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    A Review of the Histologic, Genetic and Molecular Characteristics of Meningioma Pathogenesis and Progression

    Adrian Maurer 1       Jacob Archer 1     Sam Safavi-Abbasi 1     Michael Sughrue 1    

    1Department of Neurosurgery, University of Oklahoma, Oklahoma City, Oklahoma, USA

    Abstract

    Meningiomas are the most common intracranial tumor in humans. The heterogeneity of these tumors lends difficulty to the genetic, epigenetic, and molecular changes that occur in meningioma pathogenesis, progression, and recurrence. Current de facto classification schemes are based on histologic evaluation of tumor specimens and do not consider molecular markers or other newer modalities. In this paper, we review the major genetic, epigenetic, and molecular changes that have been associated with the oncogenesis and progression of meningiomas. We pay special attention to those changes associated with recurrence and higher grade tumors. Finally, we comment on the challenges and potential for future therapies of these tumors.

    ReceivedAccepted 10 Nov 2015; Published 24 Dec 2013; 11 Aug 2017;

    Academic Editor:Runjan Chetty1,

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright©  2017 Adrian Maurer, et al

    License
    Creative Commons License    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    The authors have declared that no competing interests exist.

    Citation:

    Adrian Maurer, Jacob Archer, Sam Safavi-Abbasi, Michael Sughrue (2013) A Review of the Histologic, Genetic and Molecular Characteristics of Meningioma Pathogenesis and Progression. Journal Of Cancer Genetics And Biomarkers - 1(2):24-38.
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    DOI10.14302/issn.2572-3030.jcgb-14-383

    Introduction

    Meningiomas are the most commonprimary intracranial neoplasm, comprising 35.8% of CNS tumors. The annual incidence of these tumors is 7.44 cases per 100,000 persons; the incidence increases with age, increasing dramatically after age 651. Females are more than twice as likely to develop a meningioma than males2. Though they are typically slow-growing and non-invasive, meningiomas commonly compress adjacent structures, causing neurologic signs and symptoms which often lead to patients seeking treatment. Risk of recurrence is increased with younger age at diagnosis, subtotal resection, increasing histologic grade, specific histologic subtypes, high proliferative index, and brain infiltration2, 3, 4.

    The neoplastic origin is thought to be of arachnoid cap cells from the outermost layer of the arachnoid. This is based on observation of functional and cytologic similarities between these and meningioma cells, especially considering the changes arachnoid cap cells undergo with age: i.e., increased clusters forming whorls and psammoma bodies, identical to histologic findings in meningioma specimens5, 6. The current WHO grading scheme classifies the tumors as Grade I (benign, approx. 80%), Grade II (atypical, 15-20%), or Grade III (malignant/anaplastic, 1-3%)7, 6, 8, 9, 10, 11, 12. Grade II and III meningiomas are significantly more aggressive locally; dissemination is rare, although some studies have found evidence of tumor cells in areas of normal dura away from the tumor mass, as well as cases of multiple meningiomas in which all resected tumors from the same patient displayed identical NF2 mutations13, 14, 15.

    There have been several models proposed to understand the pathogenesis of meningiomas. The WHO grading scheme utilizes histologic subclassification16. Meningiomas have also been classified on an anatomic basis, correlated by location with prognosis and histologic grade (i.e., non-skull-base meningiomas are at increased risk of higher WHO grade versus skull-base meningiomas)17, 18. However, this may be an epiphenomenon, as the location of the tumor significantly influences the extent of resection, which in turn influences the risk of recurrence19.

    Histologic Classification of Meningiomas

    There are nine Grade I subtypes, three Grade II subtypes, and three Grade III subtypes in the WHO grading scale, most recently revised in 2007 (Table 1)16. Although genetic and immunohistochemical (IHC) markers have been increasingly employed in the evaluation of meningiomas, grading of meningiomas is based entirely on conventional histologic criteria as defined by the WHO12, 20, 21.

    WHO Grade I Meningiomas

    As many as 80% of all meningiomas are slow-growing benign tumors of WHO grade I22. The nine WHO Grade I meningioma subtypes are considered benign; for these lesions there is a greater than 2:1 female predilection23. Although these tumors may be managed in a variety of ways depending on location, symptoms, and patient’s age and wishes, gross total resection (GTR) of Grade I tumors is usually curative. One series demonstrated a 9.8% 10-year retreatment rate (repeat surgery, of benign meningiomas for all resection grades. Additionally, although traditionally the extent of resection of meningiomas has been considered the primary predictor of recurrence4, some authors have demonstrated that the risk of recurrence does not differ between Simpson Grade I-III grades24, 25.

