructural studies

We report a case of a large cystic astrocytoma associated with arteriovenous malformation in the right cerebral hemisphere of a 16-year-old boy. Neuroimaging showed large abnormal vessels with flow voids and arteriovenous shunt around the cystic lesion. Histologically, the cyst wall was formed by abnormal vasculature and clusters of glial cells forming a papillary growth pattern. The abnormal vasculature consisted of dilated vein-like vessels and medium-sized arteries with incomplete media, and was diagnosed as an arteriovenous malformation. Immunohisto-chemically, glial fibrillary acidic protein (GFAP) decorated both the perikaryon and the processes of the glial tumor cells. They were negative for epithelial membrane antigen (EMA), cytokeratin, and S-100 protein. Ultrastructurally, the tumor cells were rich in intermediate filaments, and neither cilia, microvilli, nor ependymal rosettes were verified. Based on these morphological features and the low MIB-1 labeling index of 0.8%, the glial tumor was diagnosed as astrocytoma, Grade II, according to the World Health Organization (WHO) tumor classification. An association of glioma with various types of vascular anomalies has been designated as angioglioma. A unique feature of the present case, however, is a papillary growth pattern, which is not listed in the current WHO classification of brain tumors. The recognition of the occurrence of such cases would be important in differential diagnosis of papillary ependymoma and choroid plexus papilloma.     

A case of anaplastic clear-cell ependymoma presenting with high erythropoietin concentration and 1p/19q deletions

We describe a 19-year-old woman with onset of epileptic seizure, and a small mural nodule and multicystic lesions with severe brain edema located in the right frontal lobe. At surgery, the tumor and a clear margin was removed, and symptoms improved postoperatively. Extended local radiotherapy (60 Gy) was performed. Histopathological examination revealed oligodendroglioma-like tumor cells with a perinuclear halo. The tumor cells extended processes toward CD34-positive proliferating vessels, which resemble a basement membrane. These proliferating vessels formed a tumor membrane so that there was a clear margin between the tumor and brain tissue. Tumor cells were positive for epithelial membrane antigen in a dot-like pattern. MIB-1 staining index was 50.6%. Electron microscopy showed cilia and zipper-like junctions, and anaplastic clear-cell ependymoma grade III was diagnosed. A characteristic of the case was formation of a tumor membrane by proliferating tumor blood vessels. Fluorescence in situ hybridization showed 1p/19q deletions, and the concentration of erythropoietin in the cyst fluid was abnormally high, at 1,859.4 mIU/ml. Erythropoietin and erythropoietin receptors were verified with immunohistochemical staining.     

Supratentorial Tanycytic Ependymoma in an Adult Male: Case Report and Review of Literature

Ependymomas, tumors of the ependymal cells, are very rare and usually present in the pediatric population. Furthermore, there are even rarer variants of ependymomas that can include cellular, papillary, clear cell, and tanycytic subtypes. We present a case of a supratentorial tanycytic ependymoma in an adult male and review the literature in regard to this rare primary central nervous system neoplasm.Key Words: Tanycytic ependymoma, Supratentorial tanycytic ependymoma, Adult     

Tanycytic ependymoma of the spinal cord with anaplastic cytological features

In a 43-year-old man, an intramedullary spinal cord tumor spreading from the level of the T2 to T5 vertebrae was subtotally resected. The tumor predominantly consisted of a fascicular proliferation of spindle cells having bland nuclei and bipolar, long cytoplasmic processes, and a few perivascular pseudo-rosettes were found. Although there were no true ependymal rosettes, intracytoplasmic dot-like immunoreactivity for epithelial membrane antigen (EMA) was found in a few cells. In some areas, a dense and diffuse proliferation of anaplastic, short-spindled cells having hyperchromatic nuclei and scant cytoplasm was noted, and the Ki-67 labeling index was remarkably higher (18.2%) in these areas. Neither microvascular proliferation nor necrosis was observed. In the boundary region, these two areas showed gradual transition from one to the other. The patient has remained free from recurrence for 10 months postoperatively. This is the first documentation of tanycytic ependymoma in which tumor cells showed anaplastic cytological features.     

