Telomerase activity, TERT expression, hTERT promoter alterations, and alternative lengthening of the telomeres (ALT) in meningiomas - a systematic review.

Telomerase activity and (human) Telomerase Reverse Transcriptase (hTERT) expression are considered hallmarks in oncogenesis of neoplasms and are upregulated by alterations of the hTERT promoter. In meningiomas, numerous studies investigated hTERT expression, telomerase activity, promoter mutations, and methylations. Moreover, reports about hTERT-targeted chemotherapy in meningiomas have recently been published. We provide a systematic review of the literature about the role of hTERT in meningiomas. TERT expression and telomerase activity is found in benign and high-grade meningiomas and increase with WHO grade. Remarkably, rates of TERT expression/telomerase activity usually exceed mutation frequency and both telomerase activity and TERT expression have also been found in hTERT promoter wildtype meningiomas, indicating further mechanisms of TERT upregulation. Although hTERT promoter methylation has been reported in the vast majority of meningiomas, correlation with TERT expression remains controversial. Rates of promoter mutations, and methylation were shown to increase with rising WHO grade. Moreover, promoter methylation and mutations strongly correlate with prognosis. Although mutations predicted malignant progression, de novo mutations in high-grade recurrences of former benign lesions were also observed. Retroviral transduction of the TERT gene enabled immortalization in several grade I-III meningioma cell lines. In vitro analyses revealed significant effects on viability in hTERT-mutated meningioma cells after targeted treatment. Alternative mechanisms of telomere lengthening are usually absent in meningiomas. TERT and hTERT promoter alterations play a major role during oncogenesis of meningiomas with implications for prognosis and potentially treatment.

The rim pattern of meningioma on 3D FLAIR imaging: correlation with tumor-brain adhesion and histological grading.

PURPOSE: We evaluated the rim patterns of intracranial meningiomas on nonenhanced (NE) and contrast-enhanced (CE) 3-dimensional fluid-attenuated inversion recovery (3D FLAIR) imaging on 3-tesla magnetic resonance (MR) imaging to clarify the associated imaging and pathological findings and the value of the rims in predicting tumor cleavability. METHODS: Thirty-two patients with meningioma underwent tumor excision. We classified the rim patterns on 3D FLAIR, subdivided into "rim-NE," a rim with relatively low signal intensity on NE 3D FLAIR and "rim-CE," a rim with relatively high signal intensity on CE 3D FLAIR, into 4 grades by their extent from 0 (no rim visible) to 3 (rim visible over most of the tumor-brain interface) and correlated them with tumor size, grade of peritumoral brain edema, presence/absence of pial supply, grade of tumor-brain adhesion, and histological findings. RESULTS: On NE 3D FLAIR, "rim-NE" was graded 0 in 5 patients, one in 5, 2 in 6, and 3 in 16. On CE 3D FLAIR, "rim-CE" was graded 0 in one patient, one in 13, 2 in 4, and 3 in 14. The grade of "rim-NE" correlated negatively with the grade of brain edema (P = 0.023) and positively with surgical tumor-brain cleavability (P < 0.001). It also correlated with the amount of connective tissue at the tumor-brain interface histologically (P = 0.041). Furthermore, a lower grade of "rim-NE" was more often seen in atypical than benign meningioma (P = 0.003). Although "rim-CE" was more prominent in tumors with pial supply on digital subtraction angiography (DSA) (P = 0.002), it was not useful in predicting tumor-brain adhesion or histological tumor grading. CONCLUSION: The rim pattern of meningioma on NE 3D FLAIR can predict surgical cleavability and histological tumor grading. A higher grade of rim pattern on CE 3D FLAIR suggests prominent pial supply to the tumor but has no added value in predicting tumor-brain adhesion and histological tumor grading.

Secretory meningiomas: immunohistochemical pattern of lectin and ultrastructure of pseudopsammoma bodies.