    Table 1. WHO GRADE SUBTYPES
    TABLE 1— WHO GRADE SUBTYPES
    SUBTYPE HISTOLOGIC FEATURES
    GRADE I
    Meningothelial Arachnoid-like cells in lobules surrounded by collagenous septae, intralobular pseudosyncytial arrangement; intranuclear clear spaces with eosinophilic pseudoinclusions
    Fibrous/fibroblastic Fibroblast-like cells with elongated nuclei forming intersecting fascicles; collagen- and reticulin-rich matrix
    Transitional/mixed Combination of meningothelial and fibrous features; extensive concentric whorls and psammoma bodies
    Psammomatous Predominant psammoma bodies; extensive calcification or possible ossification
    Angiomatous Greater than 50% of the tumor volume occupied by blood vessels of diverse appearance; vasculature greatly hyalinized; tumor cells demonstrate degenerative nuclear changes
    Microcystic Thin elongated cell processes and mucinous matrix; resemble arachnoidal trabecular cells; pleomorphic cells common
    Secretory Gland-like intracellular spaces filled with PAS-positive inclusions (pseudopsamtnoma bodies); inclusions also demonstrate CEA, epithelial, and secretory marker immunoreactivity; mast and histiocytic cells relatively common
    Lymphoplasmacyte - rich Prominent inflammatory infiltrate; rare
    Metaplastic Variable mesenchymal differentiation (bony, cartilaginous, fat, and xanthomatous tissue elements); rare
    GRADE II
    Chordoid Regions of eosinophilic cellular trabeculae with vacuolated cytoplasm in myxoid background, interspersed with tissue with meningothelial appearance
    Clear cell Glycogen-rich cytoplasm; typically lack whorl pattern
    Atypical Tumors which do not fall into another category but have 4 mitotic figures per HPF OR 3 of the following:- Patternless growth- Hypercellularity- Small cell foci with high N:C ratio- Prominent nucleoli- Necrotic fociAdditionally, tumor histology consistent with a Grade I subtype are considered Grade II if brain invasion is evident (WHO 2007)
    GRADE III
    Papillary Perivascular psudopapillary pattern (clearly visualized with CD34 immunohistochemical staining); commonly demonstrate brain invasion
    Rhabdoid Cytoplasmic eosinophilic inclusions consisting of intermediate filaments; frequently have high proliferative index.
    Anaplastic Tumors which do not clearly fall into another category, but demonstrate cytologic features of frank malignancy, or ?20 mitotic figures/HPF.

    Abbreviations: PAS = periodic acid-Schiff;
    CEA = carcinoembryonic antigen;
    HPF = high-powered field;
    N:C ratio = nucleus:cytoplasmic ratio; Tab
    WHO = World Health Organization

    WHO Grade II Meningiomas

    Since the WHO revised the diagnostic criteria of Grade II meningiomas in 2000 and 2007, there has been a significant increase in atypical meningioma diagnosis26. Tumors classified as Grade II now comprise 10-30% of all meningiomas11. Grade II meningiomas behave more aggressively than Grade I tumors, and have a high rate of recurrence (41% at 5 years)3, 27. For instance, in chordoid meningiomas, subtotal resection has been shown to be an invariable predictor of recurrence, even up to 16 years postoperatively28.

    WHO Grade III Meningiomas

    Meningiomas classified as WHO Grade III are considered anaplastic/malignant and are further differentiated into three subtypes (Table 1). Papillary meningiomas are more common in younger patients and frequently recur; they can metastasize within the subarachnoid space or even outside of the CNS29, 30, 31.

    The Prognostic Importance of WHO Grading – is it becoming Less Relevant?

    Although molecular and genetic studies of meningiomas are being increasingly used to characterize these tumors, the standard classification scheme remains the WHO grading scale. As tumor grade increases, the recurrence rate increases and prognosis of the patient markedly decreases; the ten-year survival rate for Grade III tumors is 14.2%32, 33. However, even benign meningiomas may still recur following Simpson Grade I resection4, 24, 25, 33, 34. Therefore, timely definitive diagnosis of the tumor and determination of its specific characteristics is paramount to the patient’s well-being. Some have suggested the use of MIB-1 labeling indices as a key to predict recurrence35. Although the WHO grading scale has recently been revised (in 2000 and 2007) to standardize the diagnostic criteria for each grade, like any subjective scale it is susceptible to sampling error and inter-user variability36, 37. Additionally, some tumors vary in aggressiveness from the norm, within the spectrum of each grade35, 38. Multiple studies have also shown that tumor location (i.e., non-skull base vs. skull base) is a significant factor in tumor grade and malignant potential at both diagnosis and recurrence17, 19, 35, 39. Adjuvant radiation modalities, including stereotactic radiosurgery, have been shown to be effective in arresting the growth of intracranial meningiomas, including those tumors arising from difficult-to-access skull base locations, with minimal morbidity40, 41, 42, 43, 44, 45, 46, 47, 48. At any rate, the WHO classification scheme does not always accurately predict the behavior of these lesions, and some authors have called for new schemes based in part on molecular markers and/or cytogenetic evaluation of the tumor38, 49, 50. Indeed, a great deal of recent investigation in the genetic and epigenetic changes of these tumors has begun to clarify the complex heterogeneity of meningioma pathogenesis and progression6, 20, 51.

    Genetic Changes in Meningioma Pathogenesis and Progression

    Although many genes have been implicated in the pathogenesis of meningiomas, a clear understanding of the specific, stepwise genetic changes required for meningiomas to develop and progress has not been elucidated. In benign tumors, loss of heterozygosity of chromosome 22 is a common finding, but other mutations are rarely found52, 53. Meningiomas with higher grade have more complex karyotypes, but there is a great deal of heterogeneity among tumors of the same grade. Chromosomal losses on 1p, 6q, 9p, 10q, 14q, and 18q, as well as gains on 1q, 9q, 12q, 15q, 17q, and 20q, have been identified in this subset of meningiomas53, 54, 55, 56. Here we review the major known genetic aberrations in meningiomas, in light of the associations with the WHO grading scale.

