Malignancy In Meningiomas Research Articles

The hTERT protein as a marker for malignancy in meningiomas.

The meningioma evolution remains problematic as 6 to 19% relapse after total resection. We have no criterion or marker to predict with certainty the tumour behaviour, and the WHO grading system is to a certain degree controversial. Telomerase expression seems to play an active role in conferring to the tumour cell indefinite life span. Telomerase activity has been documented via TRAP protocol and telomerase messenger expression (hTERT mRNA). In meningiomas the protein hTERT itself has not been studied directly. Thirty tumour samples of meningiomas operated in our Neurosurgical Department are reviewed with a mean follow-up of 4 years. Specifically hTERT protein, resection type, proliferation markers (Ki-67), and recurrences are evaluated. MRI is used for recurrence controls. Seven samples appeared to be hTERT-positive and all seven showed recurrence. Four patients had undergone a subtotal resection (STR). Among them two were hTERT-positive; only these showed recurrence and malignancy. Of the five macroscopically total resections (MTR), two were initially histologically benign and progressed to malignancy. A strong correlation was found between hTERT and recurrences (coefficient=0.989; p=0,01) with the Spearman's rho test, and weaker one between the Ki-67 and hTER (coefficient=0.672; p<0.0001). The hTERT staining revealed the presence of the hTERT protein not only in their nucleoli but sometime outside as nuclear speckles. The presence of nucleolar or subnuclear hTERT is directly correlated to recurrence and progression towards malignancy. Relocalisation of this protein was confirmed. A distinction is proposed between regrowth, based on normal proliferation (Ki-67) which can accompany subtotal resection and recurrence. Recurrence appears to be pathologic proliferation linked to hTERT presence. The hTERT presence predicts a sombre clinical outcome at mid-term for the individual patient.

Expression of E‐cadherin and catenins in meningioma: Ubiquitous expression and its irrelevance to malignancy

The expression of cell adhesion molecules in 107 meningiomas was analyzed with immunohistochemical methods using antibodies to epithelial (E)-cadherin and catenins (alpha, beta and gamma). According to the provided World Health Organization (WHO) grading, 84, 18 and five cases were classified as grade I, II and III, respectively. In addition, hemangioblastoma (15 cases) and hemangiopericytoma (four cases) were also evaluated. In most meningiomas, E-cadherin, alpha- and beta-catenins were expressed along the cell membrane or inside the cytoplasm. The tumor cells constituting whorls and glandular structures of secretory type showed a strong immunoreactivity. gamma-Catenin expression tended to be weak and infrequent in fibrous meningiomas, while other types exhibited diffuse stainings. Even in meningiomas of more than grade II, the expressions of cell adhesion molecules were detected in all cases. Hemangiopericytoma was positive for alpha- and beta-catenins, and hemangioblastomas were positive for beta-catenin alone, which was distinct from the expression pattern in meningiomas. Quantitatively, there were no correlations between the histological variants, Ki-67 indexes, or grades of meningiomas and the immunoreactive scores except for gamma-catenin scores of fibrous meningiomas. The present study demonstrates that cell adhesion molecules are ubiquitously expressed in all variants of meningioma and may be involved in the tumor morphogenesis. This result suggests that the expression of cell adhesion molecules is not a reliable indicator of malignancy in meningiomas. The present study also suggests that these markers may be useful for the differential diagnosis of meningioma.

The expression of tissue factor correlates with proliferative ability in meningioma

Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the extrinsic pathway of coagulation; this is inhibited by tissue factor pathway inhibitor (TFPI). As TF reportedly regulates tumor growth and angiogenesis, we investigated the role of TF in meningioma. Using immunohistochemical methods, we studied the expression of TF, TFPI, MIB-1 labeling index in 44 meningiomas to determine whether those factors reflect histological grade and proliferative ability. CD31 and CD68 immunostaining was used to assess vascular density and macrophage infiltration, respectively. Additionally we assessed the influence of TF on meningioma cell proliferation by MTT assay. TF was expressed in 1 of 34 (2.9%) benign, 1 of 5 (20%) atypical, and all of 5 anaplastic meningiomas. TFPI was detected in 2 benign (5.9%), 1 atypical (20%), and 3 (60%) anaplastic meningiomas. Both TF and TFPI expression was significantly correlated with the MIB-1 labeling index (LI). However, neither TF nor TFPI showed a correlation with vascular density. The density of tumor-associated macrophages was not correlated with TF or TFPI immunoreactivity. MTT assay revealed that TF increased the proliferation of meningioma cells. Although some macrophages expressed TF, a great number of the TF immunopositive parenchymal cells in the meningiomas were tumor cells. The present study suggest that the TF system reflects the proliferative ability and malignancy of meningiomas.

Malignant Meningioma - Clinicopathological Study of an Unusual Presentation of a Rare Malignancy.