Secretory meningioma is an infrequent histological subtype of benign, WHO grade I meningioma, that is characterized by focal epithelial and secretory transformation of meningothelial cells. The leading histopathological feature of neoplastic tissue is the presence of eosinophilic hyaline inclusions, defined as "pseudopsammoma bodies". These inclusions are mostly intracytoplasmic, different in size and often multiple. They are stained with periodic acid-Schiff (PAS) and are immunopositive for epithelial and secretory markers. The aim of this study was to determine the pattern of lectin bindings and ultrastructural features of secretory meningiomas. The examination was performed on 8 cases of secretory meningiomas that occurred in women and were mostly associated with prominent peritumoural oedema. Histologically, the tumours exhibited numerous eosinophilic, PAS positive pseudopsammoma bodies. Immunohistochemical studies revealed a strong, ring-like cytokeratin expression around the pseudopsammoma bodies. The inclusions were CEA and EMA positive but negative for vimentin. The immunolabeling with four lectins (PNA, SBA, Con A and DBA) was studied. The majority of pseudopsammoma bodies and surrounding tumour cells were strongly labelled with PNA and SBA. Immunolabelling with Con A showed irregular staining with high intensity in small inclusions. Immunostaining with DBA was seldom positive in inclusions and negative in the tumour cell cytoplasm. Ultrastructure of pseudopsammoma bodies exhibited advanced heterogeneity. The size of inclusions and the content of intracytoplasmic lumina varied greatly. Some pseudopsammoma bodies seemed to be located extracellularly and lacked the obvious lumina. Our ultrastructural study and lectin binding pattern support the unique epithelial and secretory transformation of neoplastic cells connected with their altered glycosylation.

A case of clear cell meningioma with tyrosine-rich crystals.

We present a case of clear cell meningioma with unusual clinical and pathologic features. The patient was a 54-year-old man who underwent laminectomy and durotomy for an intradural tumor in the lumbar spinal canal. Sections showed a predominance of dense collagenous tissue with irregularly shaped and irregularly sized magenta-colored extracellular deposits. On electron microscopy, these deposits were osmiophilic and "petaloid." The final diagnosis of clear cell meningioma rested on relatively inconspicuous intervening nests of glycogen-containing clear cells that were positive for epithelial membrane antigen. The unusual extracellular deposits seen in this case have previously been characterized as tyrosine-rich crystals of the type most commonly seen in salivary gland tumors. Recognition of this tumor as a clear cell meningioma, despite misleading clinical features and initially challenging histologic findings, is not only a matter of diagnostic accuracy but also imparts important prognostic information.

Ultrastructure of meningiomas: autophagy is involved in the pathogenesis of "intranuclear vacuoles".

We report here common ultrastructural findings in a short list of meningiomas. At the lower power magnification, a tumour consisted of elongated or round cells and innumerable cellular processes connected with diverse intercellular junctions. Nuclei presented no specific features, nucleoli were infrequently seen and heterochromatin was clumped beneath the nuclear membranes. In a case of clear cell meningioma, cells were of watery cytoplasm. Occasionally, immobile cilia, completely ensheathed by the cytoplasm and anchored by blepharoplasts were seen; as we did not encounter those rare cilia in cross-sections, no further insight into their inner microtubular-doublet structure was possible. The cytoplasm of the cells and the processes were filled with the intermediate filaments. In the intercellular space, collagen fibrils and electron-dense material was occasionally observed. The majority of the tumour samples were filled with processes. Several types of junctional complexes were observed. The most frequent were desmosomes and in the proper plane of section their whole pentalaminar structure was readily discernible. However, robust tonofilaments, as seen in epithelial neoplasms, were not observed. Those desmosomal junctions were either completely symmetric or asymmetric, but the exact symmetry could not be judged without the assistance of a goniometer. Some junctional complexes were more elaborate, with desmosomal junctions separated by a tight apposition of membranes, which suggests tight junctions. "Intranuclear vacuoles" well-visible even at low power were defined as indentation of the cytoplasm into the nucleus. Within these vacuoles, autophagic vacuoles and lysosomal bodies were seen, suggesting an active macroautophagy process. In 2 cases, severe lipidization of meningioma cell cytoplasm was observed. In a case of anaplastic meningioma, a mitotic figure was found. In another case, empty rectangular spaces in the cytoplasm, suggestive of pre-existing crystalloid structures, were seen.

Pediatric rhabdoid meningioma: a morphological, immunohistochemical, ultrastructural and molecular case study.

Rhabdoid meningioma is an uncommon meningioma variant categorized as WHO grade III. The majority of cases occur in adulthood. Herein, we describe a right fronto-temporal rhabdoid meningioma affecting a 3-year-old boy. The lesion measured approximately 4 cm in diameter and incorporated the ipsilateral middle cerebral artery. Sub-total surgical excision of the mass was performed. Histologically, the tumor was mainly composed of globoid plump cells with inclusion-like eosinophilic cytoplasm, peripheral nuclei, prominent nucleoli and occasional intra-nuclear cytoplasmic pseudo-inclusion. The cells appeared in many areas loosely arranged and focally disclosed a papillary architecture. At immunohistochemistry, the tumor cells were EMA, vimentin, HHF35, PgR, INI-1 and p53 positive. The proliferative index (Mib-1) was 15% in the most positive areas. Ultrastructurally, tumoral cells showed an abundant cytoplasm, which was filled with numerous intermediate filaments. Desmosomal junctions were seen. RT-PCR revealed the presence of NF2 gene expression. Molecular study did not indicate alterations of the INI-1 gene, whereas it showed the presence of Pro72Arg in exon 4 at heterozygous state in the TP53 gene. Morphologic features along with immunohistochemical, ultrastructural and molecular results were consistent with the diagnosis of rhabdoid meningioma. The patient was treated with chemotherapy. The lesion remained stable after 33 months of follow-up. Rhabdoid meningiomas rarely occur in children. Owing to its rarity, each new case should be recorded to produce a better clinical, pathological, molecular, prognostic and therapeutic characterization of this lesion.