    Loss of Heterozygosity of Chromosome 22 and the Merlin Protein

    Loss of heterozygosity (LOH) of chromosome 22 is the most frequent abnormality in all meningioma types; it is always found in meningiomas occurring in patients with neurofibromatosis 2 (NF2) gene mutations16, 20, 57, 58, 59, 60. Loss of NF2 expression is variable within the most common WHO Grade I subtypes, with mutations occurring in fibroblastic (70%) and transitional (83%) types far more frequently than in meningothelial (25%) types61. Inactivation of NF2 in grade II and III meningiomas is present in about 70% of cases, suggesting that the loss of the gene is a common event of tumorigenesis rather than malignant progression62, 63, 64.

    The NF2 gene is located on 22q12.2, encoding a tumor suppressor protein called schwannomin or merlin (moesin, ezrin, radixin-like protein)65, 66. This 70-kDa protein is part of the 4.1 superfamily of cystoskeletal proteins, linking actin cytoskeleton to plasma membrane proteins. Merlin contains three domains, including the N-terminal FERM domain, which interacts with other cytoskeletal regulators, including other ERM proteins67, 68.

    Proposed functions of the merlin product includes contact-mediated growth inhibition and secondary signaling pathways64, 66, 67, 69, 70, 71, 72. Various NF2 gene mutations have been found in up to 60% of meningiomas, including small insertions, nonsense mutations, deletions affecting splicing sites, or terminal deletions of the NF2 sequence73, 74; these mutations result in an inactive form of merlin which has been shown to aid tumorigenesis through decreased cell adhesion and dysregulation of several pathways, including the Ras and Hippo pathways75, 76, 77.

    Merlin has also been demonstrated to regulate contact inhibition of growth through a complex with other 4.1 superfamily proteins and CD4472. It has been suggested that the merlin-ERM-CD44 interaction forms a molecular “switch”: in a phosphorylated state the merlin protein interacts with ezrin, moesin, radixin, and CD44 to promote growth in the absence of cell/matrix contact. Once contact is achieved, the complex reconfigures without the ERM proteins and results in cellular arrest71.

    Recently, merlin has been proposed to interact with as-yet unspecified membrane proteins, resulting in signal transduction that phosphorylates LATS1/2. LATS1/2 inhibits a downstream effector of the Hippo pathway called Yes-associated peptide (YAP). When the expression of merlin is reduced, YAP is upregulated which results in cellular hyperplasia, delayed cell-cycle exit, apoptosis inhibition, and enhanced cell survival77.

    DAL-1 (4.1B) and 4.1R

    The DAL-1 gene on the 18p11.3 locus encodes another member of the 4.1 superfamily (namely, protein 4.1B); the loss of expression of this gene has been demonstrated in up to 76% of Grade II and 87% of Grade III lesions and has also been associated with familial meningiomas. Although originally thought to be part of early tumorigenesis, the loss of the DAL-1 gene product has more recently been implicated in meningioma progression78, 79, 80. The gene for a third 4.1 superfamily protein, 4.1R, is located at 1p36; it is also lost in up to 40% of meningiomas Overexpression of this protein in vitro has been shown to reduce cellular proliferation81, 82, 83.

    Collectively, this data suggests a critical role of the protein 4.1 superfamily of cytoskeletal in the formation and progression of meningiomas, although the exact mechanisms have yet to be defined.

    1p and 14q aberrations and elusive tumor suppressor candidates

    Losses on 1p and 14q are the next most common mutations after LOH of 22q, and these aberrations have been independently correlated with increased tumor grade and increased recurrence rate54, 55, 84, 85, 86, 87, 88, 89, 90, 91. Several candidates genes on 1p (including CDKN2C, p18, ALPL, RAD54 L, p73, and EPB41) have been identified, but further analysis has failed to find mutations or polymorphisms of these genes92, 93, 94, 95, 96.

    Loss of Expression of NDRG3 and MEG3 is Associated with Aggressive Tumor Phenotype

    Potential tumor suppressor genes on 14q include NDRG3 at 14q11.2 and MEG3 at 14q3288. Inactivation of the NDRG2 gene has been shown to be a frequent feature in Grade III meningiomas as well as in a subset of Grade II tumors with clinically aggressive behavior88. However, the precise role of NDRG2 in the progression of meningiomas remains unknown. Recently, a study evaluating the role of the MEG3 gene has suggested an important role in the progression of these tumors97. The MEG3 transcript is a non-coding RNA with anti-proliferative functionality; it is readily expressed in normal arachnoidal cells, but loss of expression was common in both human meningioma specimens and two established human meningioma cell lines. The degree of expressional loss/prevalence of allelic loss in human specimens was also correlated with increasing tumor grade.

    The 9p21 Locus Contains Three Cell-Cycle Regulatory Genes

    Losses of 9p have been proportionately associated with increasing tumor grade; tumor suppressor genes implicated include CDK2NA/P16INKa, p14ARF, and CDK2NB/p15ARF, all found at the 9p21 locus6, 20, 56, 92, 98. The products of these genes are associated with regulation of the G1/S-phase cell cycle checkpoint.

