Proliferative potential of human meningiomas of the brain. A cell kinetics study with bromodeoxyuridine

Twenty patients with intracranial meningiomas were given a 1-hour intravenous infusion of bromodeoxyuridine (BrdU), 200 mg/m2, at the time of surgery to label tumor cells in the DNA synthesis phase (S phase). The excised tumor specimens were fixed with 70% ethanol, embedded in paraffin, sectioned, and stained by an indirect immunoperoxidase method using anti-BrdU monoclonal antibody as the first antibody. The BrdU labeling index (LI), or S-phase fraction, was determined by counting the number of BrdU-labeled cells in the tissue sections. The average LIs for nonmalignant (11 cases) and histologically malignant meningiomas (seven cases) were 0.45% and 3.9% respectively (P less than 0.05). Two hemangiopericytic variants showed average LIs of 0.53% and 4.1%. Four of seven malignant meningiomas and both hemangiopericytomas were recurrent tumors. Nine of 20 meningiomas had an LI greater than 1%, and six of those nine (67%) were recurrent. Thus, meningiomas with an LI greater than 1% appear to grow faster and recur more frequently than those with LIs less than 1%; the higher LI may indicate biological malignancy. The measurement of BrdU LI in meningioma may prove valuable in establishing the diagnosis of "malignant meningioma."     

Proliferative activity in thyroid tumors.

To clarify the proliferative activity of papillary thyroid carcinoma, the bromodeoxyuridine (BrdU) labeling index (LI) of 61 various thyroid tumors was investigated using an in vitro labeling technique and immunohistochemical staining with anti-BrdU monoclonal antibody. The mean LI (+/- standard deviation) of 31 papillary carcinomas, 12 adenomas, 10 adenomatous goiters, 3 follicular carcinomas, and 2 medullary carcinomas were 1.2% (+/- 1.3%), 0.6% (+/- 0.3%), 0.7% (+/- 0.6%), 1.5% (+/- 2.2%), and 0.7% (+/- 0.6%), respectively. The LI of the papillary carcinomas ranged from 0.1% to 4.6%, and approximately 66% of these showed less than a 1% similarity with almost all benign tumors. However, the LI of the two malignant lymphomas and the one anaplastic carcinoma were more than 13%. When the LI of the papillary carcinomas was compared with their various prognostic factors, there was no correlation with tumor size, nodal status, or morphologic features. However, the patients who were 50 years of age or older tended to have relatively high LI, and the LI of the papillary carcinomas correlated with patient age. According to these results, the biologic characteristics of papillary carcinomas vary with age and high proliferative activity may contribute to the poor prognosis of this tumor in elderly patients.     

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.     

Immunohistochemical approach to reveal the growth potential of uterine cancers using anti-BrdU antibody and Ki-67

To reveal the growth potential of uterine cancer, the population of S-phase and proliferating cells were examined with immunohistochemical technique using anti-BrdU antibody and Ki-67. BrdU is a thymidine analogue that is also incorporated into nuclear DNA and S-phase cells are recognized with anti-BrdU antibody. Ki-67 reacts a nuclear antigen present in proliferating cells (late G1, S, M and G2 phase). The percentage of BrdU-labeled cells (labeling index: LI) and that of cells recognized with Ki-67 (growth fraction: GF) were calculated. LI and GF were examined in 12 cervical cancers (LI: 16.0 +/- 6.0; GF: 32.2 +/- 11.2, mean +/- SD), 18 normal ectocervical portions (LI: 6.9 +/- 3.1; GF: 11.4 +/- 5.0), 13 endometrial cancers (LI: 15.9 +/- 5.0; GF: 26.2 +/- 9.0) and 11 normal endometrial tissues (LI: 12.2 +/- 6.1; GF 20.3 +/- 6.8). Indices of GF were always higher than LI in any cases. Both indices of LI and GF in malignant cases were higher than normal cases, therefore, high growth potential of uterine cancer was demonstrated. Both LI and GF of squamous cell carcinoma were higher than adenocarcinoma. In general, the values of GF were parallel to those of LI, and a regression line: Y = 1.44 X + 3.93 (r = 0.80) was obtained. Therefore, S-phase cells occupied about 60-70% of all proliferating cells. These results showed that these two parameters were useful to evaluate growth potential of uterine cancer, but calculation of GF using Ki-67 might be superior to LI using anti-BrdU antibody in terms of simplicity and rapidity.(ABSTRACT TRUNCATED AT 250 WORDS)     