[Extracranial meningioma: morphological and histogenetical aspects and relations with perineurioma].

The clinicomorphological, immunohistochemical, and ultrastructural characteristics of 11 cases of extracranial meningioma versus 79 soft tissue perineuriomas were studied. There were significant similarities (cell morphology, immunoprofile, ultrastructural features of perineurial differentiation) of both entities. Considering the point of view that arachnoid and perineurial cells are anatomically, embryologically, and functionally related, it is most possible that extracranial meningiomas may be derived from perineurial cells (or their progenitor cell) rather than from displaced arachnoid cells.

Ultrastructural profile of microcystic meningioma.

OBJECTIVE: Microcystic meningioma was originally classified as a subtype of meningioma by the World Health Organization classification of brain tumours in 1993, and accounts for 1.6% of intracranial meningiomas. This subtype is a variety of meningioma in which micro- and macro-cysts are diffuse. The morphologic characteristics are well defined, while the histogenetic mechanism that give rise to these patterns remain unclear. MATERIALS AND METHODS: The authors present an electron microscopic study of an unusual case of fronto-temporal microcystic meningioma, manifesting as history of headache, right paresis and dysphasia in a 73-year-old female. Computer tomography revealed a large hypodense mass in the left fronto-temporal region, with slight contrast enhancement. RESULTS: Ultrastructural observation showed complex alterations among small vessels and intratumoral capillaries in a background of severe modification in vessel permeability. CONCLUSIONS: This electronic microscopy study documented that growth of the cyst was due not only to accumulation of in extracellular fluid, but also to cytolysis consequent to ingravescent hydropic degeneration.

Secretory meningioma of the middle ear: a light microscopic, immunohistochemical and ultrastructural study of one case.

A 66-year-old woman was referred with left hearing loss. A probable diagnosis of left secretory otitis media with effusion was formulated. A left myringotomy was performed to remove hyperplastic hard tissue from the tympanic cavity. A high resolution CT scan of the temporal bone disclosed a soft-tissue mass completely involving the mastoid and tympanic cavity, surrounding the ossicular chain which appeared spared with no signs of infiltration. The histopathologic, immunohistochemical and ultrastructural response was secretory meningioma, a rare variant of conventional meningothelial meningioma in atypical sites.

Characterization of a novel type of adherens junction in meningiomas and the derived cell line HBL-52.

Adhering junctions are generally grouped into desmosomes and adherens junctions based on their ultrastructural appearance and molecular composition. The armadillo-protein plakoglobin is common to both types of junctions, which are otherwise composed of mutually exclusive proteins. This view is based on observations in epithelial tissues but cannot easily be transferred to other cell types and tissues, as has become apparent during the last decade with the identification of new junctional proteins and the investigation of further non-epithelial junctions. Using a broad array of well-characterized specific antibodies against key junctional proteins in immunoblot reactions, high-resolution double-label laser scanning confocal microscopy, and immunoelectron microscopy, we describe a new type of adherens junction in human meningiomas and the human meningioma cell line HBL-52. This novel junction has a unique composition of proteins not found in any other tissue; it contains the desmosomal armadillo-protein plakophilin 2 together with the classic proteins of "epithelial" adherens junctions, i.e., E-cadherin (in some instances replaced by N-cadherin), alpha-catenin, beta-catenin, plakoglobin, and p120(ctn). Ultrastructurally, it is formed between two or three neighboring cells. For pragmatic reasons, we suggest the name "meningeal junction" for this new structure.

Microcystic meningioma in a dolphin (Delphinus delphis): immunohistochemical and ultrastructural study.