    CDK2NA/CDK2NB

    The CDK2NA gene alternate reading frame product p14ARF interacts with the p53 pathway via the inhibition of mouse double homolog 2 (MDM2), which allows promotion of p53 to regulate the G1-S-phase checkpoint. Several studies have suggested that inactivation of the CDK2NA gene through various mechanisms (homozygous deletions, hypermethylation) is an important factor in the tumorigenesis and progression of higher-grade meningiomas98, 99, 100, 101.

    Epigenetic mechanisms such as hypermethylation of genes and gene promoters have been correlated with atypical and anaplastic tumors102, but a clonal evolution model based on the loss of expression of these genes has not yet been made clear84, 92, 103, 104.

    TIMP3

    The tissue inhibitor of metalloproteinase 3 (TIMP3) gene is located close to the NF2 gene, at 22q12.3. Its protein product is an inhibitor of matrix metalloproteinases (MMPs), a family of extracellular matrix proteases whose dysregulation has been implicated in the progression and invasive and metastatic potential of many human tumors, including meningiomas105, 106, 107. An additional tumor suppression function of the TIMP3 gene unrelated to MMPs has also been elucidated108. Gene silencing of TIMP3 through hypermethylation has been shown to correlate with higher-grade, aggressive meningiomas109. Upregulation of another protein known as urokinase plasminogen activator (uPA) (part of an additional extracellular matrix protease pathway that interacts with TIMP3), has also been correlated with increased tumor grade, invasive behavior, and recurrence106, 110.

    The Role of Sex Hormone Receptors

    Sex hormone receptors have long been suspected to play a role in the pathogenesis of meningiomas due to the higher overall predominance in females111. It has been well studied that a majority of benign meningiomas express progesterone receptors111, 112, 113, 114, 115, 116, 117, 118, 119. Despite the female predominance, meningiomas tend to be more aggressive in males, which further clouds the involvement of sex hormones in pathogenesis.

    Progesterone Receptor

    Early studies have shown that a high percentage of meningiomas express PR112, 120, 121, 122. Others have demonstrated that meningiomas with PR-positive cells, even if few in number, have a better prognosis than tumors with complete absence of the receptor116. However, reports of higher incidences of PR-positive cells in recurrent disease suggests that PR may play a role in recurrent meningiomas123.

    Estrogen and androgen receptors

    The role of estrogen and androgen signaling has also been controversial. Estrogen receptor (ER) positivity ranges from 7.1%-40.3% in Grade I tumors, and ER-positive cells have been shown to have a higher MIB-1 proliferation index than ER-negative tumors116, 123. Androgen receptor and artomatase have also been implicated in tumorigenesis and recurrence115, 119, 120, 123. Although there is a strong case for the role of estrogen and androgens signaling in tumorigenesis, studies reporting no difference in receptor levels between men and women invalidate the conclusion that PR and ER is responsible for the predominance of meningiomas in females123.

    The Current Challenges and Future Therapies of Meningioma Treatment

    As meningioma treatment moves towards therapies targeted at the specific genetics and biology of the patient’s tumor, a formidable challenge remains due to the limited understanding of the complex heterogeneity of this disease. Studies have identified karyotypically frequent areas of aberrations and some specific gene candidates for tumorigenesis and progression, but the associations of these mutations with specific oncogenic events remains unknown. Epigenetic analytical data has also produced promising correlations of gene expression regulation and tumor properties, but the data is difficult to synergize with an incomplete picture of the cytogenetic progression of disease. Also frustrating is the lack of effective chemotherapeutics for these tumors as well as the difficulty in creating stable cell lines and animal models for experimentation. As such, the mainstay treatments for meningiomas remain: surgical resection, stereotactic radiosurgery, and radiotherapy. Although these modalities may never disappear, in the future a combination of these coupled with molecular therapies tailored to the individual genetics and molecular biology of the patient’s tumor holds great promise in the treatment of this disease.