Supratentorial extraventricular ependymal neoplasms: a clinicopathologic study of 32 patients

BACKGROUND: Published research on the clinicopathologic features of extraventricular ependymal neoplasms of the cerebral hemispheres has been scant. METHODS: Thirty-two archival cases were studied to investigate the prognostic impact of clinicopathologic parameters including flow cytometry, the proliferation (Ki-67) labeling index, and p53 expression. RESULTS: Among these 32 cases were 2 subependymomas, 19 ependymomas, and 11 anaplastic ependymomas. No significant gender predilection was observed, and 45% of patients were in their second or third decade of life. The left cerebral hemisphere was 1.5 times more commonly involved. On available imaging studies, lesions were often cystic, with or without a mural nodule. Tumors expressed glial fibrillary acidic protein (87%), S-100 protein (77%), cytokeratin (43%), and epithelial membrane antigen (17%). Ki-67 proliferation index paralleled tumor grade. Immunoreactivity for p53 protein was observed in the 2 cases of subependymoma, in 10 of 11 anaplastic ependymomas, and in 6 of 17 ependymomas. Flow cytometry performed in 27 tumors revealed diploidy in 20 cases and aneuploidy in 4 cases (3 anaplastic and 1 classic ependymomas), with S-phase fraction ranging from 0.2-9.7. Eleven subjects were additionally treated with radiotherapy, and 3 with chemotherapy. Follow up was available in 25 (78%) patients. CONCLUSIONS: The results of the current study suggest that there is no significant relation between histopathology, Ki-67 proliferation index, p53 immunolabeling, tumor ploidy, and biologic behavior.     

The proliferative potential of human ependymomas measured by in situ bromodeoxyuridine labeling

Twelve patients with ependymomas received a 30- to 60-minute intravenous infusion of bromodeoxyuridine (BrdU), 150 to 200 mg/m2 at surgery, to label tumor cells in the DNA synthesis phase. Labeled cells were detected in excised tumor specimens by indirect immunoperoxidase staining using anti-BrdU monoclonal antibody as the first antibody. The BrdU labeling index (LI, defined as the percentage of labeled cells in relation to the total number of cells scored) was calculated for each specimen. All four spinal cord ependymomas had a BrdU LI of less than 1%, which is consistent with our clinical experience that most such tumors grow slowly and have an excellent prognosis. Five of the eight intracranial ependymomas also had a low BrdU LI of approximately 1% or less, and three had a BrdU LI of 3.2%, 3.4%, and 4.8%. The latter three tumors, only one of which was diagnosed as a malignant ependymoma at the time of study, were either recurrent or recurred within 2 years after gross or subtotal removal. Cytologic analysis of cerebrospinal fluid (CSF) was performed in five cases; CSF seeding of tumor cells was found in only one patient, who had a malignant ependymoma. A high BrdU LI did not always correlate with CSF seeding. Measurement of the LI using BrdU and anti-BrdU monoclonal antibodies can provide more accurate information on the proliferative potential of individual tumors and may lead to a more rational grading system of ependymomas. The results of such studies do not always predict the potential for CSF seeding.     

Cerebrospinal fluid cytology in patients with ependymoma

BACKGROUND.

Ependymoma cells are known to occasionally exfoliate into cerebrospinal fluid (CSF). However, the frequency of CSF involvement in patients with ependymoma is unclear, and to the authors' knowledge the cytomorphologic features of the tumor cells have not been described in detail to date. In this study, the CSF findings in patients with ependymal neoplasms are summarized and the cytomorphologic features of ependymoma, including its variants, are illustrated.

METHODS.

A search of the pathology databases of 2 medical centers was performed to identify all patients with a histologic diagnosis of ependymoma in whom CSF samples were examined. Slides from CSF samples originally reported as atypical, suspicious, or positive were reviewed and the cytomorphologic features assessed. Follow‐up included a review of the medical records and histologic correlation.

RESULTS.

In all, 177 patients with a diagnosis of ependymoma were identified. Of these, 48 had a total of 94 cytologic preparations of CSF. Positive, suspicious, atypical, negative, and nondiagnostic results were noted in 6.4%, 5.3%, 4.3%, 79.7%, and 4.3%, respectively, of the specimens. The detection rate of tumor cells in CSF was 6.7% in 15 adults and 21.2% in 33 children, with an overall rate of 16.7%. Of the 8 patients with positive and/or suspicious diagnoses, 5 ependymomas exhibited anaplastic features and 1 tumor was a myxopapillary ependymoma. The positive samples were usually hypercellular, with cohesive epithelioid cells; long cytoplasmic processes resembling bipolar tanycytes were observed in the tanycytic variant of ependymoma.