Malignancy in meningiomas is rare and very rapid extracranial metastasis to the cervical and abdominal lymphnodes is even rarer. Presently the aggressive or malignant phenotype of meningiomas are difficult to characterize due to broad spectrum of behaviour exhibited by meningiomas. In practical use, the diagnosis of malignant meningioma is reserved for those tumours displaying histologic evidence of brain invasion or evidence of distant metastasis, features that are not easily assessed. Traditionally, pathologists are reluctant to classify meningiomas as malignant unless definite brain invasion is present. Less than 1% of all meningiomas and less than one third of those designated as malignant, metastasize and would by definition need vascular invasion, occult or primary, to accomplish distant spread. A very unusual case is presented who was operated as a case of typical meningioma, was reported histologically as malignant meningioma and developed very rapid, wide spread metastasis to all lymph nodes and lungs in the immediate postoperative period.

Involvement of disregulated c-myc but not c-sis/PDGF in atypical and anaplastic meningiomas

We investigated the expression of c-myc and c-sis/PDGF mRNA and protein products in 20 cases of meningiomas of various grades: 10 benign, 5 atypical and 5 anaplastic meningiomas. All cases of atypical and anaplastic meningiomas were positive for c-myc protein and mRNA by immunohistochemistry and in situ hybridisation, respectively, while all 10 benign meningiomas were negative for c-myc immunostaining, with only one benign tumour positive for c-myc mRNA. Expression of PDGF-BB protein and c-sis mRNA were seen in more than 80% of the meningioma cases and was not restricted to the histological grades of meningiomas. Semiquantitive analysis showed that the frequency of c-myc immunopositive cells positively correlated with Ki-67 proliferative indices. Our findings suggest that c-myc, but not c-sis/PDGF, has some concern to the malignancy of meningiomas.

Transformação sarcomatosa em meningeoma: Relato de caso e revisão da literatura

ResumoOs autores relatam o caso de paciente de 40 anos, raça amarela, sexo masculino, que apresentou história arrastada de déficit de força em hemicorpo direito com predomínio em membro inferior direito, cujo diagnóstico de imagem (tomografia computadorizada de crânio e ressonância magnética) revelou tratar-se de neoplasia parassagital esquerda com características semelhantes às de um meningeoma. Foi submetido à cirurgia com ressecção radical, incluindo o seio sagital invadido, com boa evolução no pós-operatório. O diagnóstico anatomopatológico foi de meningeoma com transformação sarcomatosa (meningeossarcoma/sarcoma meníngeo). Foi submetido à radioterapia e o seguimento de 8 meses não evidenciou recidiva.A transformação sarcomatosa é rara e infere um prognóstico reservado. Os autores discutem a doença e procuram identificar semelhanças e diferenças clínicas e radiológicas com as principais neoplasias do sistema nervoso central derivadas de células meningoteliais e de hemangiopericitos.

Telomerase activity and expression of the telomerase catalytic subunit, hTERT, in meningioma progression.

In recent reports, 6 to 19% of meningiomas have been classified as atypical or anaplastic/malignant. Some atypical and anaplastic meningiomas appear to arise from benign tumors by progression. Telomerase activation has recently been associated with malignant progression of human tumors. The authors have investigated a series of benign, atypical, and anaplastic/malignant meningiomas for telomerase activity and expression of the telomerase catalytic subunit human telomerase reverse transcriptase (hTERT). A quantitative telomeric repeat amplification protocol was used to detect telomerase enzyme activity in seven (21%) of 34 benign, but in nine (75%) of 12 atypical and in seven (100%) of seven anaplastic/malignant meningiomas. Very high levels of telomerase activity were observed only in highly aggressive tumors. Messenger (m)RNA expression of the catalytic subunit hTERT was found in 11 (33%) of 33 benign, 12 (92%) of 13 atypical, and all seven anaplastic/malignant tumors. All telomerase-positive lesions were also positive for hTERT mRNA, whereas no telomerase activity was detected in six (21%) of 29 hTERT-positive tumors. This indicates that upregulation of hTERT is the rate-limiting step for telomerase activation in the majority of meningiomas. Expression of telomerase and hTERT was seen in all four tumors with gross brain invasion. All recurrent tumors or meningiomas recurring during follow up expressed hTERT. The results are consistent with a role for telomerase activation during the development of malignancy in meningiomas. Hence, expression of telomerase activity and hTERT might prove to be potentially useful markers for the evaluation of these tumors.

"Malignancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications.