    References

    1.Ostrom Q T, Gittleman H, Farah P. (2013) . CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2006-2010. Neuro-oncology 2013;15(suppl 2):ii1-ii56 .
    2.Morrison H, Sperka T, Manent J, Giovannini M, Ponta H et al. (2007) Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras. 67(2), 520-527.
    3.Perry A, Stafford S L, Scheithauer B W, Suman V J, Lohse C M.Meningioma grading: an analysis of histologic parameters. The American journal of surgical pathology. , Dec 21(12), 1455-1465.
    4.Simpson D.The recurrence of intracranial meningiomas after surgical treatment. , Journal of neurology, neurosurgery, and psychiatry. Feb 20(1), 22-39.
    5.McCarthy B J, Davis F G, Freels S.Factors associated with survival in patients with meningioma. , J Neurosurg. May 88(5), 831-839.
    6.Mawrin C, Perry A.Pathological classification and molecular genetics of meningiomas. , Journal of neuro-oncology. Sep 99(3), 379-391.
    7.Saraf S, McCarthy B J, Villano J L.. Update on meningiomas. The oncologist 16(11), 1604-1613.
    8.Cahill K S, Claus E B.Treatment and survival of patients with nonmalignant intracranial meningioma: results from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Clinical article. , J Neurosurg. Aug 115(2), 259-267.
    9.Wiemels J, Wrensch M, Claus E B.Epidemiology and etiology of meningioma. , Journal of neuro-oncology. Sep 99(3), 307-314.
    10.Claus E B, Bondy M L, Schildkraut J M, Wiemels J L, Wrensch M et al.. , Epidemiology of intracranial meningioma. Neurosurgery. Dec 57(6), 1088-1095.
    11.Backer-Grondahl T, Moen B H, Torp S H.The histopathological spectrum of human meningiomas. International journal of clinical and experimental pathology. 5(3), 231-242.
    12.Louis D, Ohgaki H, Wiestler O, Cavenee W. (2007) WHO classification of tumours of the central nervous system. World Health Organization Classification of Tumours. World Health Organization;.
    13.Borovich B, Doron Y.Recurrence of intracranial meningiomas: the role played by regional multicentricity. , J Neurosurg. Jan 64(1), 58-63.
    14.Nanda A, Vannemreddy P.Recurrence and Outcome in Skull Base Meningiomas: Do They Differ from Other Intracranial Meningiomas? Skull base : official journal of North American Skull Base Society ... [et al.].
    19.. 18(04), 243-252.
    15.Stangl A P, Wellenreuther R, Lenartz D.Clonality of multiple meningiomas. , J Neurosurg. May 86(5), 853-858.
    16.Louis D N, Ohgaki H, Wiestler O D. (2007) The. 114(2), 97-109.
    17.Cornelius J F, Slotty P J, Steiger H J, Hanggi D, Polivka M et al.Malignant potential of skull base versus non-skull base meningiomas: clinical series of 1,663 cases. Acta neurochirurgica. , Mar 155(3), 407-413.
    18.Jaaskelainen J.Seemingly complete removal of histologically benign intracranial meningioma: late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surgical neurology. , Nov 26(5), 461-469.
    19.Kane A J, Sughrue M E, Rutkowski M J.Anatomic location is a risk factor for atypical and malignant meningiomas. , Cancer. Mar 117(6), 1272-1278.
    20.Lamszus K.Meningioma pathology, genetics, and biology. Journal of neuropathology and experimental neurology. , Apr 63(4), 275-286.
    21.Fuller G N.The WHO Classification of Tumours of the Central Nervous System. 4th Edition. Archives of Pathology & Laboratory Medicine 132(6), 906-906.
    22.Willis J, Smith C, Ironside J W, Erridge S, Whittle I R et al.The accuracy of meningioma grading: a 10-year retrospective audit. Neuropathology and applied neurobiology. , Apr 31(2), 141-149.
    23.Torp S H, Lindboe C F, Gronberg B H, Lydersen S, Sundstrom S.Prognostic significance of Ki-67/MIB-1 proliferation index in meningiomas. Clinical neuropathology. , Jul-Aug 24(4), 170-174.
    24.Sughrue M E, Kane A J, Shangari G.The relevance of Simpson Grade I and II resection in modern neurosurgical treatment of World Health Organization Grade I meningiomas. , J Neurosurg. Nov 113(5), 1029-1035.
    25.Nakasu S, Fukami T, Jito J, Nozaki K.Recurrence and regrowth of benign meningiomas. Brain tumor pathology. 26(2), 69-72.
    26.Pearson B E, Markert J M, Fisher W S. (2008) Hitting a moving target: evolution of a treatment paradigm for atypical meningiomas amid changing diagnostic criteria. Neurosurgical focus.
    27.Aghi M K, Carter B S, Cosgrove G R.Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. , Neurosurgery. Jan 64(1), 56-60.
    28.Couce M E, Aker F V, Scheithauer B W.Chordoid meningioma: a clinicopathologic study of 42 cases. The American journal of surgical pathology. , Jul 24(7), 899-905.
    29.Wang D J, Zheng M Z, Gong Y.Papillary meningioma: clinical and histopathological observations. International journal of clinical and experimental pathology. 6(5), 878-888.
    30.Ludwin S K, Rubinstein L J, Russell D S.Papillary meningioma: a malignant variant of meningioma. , Cancer. Oct 36(4), 1363-1373.
    31.Avninder S, Vermani S, Shruti S, Chand K.Papillary meningioma: a rare but distinct variant of malignant meningioma. Diagnostic pathology. 2007-2.
    32.Durand A, Labrousse F, Jouvet A.WHO grade II and III meningiomas: a study of prognostic factors. , Journal of neuro-oncology. Dec 95(3), 367-375.
    33.Heald J B, Carroll T A, Mair R J. (2013) Simpson grade: an opportunity to reassess the need for complete resection of meningiomas. , Acta neurochirurgica. Nov 6.