A cell kinetic study of pulmonary adenocarcinoma by an immunoperoxidase procedure after bromodeoxyuridine labeling

By in vitro labeling with bromodeoxyuridine (BrdU) and immunohistochemical staining with anti-BrdU monoclonal antibody, the tumor cell kinetics were investigated in 52 resected pulmonary adenocarcinomas. The values of the BrdU labeling index (LI) varied widely among cases of adenocarcinoma in comparison with four cases of small cell carcinoma and ten cases of squamous cell carcinoma examined as controls. The LI was below 3.0 in 60% of the adenocarcinomas. When the LI was analyzed according to the cytologic subtypes of adenocarcinoma, the values were low for goblet cell type and type II alveolar cell type, whereas the values for the bronchial surface epithelial cell type varied widely (average, 5.2) and those for the Clara cell type were intermediate (average, 1.8). A comparison of the LI with TNM classification, histologic differentiation, degree of nuclear atypia, and mitotic cell count showed a correlation between the LI and each of these prognostic factors. Thus, the possibility of the BrdU LI being a useful new prognostic factor of pulmonary adenocarcinomas was suggested.     

Determination of proliferative activities in human brain tumor specimens: a comparison of three methods

Summary Proliferative activities were determined in 72 human brain tumors, including 20 metastatic carcinomas, 41 gliomas, 8 meningiomas and 3 hematological tumors. Immunocytochemical techniques included labeling with monoclonal antibody (mAb) to bromodeoxyuridine (BrdU) which identifies S phase cells after previous in vitro BrdU incubation and paraffin embedding of fixed tissue specimens, and with mAb Ki-67 which reacts, in frozen sections, with a nuclear antigen expressed by all proliferating cells. BrdU labeling index (LI), Ki-67 LI and mitotic index (MI) correlated well with histological malignancy. Among the three proliferation indices, Ki-67 LI and BrdU LI were highly significantly correlated. With the exception of hematological malignancies, hyperbaric oxygenation of in vitro BrdU labeling did not significantly increase BrdU LI or depth of BrdU penetration into tissue. This study indicates that in vitro BrdU labeling is a useful alternative to Ki-67 immunolabeling of human brain tumor specimens. By such determination of tumor proliferation, it might be possible to design a more adequate postoperative therapy tailored to patients individually.     

AR、PCNA表达与脑膜瘤临床病理因素的相关性研究

目的探讨雄激素受体(AR)在脑膜瘤组织中的表达及其与肿瘤增殖潜力的关系.方法采用免疫组化SABC法,检测AR、增殖细胞核抗原(PCNA)在39例脑膜瘤组织中的表达.结果51.3%(20/39)的脑膜瘤组织中AR呈不同程度的表达.良性、非典型性、恶性脑膜瘤中AR表达率分别为31.6%(6/19)、58.3%(7/12)、87.5%(7/8).恶性脑膜瘤中AR阳性细胞数显著高于非典型性和良性脑膜瘤(P＜0.05).恶性脑膜瘤平均PCNA标记指数(PCNA U)明显高于非典型性(P＜0.05)和良性脑膜瘤(P＜0.05).AR阳性脑膜瘤的PCNA U高于AR阴性脑膜瘤(P＜0.05),AR表达与PCNA的表达呈正相关.结论脑膜瘤AR表达与其病理级别有关,AR参与了肿瘤的生长和血管生成;检测脑膜瘤中AR表达可间接反映肿瘤的增殖潜力.     