CONCLUSIONS.

Exfoliated cells from ependymomas are recognizable in CSF samples, especially in patients with myxopapillary tumors and tumors with anaplastic features. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Prognostic and therapeutic implications of the MIB-1 labeling index in breast cancer

Background  Assessment of tumor proliferative activity is considered to be the most powerful prognostic factor aside from axillary lymph node status. The purpose of this study is to assess the clinical value of measurement of proliferative activity using the MIB-1 labeling index in patients with breast cancer. Methods  Surgical specimens from 36 patients with benign breast disorders and 146 patients with breast cancer were investigated. The MIB-1 labeling index was determined on the specimens stained by immunohistochemical methods as much as possible. Clinical factors associated with the MIB-1 labeling index were reviewed. Results  The MIB-1 labeling index for non-proliferative disorders, proliferative disorders, and breast cancer was 3.4±1.9%, 8.9±6.2% and 20±12%, respectively. The MIB-1 labeling index and tumor size, lymph node metastasis status, and clinical stage according to the TNM classification correlated significantly. Survival rate was inversely correlated with the MIB-1 labeling index. No patient with an MIB-1 labeling index of less than 10% had lymph node metastases, and all are alive without recurrence. Patients with an MIB-1 labeling index of over 30% had an extremely poor prognosis. Conclusions  The MIB-1 labeling index is very useful for predicting both either extremely good or extremely poor prognosis, and axillary lymph node metastasis.     

Ependymoma with extensive lipidization mimicking adipose tissue: A report of five cases

Lipomatous ependymoma is a recently described entity and only 3 cases of this variant have been reported in the literature. We report 5 cases of this rare variant of ependymoma. Patients age ranged from 4 years to 45 years and, interestingly, all of them were males. Two tumors were supratentorial in location, 2 in the fourth ventricle and 1 was intramedullary. Microscopically all of them showed the classical histology of ependymoma along with lipomatous differentiation. The lipomatous component was composed of cells with a large clear vacuole pushing the nucleus to the periphery and giving a signet ring cell appearance. This component demonstrated positivity for GFAP and S-100 protein thereby confirming its glial lineage. Three of the 5 tumors were high grade (WHO-grade III), had a high MIB-1 labelling index (MIB-1 LI) and showed recurrence on follow-up. However, 2 were low grade (WHO grade II) and patients are free of disease till the last follow up.     

Tanycytic ependymoma of the filum terminale with pleomorphic giant cells

A tanycytic ependymoma measuring 1.5 cm in maximal dimension, which involved the filum terminale and conus medullaris of a 55-year-old woman, is reported. The tumor consisted of a compact fascicular proliferation of spindle cells having long bipolar cytoplasmic processes, and immunohistochemical and ultrastructural studies demonstrated the ependymal features of neoplastic cells. The most prominent finding was an appearance of many atypical and pleomorphic, often monstrous, giant cells, which was not associated with an increase in proliferative activity. Remarkable nuclear atypism and pleomorphism with formation of giant cells have not been documented previously in tanycytic ependymoma. These nuclear changes are considered essentially degenerative in nature and probably do not portend a worse prognosis despite their worrisome appearance. This tumor could be appropriately termed “giant cell tanycytic ependymoma.”     