    34.Oya S, Kawai K, Nakatomi H, Saito N.Significance of Simpson grading system in modern meningioma surgery: integration of the grade with MIB-1 labeling index as a key to predict the recurrence of WHO Grade I meningiomas. , J Neurosurg. Jul 117(1), 121-128.
    35.McGovern S L, Aldape K D, Munsell M F, Mahajan A, DeMonte F et al.A comparison of World Health Organization tumor grades at recurrence in patients with non-skull base and skull base meningiomas. , J Neurosurg. May 112(5), 925-933.
    36.Jung H W, Yoo H, Paek S H, Choi K S.Long-term outcome and growth rate of subtotally resected petroclival meningiomas: experience with 38 cases. , Neurosurgery. Mar 46(3), 567-574.
    37.Yang S Y, Park C K, Park S H, Kim D G, Chung Y S et al. () Atypical and anaplastic meningiomas: prognostic implications of clinicopathological features. Journal of neurology, neurosurgery, and psychiatry. 79(5), 574-580.
    38.Karamitopoulou E, Perentes E, Tolnay M, Probst A.Prognostic significance of MIB-1, p53, and bcl-2 immunoreactivity in meningiomas. Human pathology. , Feb 29(2), 140-145.
    39.Sade B, Chahlavi A, Krishnaney A, Nagel S, Choi E et al.World Health Organization Grades II and III meningiomas are rare in the cranial base and spine. , Neurosurgery. Dec 61(6), 1194-1198.
    40.Starke R M, Williams B J, Hiles C, Nguyen J H, Elsharkawy M Y et al.Gamma knife surgery for skull base meningiomas. , J Neurosurg. Mar 116(3), 588-597.
    41.Combs S E, Ganswindt U, Foote R L, Kondziolka D, Tonn J C. (2012) State-of-the-art treatment alternatives for base of skull meningiomas: complementing and controversial indications for neurosurgery, stereotactic and robotic based radiosurgery or modern fractionated radiation techniques. Radiation oncology (London. , England) 7, 226.
    42.Modha A, Gutin P H.Diagnosis and treatment of atypical and anaplastic meningiomas: a review. , Neurosurgery. Sep 57(3), 538-550.
    43.Kreil W, Luggin J, Fuchs I, Weigl V, Eustacchio S et al.Long term experience of gamma knife radiosurgery for benign skull base meningiomas. Journal of neurology, neurosurgery, and psychiatry. , Oct 76(10), 1425-1430.
    44.Iwai Y, Yamanaka K, Yasui T.Gamma knife surgery for skull base meningiomas. The effectiveness of low-dose treatment. Surgical neurology. , Jul 52(1), 40-44.
    45.Barbaro N M, Gutin P H, Wilson C B, Sheline G E, Boldrey E B et al.Radiation therapy in the treatment of partially resected meningiomas. , Neurosurgery. Apr 20(4), 525-528.
    46.Petty A M, Kun L E, Meyer G A.Radiation therapy for incompletely resected meningiomas. , J Neurosurg. Apr 62(4), 502-507.
    47.Carella R J, Ransohoff J, Newall J.Role of radiation therapy in the management of meningioma. , Neurosurgery 10(3), 332-339.
    48.Stippler M, Kondziolka D.Skull base meningiomas: is there a place for microsurgery? Acta neurochirurgica. , Jan 148(1), 1-3.
    49.Perry A, Stafford S L, Scheithauer B W, Suman V J, Lohse C M.The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. , Cancer. Jun 82(11), 2262-2269.
    50.Kolles H, Niedermayer I, Schmitt C.Triple approach for diagnosis and grading of meningiomas: histology, morphometry of Ki-67/Feulgen stainings, and cytogenetics. Acta neurochirurgica. 1995-137.
    51.Campbell B A, Jhamb A, Maguire J A, Toyota B, Ma R.Meningiomas in 2009: controversies and future challenges. American journal of clinical oncology. , Feb 32(1), 73-85.
    52.Vagner-Capodano A M, Grisoli F, Gambarelli D, Sedan R, Pellet W et al.Correlation between cytogenetic and histopathological findings in 75 human meningiomas. , Neurosurgery. Jun 32(6), 892-900.
    53.Zattara-Cannoni H, Gambarelli D, Dufour H.Contribution of cytogenetics and FISH in the diagnosis of meningiomas. A study of 189 tumors. Annales de genetique. 41(3), 164-175.
    54.Simon M, A von Deimling, Larson J J.Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. , Cancer Res. Oct 55(20), 4696-4701.
    55.Lamszus K, Kluwe L, Matschke J, Meissner H, Laas R et al.Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer genetics and cytogenetics. , Apr 110(2), 103-110.
    56.Weber R G, Bostrom J, Wolter M.Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proceedings of the National Academy of Sciences of the United States of America. Dec 94(26), 14719-14724.
    57.Ragel B T, Jensen R L. (2005) Molecular genetics of meningiomas. Neurosurgical focus.
    58.Scheck A C, Hendricks W.Molecular biological determinants of meningioma progression and aggressive behavior. Frontiers in bioscience (Elite edition). 2009, 390-414.
    59.Pham M H, Zada G, Mosich G M. (2011) Molecular genetics of meningiomas: a systematic review of the current literature and potential basis for future treatment paradigms. Neurosurgical focus.
    60.Choy W, Kim W, Nagasawa D. (2011) The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments. Neurosurgical focus.
    61.Wellenreuther R, Kraus J A, Lenartz D.Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. The American journal of pathology. , Apr 146(4), 827-832.
    62.Ragel B T, Jensen R L.Aberrant signaling pathways in meningiomas. , Journal of neuro-oncology. Sep 99(3), 315-324.
    63.Lomas J, Bello M J, Arjona D.Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. , Genes, chromosomes & cancer. Mar 42(3), 314-319.
    64.Perry A, Gutmann D H, Reifenberger G.Molecular pathogenesis of meningiomas. , Journal of neuro-oncology. Nov 70(2), 183-202.