Due to the rarity of malignancy in meningiomas, prior studies have been limited to small series. Controversies regarding the definition of malignant meningioma have complicated matters further. Although histologic anaplasia and extracranial metastasis are established criteria, the former is difficult to define and the latter represents a clinical finding. Traditionally, brain invasion has also been accepted, although this has recently been debated. In a prior series, the authors were unable to prove that 23 meningiomas that had invaded the brain were more aggressive than atypical meningiomas. The authors expanded their analysis to include 116 patients diagnosed with "malignant meningioma" due to brain invasion, frank anaplasia (20 mitoses per 10 high-power fields or histology resembling carcinoma, sarcoma, or melanoma), and/or extracranial metastasis. Patients were followed until death or for a median of 3.7 years. Survival time was highly variable, ranging from 10 days to 24 years. In multivariate analysis, histologic anaplasia (P=0.0035), subtotal resection (P=0.0038), 20 mitoses per 10 high-power fields (P=0.0071), and nuclear atypia (P=0.0068) were associated with poor survival. Of the 89 cases of meningioma that had invaded the brain, 23% were otherwise benign, 61% were otherwise atypical, and 17% were frankly anaplastic. Those without anaplasia behaved similarly to atypical meningiomas from the authors' prior study. In contrast, anaplastic meningiomas were usually fatal, associated with a median survival of 1.5 years. Based on these findings, the authors suggest that brain invasion constitutes an additional criterion for the diagnosis of atypical meningioma (World Health Organization [WHO] Grade II), whereas frank anaplasia indicates high grade (WHO Grade III-IV) malignancy.

“Malignancy” in meningiomas

BACKGROUND Due to the rarity of malignancy in meningiomas, prior studies have been limited to small series. Controversies regarding the definition of malignant meningioma have complicated matters further. Although histologic anaplasia and extracranial metastasis are established criteria, the former is difficult to define and the latter represents a clinical finding. Traditionally, brain invasion has also been accepted, although this has recently been debated. In a prior series, the authors were unable to prove that 23 meningiomas that had invaded the brain were more aggressive than atypical meningiomas. METHODS The authors expanded their analysis to include 116 patients diagnosed with “malignant meningioma” due to brain invasion, frank anaplasia (20 mitoses per 10 high-power fields or histology resembling carcinoma, sarcoma, or melanoma), and/or extracranial metastasis. Patients were followed until death or for a median of 3.7 years. RESULTS Survival time was highly variable, ranging from 10 days to 24 years. In multivariate analysis, histologic anaplasia (P = 0.0035), subtotal resection (P = 0.0038), 20 mitoses per 10 high-power fields (P = 0.0071), and nuclear atypia (P = 0.0068) were associated with poor survival. Of the 89 cases of meningioma that had invaded the brain, 23% were otherwise benign, 61% were otherwise atypical, and 17% were frankly anaplastic. Those without anaplasia behaved similarly to atypical meningiomas from the authors' prior study. In contrast, anaplastic meningiomas were usually fatal, associated with a median survival of 1.5 years. CONCLUSIONS Based on these findings, the authors suggest that brain invasion constitutes an additional criterion for the diagnosis of atypical meningioma (World Health Organization [WHO] Grade II), whereas frank anaplasia indicates high grade (WHO Grade III–IV) malignancy. Cancer 1999;85:2046–56. © 1999 American Cancer Society.

Role of genomic instability in meningioma progression.

Microsatellite length instability, probably resulting from defective DNA mismatch repair mechanisms, has been described in a variety of cancers. Such genetic instability may play a significant role in tumor formation and progression. To investigate the role of microsatellite alterations in meningioma tumorigenesis and progression, we examined 33 microsatellite markers on nine chromosomes for abnormalities in 18 benign, 15 atypical, and 11 malignant meningiomas. In each tumor, at least 15 markers were investigated. Microsatellite instability was not detected in any of the cases examined. However, loss of heterozygosity for markers from various chromosomes was seen frequently among atypical and malignant meningiomas. Although some of these chromosomal losses might represent random events, our data also indicate a role for specific loci on chromosome arms 14q, 1p, 10q, and possibly 9p in the development of malignancy in meningiomas. Our results argue against a significant role for a generalized microsatellite instability phenotype in meningiomas, but they suggest that genomic instability resulting in frequent allelic deletions may contribute to meningioma progression.

The significance of atypical mitoses in malignant meningiomas.

A group of 5 selected malignant meningiomas was studied in relation to the incidence and morphology of the mitoses. Beside a high mitotic rate many structural chromosomal abnormalities were observed. In agreement with other malignant onco-types previously studied, the authors suggest that atypical mitoses together with a tissue and cytological undifferentiation may be assumed to be an important prognostic criterium for meningiomas. The problem of malignancy in meningiomas has not been, so far, satisfactorily resolved, so that, in our opinion, the definition of even minimal details may be of some interest. For example, as it clearly appears from reviewing the literature on this sugject, no particular attention has been paid to the mitotic features. Referring to previous studies on the mitotic abnormalities in different malignant cerebral onco-types, the authors aimed to examine the various mitotic aspects in a limited group of tumors selected on the basis of clinical and histological malignancy.