Ependymal and choroid plexus tumors. Cytokeratin and GFAP expression

Twenty-six ependymal and 15 choroid plexus tumors were examined with monoclonal antibody against cytokeratin using the avidin-biotin-peroxidase complex (ABC) technique. Serial sections were examined with antisera to glial fibrillary acidic protein (GFAP). In five ependymal tumors (one ependymoma, two papillary ependymomas, and two primitive neuroectodermal tumors [PNET] with ependymal cells), a variable number of cytokeratin-positive cells were present. Most tumor cells (except two PNET) were positive with GFAP antisera. Many cytokeratin-positive cells were present in all choroid plexus tumors. GFAP-positive cells were present focally in six of 11 papillomas and in one of four carcinomas. Although their staining patterns and distribution were clearly different, focal coexistence of cytokeratin and GFAP was observed in six papillomas and two ependymal tumors. Thus, some ependymal tumors (especially papillary ependymomas and occasional PNET) and many choroid plexus tumors have demonstrable positivity with antibody to cytokeratin, suggesting a transitional cell type with features of both ependyma and choroid plexus.     

S-phase fraction of human prostate adenocarcinoma studied with in vivo bromodeoxyuridine labeling

Forty-six patients with adenocarcinoma of the prostate were given an intravenous infusion of the thymidine analogue, bromodeoxyuridine (BrdU), 200 mg/m2, at the time of needle biopsy or transurethral resection to label tumor cells in the DNA synthesis phase. The tumor specimens were stained by an indirect immunoperoxidase method with anti-BrdU monoclonal antibody. The BrdU labeling index, S-phase fraction, was determined by counting the number of BrdU-labeled cells in the tissue sections. S-phase fraction correlates with the results of histologic tumor grade, Gleason score, and growth patterns. The higher S-phase fraction may indicate biologic malignancy. Moreover, the degree of heterogeneity concerning S-phase fraction distribution within prostate cancer tissue could be evaluated and the findings compared with the morphologic appearance. The authors results suggest that the measurement of BrdU labeling index in prostate cancer may prove to be a new objective and quantitative assay for biologic potential of individual tumors.     

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.     

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.     

Epidermal growth factor receptor status and S-phase fractions in gastric carcinoma

The correlation with epidermal growth factor (EGF) receptor expression and clinicopathologic findings were studied in 242 gastric carcinomas. They were stained for EGF receptor by means of an immunohistochemical technique using a monoclonal antibody against the receptor. S-Phase fractions were measured by in vivo bromodeoxyuridine (BrdU) labeling and indirect immunohistochemical staining using anti-BrdU monoclonal antibody. In normal gastric epithelium, EGF receptor immunoreactivity could not be found. EGF receptor was found in 76 (31.4%) of 242 gastric carcinomas. Diffusely infiltrating types of carcinomas were more likely than localized tumors to be EGF receptor-positive. In addition, EGF receptor-positive tumors had significantly higher values of BrdU labeling indices than EGF receptor-negative tumors. The patients with EGF receptor-positive carcinomas also had a poorer prognosis than did negative cases. These results suggested that EGF receptor-positive tumors may have higher proliferative activity and local extension may progress more rapidly, and also seem to show that EGF receptor status may possibly be a useful prognostic marker for gastric carcinomas.     

Fas Engagement Increases Expression of Interleukin-6 in Human Glioma Cells

The aim of this investigation was recognition of the epithelial differentiation and proliferative activity of ependymomas in the spinal cord compared with astrocytomas in the spinal cord and ependymoma in the brain. We investigated histopathological and immunohistochemical examination in thirty-five cases, including eleven ependymomas, thirteen astrocytomas in the spinal region and eleven ependymomas in the intracranial region. An anti-epithelial membrane antigen antibody (EMA), and two types of anti-cytokeratin antibodies, CAM 5.2 (45 and 52kDa) and keratin (56 and 64kDa) were applied as epithelial markers. The proliferative potential of the tumors was investigated using the Ki-67 labeling index (LI, %). Histologically, perivascular pseudorosettes were seen in all of the spinal and intracranial ependymomas. There were few ependymal structures in the spinal ependymomas except in the myxopapillary type. Immunohistochemical study demonstrated that nine (82%) were immunoreactive for EMA, eight (73%) were immunoreactive for CAM 5.2 and three (27%) were immunoreactive for keratin in the spinal ependymomas. In the spinal astrocytomas, no tumors were immunoreactive for EMA or CAM 5.2. One of thirteen cases was immunoreactive for keratin. The Ki-67 LI of the spinal ependymomas was lower than that of the intracranial ependymoma (p < 0.01). Epithelial differentiation was found in the ependymomas, which may reflect the differences in histological and biological features between ependymomas and astrocytomas in the spinal cord. Regional differences in ependymomas may influence not only clinical features but also histo-pathological characteristics.     