Immunohistochemical Markers for Prognosis of Ependymal Neoplasms

Intracranial ependymomas are the third most common primary brain tumor in children. Although clinical and histological criteria for ependymoma prognosis are recognized, studies have reported contradictory results. Prognostic significance based on immunohistochemistry of ependymomas has been reported in a few studies. One-hundred and twelve patients with intracranial ependymomas were examined retrospectively for immuno-expression of various tumor-associated antigens and apoptosis. The results demonstrated significant preponderance of expression of the tenascin, vascular endothelial growth factor protein (VEGF), epidermal growth factor (EGFR) and p53 protein in high-grade tumors. Also high-grade ependymomas revealed more prominent labeling indices (LI) for proliferative marker Ki-S1 and apoptotic index (AI), and lower LI for cyclin-dependent kinase inhibitors p27/Kip1 and p14ARF. For low-grade ependymomas the progression-free survival time (PFS) was found to be significantly shorter for Ki-S1 LI>5%, and for tenascin, VEGF and EGFR positivity. For high-grade ependymomas PFS was found to be significantly reduced for p27 LI<20%, p14ARF LI<10%, for p53 positivity, and for AI<1%. The CART modeling process exhibited five final groups of ependymoma patients (1) low-grade and tenascin-negative; (2) low-grade and tenascin-positive; (3) high-grade and p53-negative with p14 LI>0%; (4) high-grade with combination of either p53 positivity and p14 LI>10% or p53 negativity and p14 LI<10%; (5) high-grade and p53-positive with p14 LI<10%. In summary, some immunohistochemical variables were found to be the strong predictors of ependymoma recurrence and they seem to be useful for assessing individual tumor prognosis in routinely processed biopsy specimens together with tumor grade. For histologically benign ependymomas immunohistochemical study should be focused on Ki-S1, tenascin, EGFR and VEGF evaluation, whereas p53 expression and number of p27, p14 and ISEL-positive nuclei will be of value in determining PFS from high-grade ependymomas.     

Proliferative Activity as Measured by MIB-1 Labeling Index and Long-term Outcome of Cerebellar Juvenile Pilocytic Astrocytomas

Proliferative activity of cerebellar juvenile pilocytic astrocytomas (CJPA) and its significance for prognosis was retrospectively investigated.Forty-four consecutive children operated between 1981 and 1997 with a mean age of 8.3 years (3 months to 20 years) were reviewed. Clinical and radiological follow-up was available for 38 patients ranging from 0 to 18yrs (mean 6.3 years). Proliferative activity was determined by MIB-1 immunohistochemistry on sections of resected tumor specimen.Total resection was achieved in 35 children (79.5%), subtotal in 9 (20.5%). Currently, 31 are tumor-free, 6 have stable remnants, one developed spinal seeding and one died. Radiology revealed a cystic mural node type tumor in 27 patients (61.4%), a solid lesion with a small cyst in 5 patients (11.4%), and a solid tumor in 12 patients (27.3%). Mean MIB-1 labeling index (LI) of all tumors was 4.4% (range 0.6–12%, SD = 2.7) and did not correlate with age, gender, localization, amount of resection, follow-up status, histological appearence or grade of neovascularization, but showed a significant correlation to radiological types: 6.9% in solid tumors versus 3.7% in the cystic mural node type (p = 0.0037). Five year progression-free survival (PFS) of all patients was 84.4%, differences between subgroups of MIB-1<5% (27 patients, PFS = 87.4%) and MIB-1>5% (13 patients, PFS = 76.3%) were not significant.CJPA showed a remarkable high MIB-1 LI, but no significant correlation to PFS in this series. Nevertheless, radiologically solid tumors demonstrated a significantly higher MIB-1 LI and thus may need further investigation for possible increased ability of regrowth.     

Papillary Glioneuronal Tumor

Objective and importance Papillary glioneuronal tumor is a recently described neoplasm composed of gliovascular pseudopapillae associated with intervening neuronal cells ranging from neurocytes to ganglion cells. This tumor is not currently included in the WHO classification of tumors of the central nervous system. We describe a new case of papillary glioneuronal tumor and analyze the data for a series of further 15 patients from international literature.Clinical presentation A 27-year-old man presented to us for generalized seizure. CT and MRI showed a cystic tumor with mural nodule in the left frontal lobe.Intervention Frontal craniotomy with gross total removal of the tumor was performed. Histopathological examination was positive for papillary glioneuronal tumor.Conclusion The clinical, radiologic, and pathological features of our case are strikingly similar to those of the previous reported cases. A review of the literature disclosed only 15 other cases of these tumors.It is important that every new case of PGNT is reported to allow its recognition and classification.     