    65.Trofatter J A, MacCollin M M, Rutter J L.A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. , Cell. Mar 72(5), 791-800.
    66.Rouleau G A, Merel P, Lutchman M.Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. , Nature. Jun 363(6429), 515-521.
    67.Xiao G H, Chernoff J, Testa J R.NF2: the wizardry of merlin. , Genes, chromosomes & cancer. Dec 38(4), 389-399.
    68.Shimizu T, Seto A, Maita N. (2002) Structural Basis for Neurofibromatosis Type 2:. , CRYSTAL STRUCTURE OF THE MERLIN FERM DOMAIN. Journal of Biological Chemistry. March 22, 10332-10336.
    69.Hovens C M, Kaye A H.The tumour suppressor protein NF2/merlin: the puzzle continues. , Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. Jan 8(1), 4-7.
    70.Bretscher A, Chambers D, Nguyen R, Reczek D.. ERM-MERLIN AND EBP50 PROTEIN FAMILIES IN PLASMA MEMBRANE ORGANIZATION AND FUNCTION. Annual Review of Cell and Developmental Biology 16(1), 113-143.
    71.Morrison H, Sherman L S, Legg J.The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes & development. , Apr 15(8), 968-980.
    72.Bretscher A, Edwards K, Fehon R G.ERM proteins and merlin: integrators at the cell cortex. , Nature Reviews Molecular Cell Biology 3(8), 586-599.
    73.Ruttledge M H, Sarrazin J, Rangaratnam S.Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nature genetics. , Feb 6(2), 180-184.
    74.Ruttledge M H, Xie Y G, Han F Y.. Deletions on chromosome 22 in sporadic meningioma. Genes, chromosomes & cancer. Jun 10(2), 122-130.
    75.Ikeda K, Saeki Y, Gonzalez-Agosti C, Ramesh V, Chiocca E A.Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer. , J Neurosurg. Jul 91(1), 85-92.
    76.Tikoo A, Varga M, Ramesh V, Gusella J, Maruta H.An anti-Ras function of neurofibromatosis type 2 gene product (NF2/Merlin). The Journal of biological chemistry. , Sep 269(38), 23387-23390.
    77.Striedinger K, VandenBerg S R, Baia G S, McDermott M W, Gutmann D H et al. () The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. , (New York, N.Y.) 10(11), 1204-1212.
    78.Perry A, Cai D X, Scheithauer B W.DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases. Journal of neuropathology and experimental neurology. , Oct 59(10), 872-879.
    79.Gutmann D H, Donahoe J, Perry A.Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas. Human molecular genetics. , Jun 9(10), 1495-1500.
    80.Nunes F, Shen Y, Niida Y.Inactivation patterns of NF2 and DAL-1/4.1B (EPB41L3) in sporadic meningioma. Cancer genetics and cytogenetics. , Oct 162(2), 135-139.
    81.Robb V A, Li W, Gascard P, Perry A, Mohandas N et al.Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis. Neurobiology of disease. , Aug 13(3), 191-202.
    82.Sulman E P, Dumanski J P, White P S.Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. , Cancer Res. Aug 58(15), 3226-3230.
    83.Holland H, Mocker K, Ahnert P.High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas. Cancer genetics. 204(10), 541-549.
    84.Muller P, Henn W, Niedermayer I.Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate progression of meningiomas. Clinical cancer research : an official journal of the American Association for Cancer Research. , Nov 5(11), 3569-3577.
    85.Cai D X, Banerjee R, Scheithauer B W, Lohse C M, Kleinschmidt-Demasters B K et al.Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications. Journal of neuropathology and experimental neurology. , Jun 60(6), 628-636.
    86.Al-Mefty O, Kadri P A, Pravdenkova S, Sawyer J R, Stangeby C et al.Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings. , J Neurosurg. Aug 101(2), 210-218.
    87.Pfisterer W K, Hank N C, Preul M C.Diagnostic and prognostic significance of genetic regional heterogeneity in meningiomas. , Neuro-oncology. Oct 6(4), 290-299.
    88.Lusis E A, Watson M A, Chicoine M R.Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res. , Aug 65(16), 7121-7126.
    89.Maillo A, Orfao A, Espinosa A B.Early recurrences in histologically benign/grade I meningiomas are associated with large tumors and coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone. , Neuro-oncology. Oct 9(4), 438-446.
    90.Maillo A, Orfao A, Sayagues J M.New classification scheme for the prognostic stratification of meningioma on the basis of chromosome 14 abnormalities, patient age, and tumor histopathology. , Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Sep 21(17), 3285-3295.
    91.Leone P E, Bello M J, de Campos JM.NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas. , Oncogene. Apr 18(13), 2231-2239.
    92.Bostrom J, Meyer-Puttlitz B, Wolter M.Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. The American journal of pathology. , Aug 159(2), 661-669.
    93.Leuraud P, Marie Y, Robin E.Frequent loss of 1p32 region but no mutation of the p18 tumor suppressor gene in meningiomas. , Journal of neuro-oncology. Dec 50(3), 207-213.
    94.Lomas J, Bello M J, Arjona D.Analysis of p73 gene in meningiomas with deletion at 1p. Cancer genetics and cytogenetics. , Aug 129(1), 88-91.
    95.Piaskowski S, Rieske P, Szybka M.GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis. Cancer genetics and cytogenetics. , Oct 162(1), 63-67.
    96.Mendiola M, Bello M J, Alonso J.Search for mutations of the hRAD54 gene in sporadic meningiomas with deletion at 1p32. Molecular carcinogenesis. , Apr 24(4), 300-304.