A wild common dolphin was found stranded on the French Atlantic coast. At necropsy, an intracranial grey- to tan-coloured mass (7 x 5 x 4 cm) was found at the right cerebellopontine angle, compressing the right cerebellar hemisphere, the brainstem and the occipital lobe of the right cerebral hemisphere. Microscopically, the tumour was composed of small lobules of polygonal to elongated neoplastic cells with multifocal areas of stellate and vacuolated cells. Neoplastic cells strongly expressed vimentin, S-100 protein and neuron-specific enolase. They were rarely positive for cytokeratin. Ultrastructurally, the neoplastic cells displayed all the diagnostic features of meningiomas and in some areas showed long cytoplasmic processes delimiting extracellular spaces. The immunohistochemical and ultrastructural features were consistent with the histopathological diagnosis of a microcystic meningioma. This is the first report of a meningioma in dolphins or in any other cetacean species.

Primary extracranial meningioma of the pelvis: a light microscopic, immunohistochemical, and ultrastructural study.

BACKGROUND: Extracranial meningiomas are rare tumors which have been described in head and neck. The occurrence in mediastinum and retroperitoneum is even rarer. This presented case records a unique location, a meningioma arising in pelvis. CASE: A 52-year-old woman presented with an ovarian mass. The histology of the resected tumor revealed sheets of bland epithelioid cells arranged in prominent whorls with psammoma bodies typical of meningothelial meningioma. Immunohistochemical analysis demonstrated diffuse strong positivity for vimentin and epithelial membrane antigen (EMA). There was moderate reactivity for cytokeratin, estrogen (ER) and progesterone (PR) receptors. By electron microscopy, the tumor cells expressed desmosomes and abundant intermediate filaments. CONCLUSION: According to our review of literature, this is the first reported case of a primary pelvic meningioma. Its benign appearance and 4-year disease-free survival without clinical or radiological evidence of intracranial disease favors the pelvis as the primary site.

Dural invasion of meningioma: a histological and immunohistochemical study.

Meningioma usually grows and expands into the brain, but invasion into the brain parenchyma is relatively rare. Meningioma arises from arachnoid cap cells, and infiltration into dura mater is the main growth pattern of meningiomas. However, little is known about the mechanism of meningioma invasion into the dura mater. In this study, seven specimens, including dural attachments, from seven cases of meningioma were used for immunohistochemical analysis. Matrix metalloproteinase (MMP)-1, -2, -9, urokinase-type plasminogen activator (uPA), vascular endothelial growth factors (VEGF), flt-1, E-cadherin, estrogen receptor (EgR), progesterone receptor (PgR), and aquaporin (AQP)-1, -4 were used as primary antibodies. There were several patterns of meningioma invasion into the dura mater: papillary-shaped invasion with destruction of dural structure, infiltration along the fibers of the dura mater, and invasion of several tumor cell units with fibroblast infiltration. Strong immunostaining was obtained with MMP-1, followed by AQP-1 and uPA, within the invading tumor cells. Neovasculature and extravasated erythrocytes, which stained with AQP-1, were also occasionally observed around the invading tumor cells. Simpson grade II removal of meningiomas results in high recurrence rates, and the inhibition of meningioma growth via dural invasion will facilitate improved remission in many cases with meningioma. In this study, MMP-1, AQP-1, and uPA are considered to have some role in the dural infiltration of meningioma cells. The fact that AQP-1 was highly expressed at the dural attachment and invading front of meningioma may indicate that dural invasion of the meningioma may be facilitated by AQP-1-induced water flow and neovascularization.

Intracerebral schwannoma clinically and radiologically mimicking meningioma.

A case of intracerebral schwannoma (ICS) occurring in a 33-year-old woman is presented. The patient's history of headache, numbness, tingling and the recent development of weakness of the right upper extremity with right facial droop began during pregnancy. Magnetic resonance imaging (MRI) showed a 4 x 2 x 2 cm heterogeneous, gadolinium-enhanced mass at the left frontoparietal junction, with peritumoral edema and a dural-based attachment. During her pregnancy, the mass increased in size. The surgically resected specimen consisted of lobulated, somewhat gelatinous soft tissue. Microscopically, the tumor demonstrated classic biphasic Antoni type A and B patterns, admixed with degenerative changes. Immunohistochemically, the neoplastic cells were positive for S-100 protein (diffuse and strong), CD34 (primarily in Antoni B areas), glial fibrillary acidic protein (GFAP; weak and diffuse) and calretinin (mainly in Antoni A areas), while none was positive for CD31, estrogen and progesterone receptors, bcl-2, or epithelial membrane antigen (EMA). Ultrastructurally, basal laminae and Luse bodies were identified. The differential diagnosis includes fibrous meningioma, solitary fibrous tumor, and ICS. Twenty-seven cases of ICS were reviewed in which the histological diagnosis was confirmed immunohistochemically or ultrastructually, and the cases were summarized (including the present case). A combined use of immunostains (S-100 protein, EMA, CD34, and maybe calretinin) is of great help in distinguishing ICS from its histological mimickers.