Molecular genetic alterations on chromosomes 11 and 22 in ependymomas

Ependymomas arise from the ependymal cells at different locations throughout the brain and spinal cord. These tumors have a broad age distribution with a range from less than 1 year to more than 80 years. In some intramedullary spinal ependymomas, mutations in the neurofibromatosis 2 (NF2) gene and loss of heterozygosity (LOH) on chromosome arm 22q have been described. Cytogenetic studies have also identified alterations involving chromosome arm 11q, including rearrangements at 11q13, in ependymomas. We analyzed 21 intramedullary spinal, 14 ventricular, 11 filum terminale and 6 intracerebral ependymomas for mutations in the MEN1 gene, which is located at 11q13, and mutations in the NF2 gene, which is located at 22q12, as well as for LOH on 11q and 22q. NF2 mutations were found in 6 tumors, all of which were intramedullary spinal and all of which displayed LOH 22q. Allelic loss on 22q was found in 20 cases and was significantly more frequent in intramedullary spinal ependymomas than in tumors in other locations. LOH 11q was found in 7 patients and exhibited a highly significant inverse association with LOH 22q (p<0.001). A hemizygous MEN1 mutation was identified in 3 tumors, all of which were recurrences from the same patient. Interestingly, the initial tumor corresponded to WHO grade II and displayed LOH 11q but not yet a MEN1 mutation. In 2 subsequent recurrences, the tumor had progressed to anaplastic ependymoma (WHO grade III) and exhibited a nonsense mutation in exon 10 of MEN1 (W471X) in conjunction with LOH 11q. This suggests that loss of wild-type MEN1 may be involved in the malignant progression of a subset of ependymomas. To conclude, our findings provide evidence for different genetic pathways involved in ependymoma formation and progression, which may allow to define genetically and clinically distinct tumor entities.     

A clinicopathologic study of 81 patients with ependymomas and proposal of diagnostic criteria for anaplastic ependymoma

Optimal histologic criteria for the classification of and grading of ependymomas, including their anaplastic forms, remain elusive. This is especially true because of the poor correlation of these criteria with clinical outcome. The aim of this study was to identify the histopathologic parameters that could distinguish different prognostic groups of patients with ependymomas. Eighty-one patients with ependymal tumors, including those originally diagnosed ependymomas, anaplastic ependymomas and myxopapillary ependymomas, were enrolled in this study. Thirteen histologic parameters, including hypercellularity, nuclear pleomorphism, mitoses, endothelial proliferation, necrosis, clear cell, thrombi, dystrophic calcification, psammoma bodies, bone, cartilage, Rosenthal fibers and MIB-1 labeling index (LI), were evaluated in each patient and correlated with clinical outcome. We assigned one score for each histopathologic parameter evaluated and used a stepwise selection method with entry model based on the significance of the log-rank statistic to formulate a scoring model. Four parameters were chosen in this process, including mitoses > or = 4/10 hpf (1.7/mm2), hypercellularity, endothelial proliferation and necrosis. The sum of these four parameters (scores) was the histopathologic score of the tumor. The progression-free survival (PFS) and overall survival (OS) of patients with histopathologic scores 0 and 1 were significantly better than those with histopathologic scores 2, 3 and 4 (p < 0.001 and p = 0.005, respectively). Because of the latter finding, we proposed that anaplastic ependymoma could be diagnosed by the presence of any two of the aforementioned four parameters. Multivariate analyses including clinical and histopathologic variables showed that histopathologic score > or = 2 and subtotal resection were the factors related to increased risk of recurrence, while histopathologic score > or = 2 was the only factor related to overall survival. Based on the above findings, we concluded that histopathology is an important prognostic indicator for patients with ependymomas.     

Large cystic cavernous angioma of the cerebellum mimicking pilocytic astrocytoma

SummaryObjective and importance Cavernous angiomas are relatively rare vascular malformations. They are generally located supratentorially with a rare incidence in the cerebellum. Cavernous angiomas, accompanied by a large cyst, are very rare. We present a case of a cavernous angioma with the unusual MRI findings of a large cyst and a small mural nodule.Clinical presentation The patient was a 48-year-old man who complained of a history of dizziness for several weeks. The neurologic examination in the neurosurgery clinic was without deficit.Intervention The cyst measured 4.7×4.0 cm and contained serous fluid with a nodular mass in the lower part of the cyst. The cystic wall and the solid mural nodule were completely removed through a midline suboccipital approach. Postoperatively, the patient remained neurologically intact.Conclusion When a large cystic lesion is present in the cerebellum, preoperative radiological and intraoperative findings led to misdiagnosis. Therefore, a rare cystic angioma must be considered in the differential diagnosis of infratentorial cystic masses.