Radioimmunoassay of glioma-associated antigen in cerebrospinal fluid and its usefulness for the diagnosis and monitoring of human glioma

Summary Quantitative determination of human glioma-associated antigen in cerebrospinal fluids (CSFs) obtained from 66 patients with a variety of neurological diseases was performed by solid-phase radioimmunoassay with a monoclonal antibody (G-22). In this system, the minimum detectable amount of the antigen in the CSF was 8 ng/ml. It was demonstrated that CSF diagnosis of glioblastoma might be possible in the case of small tumors with a diameter of less than 2 cm. CSFs obtained from all 18 patients with glioma were positive and the level varied from 11.2 to 186.1 ng/ml. The antigen level in the cystic fluid of the tumor was higher than that in CSF. There was a tendency for the antigen level in CSF to be correlated with the tumor size and the type of histology. The malignant types of glioblastoma or medulloblastoma showed higher levels than the benign type of ependymoma and astrocytoma. Most types of non-gliomatous brain tumor were negative except immature teratoma, meningioma with central neurofibromatosis, and metastatic brain tumor from lung cancer. We also noted that tumor progression or regression of malignant glioma could be predicted by the monitoring of the antigen in the CSF.     

Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy

Purpose: To evaluate the effectiveness of complete resection and postoperative radiotherapy in spinal cord ependymomas. Methods and materials: We conducted a retrospective study over 20 patients (13 males and 7 females) with histologically confirmed spinal cord ependymomas between July 1985 and April 2001. Among them, 13 patients had ependymomas, 6 had myxopapillary ependymomas, and 1 had anaplastic ependymoma. All patients received radical surgery for tumor removal with 13 patients achieving complete resection and 7 incomplete resection due to technical difficulty. Among those with incomplete resection, 6 patients received postoperative radiotherapy to tumor bed and only one patient with anaplastic ependymoma received surgery alone. The total tumor dose ranged from 50 to 60 Gy. Results: Among the 20 patients, 19 patients were alive and showed local control. The median survival time of all patients was 109 months, with 104 months in the complete resection alone group and 135 months in the incomplete resection with postoperative radiotherapy group. One patient with anaplastic ependymoma and no postoperative radiotherapy developed leptomeningeal seeding 9 months after surgery. Salvage therapy of radiotherapy and chemotherapy maintained normal neurological functions. The patient expired 34 months from the initial diagnosis due to progression of leptomeningeal seeding. Conclusion: Complete resection alone in spinal cord ependymoma can achieve excellent local control and survival. Patients should receive complete resection if technically possible. Postoperative radiotherapy is not recommended for complete resection. For incomplete resection, postoperative local radiotherapy is recommended and it can also achieve excellent local control and survival. Local radiotherapy with 50-60 Gy is effective and safe. Salvage radiotherapy improves quality of life for local recurrence or leptomeningeal seeding patients.     

CDKN2A/p16 in ependymomas

Sixteen cases of ependymoma were studied for CDKN2A/p16 inactivation by immunohistochemistry using a p16 monoclonal antibody, by homozygous deletion (HD) assay and 5CpG promoter methylation assay (methylation-specific PCR). Three out of 16 cases were p16 immuno-negative: two corresponded to grade II ependymomas and one to grade III. The latter ependymoma, characterized by a high Ki-67/MIB-1 LI, was the only one of the whole series to show CDKN2A HD. No promoter methylation was found in the two immuno-negative cases without CDKN2A HD. Alternative mechanisms, such as point mutations or alterations in p16 post-translational regulation, may be responsible for p16 inactivation. Since in our series just one out of eight anaplastic cases showed negative immunostaining and CDKN2A HD, p16/CDKN2A inactivation may not play an important role in the malignant transformation of ependymomas.Amplification of CCND1 and CDK4, p27/Kip1 degradation and TP53 mutations were previously studied by other authors and were demonstrated not to correlate with anaplasia. Up to date, molecular genetic studies have not been useful in recognizing the anaplastic variant in ependymomas.     