    97.Zhang X, Gejman R, Mahta A.Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. , Mar 70(6), 2350-2358.
    98.Perry A, Banerjee R, Lohse C M, Kleinschmidt-DeMasters B K, Scheithauer B W. () A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain pathology. , (Zurich, Switzerland) 12(2), 183-190.
    99.Amatya V J, Takeshima Y, Inai K.Methylation of p14(ARF) gene in meningiomas and its correlation to the p53 expression and mutation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology. , Inc. Jun 17(6), 705-710.
    100.Simon M, Park T W, Koster G.Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression. , Journal of neuro-oncology. Dec 55(3), 149-158.
    101.Goutagny S, Yang H W, Zucman-Rossi J.Genomic profiling reveals alternative genetic pathways of meningioma malignant progression dependent on the underlying NF2 status. Clinical cancer research : an official journal of the American Association for Cancer Research. , Aug 16(16), 4155-4164.
    102.Liu Y, Pang J C, Dong S, Mao B, Poon W S et al.Aberrant CpG island hypermethylation profile is associated with atypical and anaplastic meningiomas. Human pathology. , Apr 36(4), 416-425.
    103.Korshunov A, Shishkina L, Golanov A.Immunohistochemical analysis of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in 271 meningiomas correlation with tumor grade and clinical outcome. International journal of cancer. , Journal international du cancer. May 104(6), 728-734.
    104.Niedermayer I, Feiden W, Henn W, Steilen-Gimbel H, Steudel W I et al.Loss of alkaline phosphatase activity in meningiomas: a rapid histochemical technique indicating progression-associated deletion of a putative tumor suppressor gene on the distal part of the short arm of chromosome 1. Journal of neuropathology and experimental neurology. , Aug 56(8), 879-886.
    105.Nordqvist A C, Smurawa H, Mathiesen T.Expression of matrix metalloproteinases 2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema. , J Neurosurg. Nov 95(5), 839-844.
    106.Siddique K, Yanamandra N, Gujrati M, Dinh D, Rao J S et al.Expression of matrix metalloproteinases, their inhibitors, and urokinase plasminogen activator in human meningiomas. International journal of oncology. , Feb 22(2), 289-294.
    107.Coussens L M, Werb Z. (1996) Matrix metalloproteinases and the development of cancer. Chemistry & biology. 3(11), 895-904.
    108.Anand-Apte B, Bao L, Smith R. (1996) A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochemistry and cell biology = Biochimie et biologie cellulaire. 74(6), 853-862.
    109.Barski D, Wolter M, Reifenberger G, Riemenschneider M J. (2010) Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q12.3 and malignancy in meningiomas. Brain pathology. , (Zurich, Switzerland) 20(3), 623-631.
    110.Kandenwein J A, Park-Simon T W, Schramm J, Simon M. (2011) uPA/PAI-1 expression and uPA promoter methylation in meningiomas. Journal of neuro-oncology. 103(3), 533-539.
    111.Brandis A, Mirzai S, Tatagiba M, Walter G F, Samii M et al. (1993) Immunohistochemical detection of female sex hormone receptors in meningiomas: correlation with clinical and histological features. , Neurosurgery 33(2), 212-217.
    112.Perrot-Applanat M, Groyer-Picard M T, Kujas M. (1992) Immunocytochemical study of progesterone receptor in human meningioma. Acta neurochirurgica. 115-1.
    113.Grunberg S M. (1994) Role of antiprogestational therapy for meningiomas. Human reproduction. , (Oxford, England) 9, 202-207.
    114.Khalid H. (1994) Immunohistochemical study of estrogen receptor-related antigen, progesterone and estrogen receptors in human intracranial meningiomas. , Cancer. Jul 15, 679-685.
    115.Black P, Carroll R, Zhang J. (1996) The molecular biology of hormone and growth factor receptors in meningiomas. Acta neurochirurgica. Supplement 65, 50-53.
    116.Hsu D W, Efird J T, Hedley-Whyte E T. (1997) Progesterone and estrogen receptors in meningiomas: prognostic considerations. , J 86(1), 113-120.
    117.Verheijen F M, Donker G H, Viera C S. (2002) Progesterone receptor, bc1-2 and bax expression in meningiomas. , Journal of 56(1), 35-41.
    118.Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. (2006) Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. , J Neurosurg 105(2), 163-173.
    119.Leaes C G, Meurer R T, Coutinho L B, Ferreira N P, Pereira-Lima J F et al.Immunohistochemical expression of aromatase and estrogen, androgen and progesterone receptors in normal and neoplastic human meningeal cells. Neuropathology :. , official journal of the Japanese Society of Neuropathology. Feb 30(1), 44-49.
    120.Lesch K P, Engl H G, Gross S.Androgen receptor binding activity in meningiomas. Surgical neurology. , Sep 28(3), 176-180.
    121.Lesch K P, Gross S.Estrogen receptor immunoreactivity in meningiomas. Comparison with the binding activity of estrogen, progesterone, and androgen receptors. , J Neurosurg. Aug 67(2), 237-243.
    122.Lesch K P, Engl H G, Schott W, Gross S.Immunoreactive estrogen receptor protein in meningiomas: comparison with the androgen receptor and progesterone receptor binding activity. Zentralblatt fur Neurochirurgie. 48(2), 124-134.
    123.Korhonen K, Salminen T, Raitanen J, Auvinen A, Isola J et al.Female predominance in meningiomas can not be explained by differences in progesterone, estrogen, or androgen receptor expression. , Journal of neuro-oncology. Oct 80(1), 1-7.