A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo

Limited availability of in vitro and in vivo model systems has hampered efforts to understand tumor biology and test novel therapies for ependymoma, the third most common malignant brain tumor that occurs in children. To develop clinically relevant animal models of ependymoma, we directly injected a fresh surgical specimen from a 9-year-old patient into the right cerebrum of RAG2/severe complex immune deficiency (SCID) mice. All five mice receiving the initial transplantation of the patient tumor developed intracerebral xenografts, which have since been serially subtransplanted in vivo in mouse brains for 4 generations and can be cryopreserved for long-term maintenance of tumorigenicity. The xenograft tumors shared nearly identical histopathological features with the original tumors, harbored 8 structural chromosomal abnormalities as detected with spectral karyotyping, maintained gene expression profiles resembling that of the original patient tumor with the preservation of multiple key genetic abnormalities commonly found in human ependymomas, and contained a small population (<2.2%) of CD133⁺ stem cells that can form neurospheres and display multipotent capabilities in vitro. The permanent cell line (BXD-1425EPN), which was derived from a passage II xenograft tumor and has been passaged in vitro more than 70 times, expressed similar differentiation markers of the xenograft tumors, maintained identical chromosomal abnormalities, and formed tumors in the brains of SCID mice. In conclusion, direct injection of primary ependymoma tumor cells played an important role in the generation of a clinically relevant mouse model IC-1425EPN and a novel cell line, BXD-1425EPN. This cell line and model will facilitate the biological studies and preclinical drug screenings for pediatric ependymomas.     

Light microscopic demonstration of the microlumen of ependymoma: A study of the usefulness of antigen retrieval for epithelial membrane antigen (EMA) immunostaining

To determine the origin of dotlike epithelial membrane antigen (EMA) immunoreactivity of ependymoma, which is consistent with the eosinophilic globular body in hematoxylin and eosin (H&E) stain, an immuno-electron microscopic study was undertaken. The usefulness of antigen retrieval pretreatment in detecting the dotlike EMA immunoreactivity in ependymomas was also studied. The materials were 29 ependymomas, 7 autopsy brains as a normal control, and 50 brain tumors of various types. The study confirmed that most of the brown dots in EMA immunostain in ependymoma represented microlumina of tumor cells. In ependymomas, plain EMA immunostaining showed dotlike positivity in only six cases (21%), and antigen retrieval pretreatment increased the number of positives up to 26 cases (90%). Antigen retrieved CD99 detected 23 positive cases (80%) in ependymomas. On the basis of the results, although some false positive findings were raised by antigen retrieval pretreatment, the authors positively recommend adoption of the technique, especially when ependymoma remains as one of the differential diagnoses of the tumor.     

A case of cervicomedullary junction tanycytic ependymoma associated with marked cyst formation

Tanycytic ependymomas are a subtype of ependymomas that were formally recognized as a new pathological entity in the latest World Health Organization (WHO) classification of 2000. They occur mostly in the spinal cord. Only a few reports have analyzed the proliferative potentials of these tumors; however, it has been reported that the MIB-1 labeling index of tanycytic ependymoma is lower than that of other subtypes of WHO grade II ependymomas. We report a rare case of cervicomedullary junction tanycytic ependymoma associated with marked cyst formation. A 62-year-old man had a history of progressive gait disturbance, diplopia, and swallowing disturbance over a one-month period prior to admission. Magnetic resonance imaging (MRI) showed a cystic mass with a mural nodule at the cervicomedullary junction with Gd-DTPA enhancement. Cyst-subarachnoid shunt was performed using a far lateral approach. After 6 years, however, the man was readmitted to the hospital because of reaccumulation of the cyst. Partial removal of a mural nodule and a cyst-subarachnoid shunt were performed simultaneously by a midline suboccipital approach. The pathological diagnosis was tanycytic ependymoma. Postoperatively, the patient recovered well and was discharged from the hospital without further treatment. Most of the tumor cells had small, round nuclei; pleomorphism was minimal. The cytoplasm was dilated. The tumor cells were positive for EMA and s-100, and negative for CD-34. GFAP was not determined due to difficulty caused by background glial processes. The MIB-1 labeling index was less than 1%. Ultrastructurally, the tumor cells had ependymal cell features, such as desmosomes and microvilli. Based on these findings, the pathological diagnosis was tanycytic ependymoma.     

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.