Pathology and genetics of meningiomas

Pathology and genetics of meningiomas

Seminars in Diagnostic Pathology (2011) 28, 314-324 Pathology and genetics of meningiomas Hussein Alahmadi, MD,a Sidney E. Croul, MD, FRCPCb a From ...

5MB Sizes 0 Downloads 131 Views

Seminars in Diagnostic Pathology (2011) 28, 314-324

Pathology and genetics of meningiomas Hussein Alahmadi, MD,a Sidney E. Croul, MD, FRCPCb a

From the Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada; b Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada. KEYWORDS CNS tumors; Meningiomas; Histopathology; Genetics

This article constitutes a mini-review of the pathology and genetics of meningiomas. Meningiomas are the most common primary intracranial tumors. They are usually durally based and are often found adjacent to venous sinuses and dural infoldings. The majority of these tumors are WHO grade I, although a minority is WHO grade II, atypical, or WHO grade III, anaplastic. Grade II and III meningiomas show a greater tendency than Grade I tumors to recur and metastasize. The current WHO scheme recognizes 15 histologic subtypes of meningiomas. Nine of these are WHO grade I, three are grade II, and three are grade III. In addition to these histologic subtypes, meningiomas can also be graded on the basis of mitotic activity, evidence of brain invasion, growth pattern cellular density, nuclear atypia, and necrosis. Loss of the long arm of chromosome 22, which is usually associated with inactivation of the NF2 gene, is the most common genetic abnormality found in meningiomas. Other chromosomal abnormalities associated with tumorogenesis and increased gradeof meningiomas include loss of heterozygosity for chromosome 1p, loss of 14q, deletion of 9p21, abnormalities of chromosome 10 and 17q. Telomerase activity increases with meningiomas grade as well. The only proven environmental risk factor for meningiomas is ionizing radiation. Radiation-induced meningiomas are more often multiple and have higher recurrence rates than standard meningiomas. © 2011 Elsevier Inc. All rights reserved.

Grading

Location

The majority of meningiomas are World Health Organization (WHO) grade I based on their benign histology and the potential for cure by surgical excision. A minority are WHO grade II, atypical, or WHO grade III, anaplastic. Grade II and III meningiomas show a greater tendency than grade I tumors to recur and metastasize.1

Meningiomas are usually dural-based tumors and are often found adjacent to venous sinuses and dural infoldings. This accounts for some of the common sites of origin—falx cerebri, olfactory grooves, optic nerves, sphenoid wings, petrous ridge, tentorium cerebelli, sella turcica, and spinal dura. Occasional intraventricular meningiomas are probably caused by arachnoid rests entrapped in the ventricular system during development.2,3 Rare meningiomas occur outside the central nervous system, particularly in the lung, again because of developmental arachnoid rests.4 Metastatic tumors, which occur in 0.1% of tumors, can be found in the lung, as well as in the liver and bone.5

Address reprint requests and correspondence: Sidney E. Croul, MD, FRCPC, Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, 11E426 Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. E-mail address: [email protected].

0740-2570/$ -see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2011.01.002

Alahmadi and Croul

Figure 1 lobe (B).

Pathology and Mimetics of Meningiomas

315

An incidental middle fossa meningioma found at autopsy (A) compresses but does not invade the inferior surface of the temporal

Incidence Meningiomas are the most common primary intracranial tumors. They comprise 32% of histologically confirmed primary brain tumors in the Central Brain Tumor Registry of the United States.6 In a population-based study, the prevalence of asymptomatic meningiomas was 0.9% (1.1% in women and 0.7% in men).7 The incidence of meningiomas rises steadily over the lifespan from a low of less than 1 per 100,000 person-years in the first 2 decades to 30 per 100,000 person-years by the 9th decade.6 Benign meningiomas (WHO grade I) are diagnosed twice as frequently in females compared with males.6 This female predominance is not replicated in atypical (WHO grade II) or anaplastic (WHO grade III) meningiomas.8,9 Although large North American studies show no compelling evidence for a difference in incidence of grade I meningiomas between populations of different racial backgrounds,6 studies of smaller populations, such as Polynesians,10 suggest that risk factors may segregate among some ethnic groups.

Pathology Macroscopic Meningiomas tend to be rubbery and firm. A gritty consistency on section is often indicative of calcific psam-

moma bodies. They are usually attached to the dura and often have a central mass of tumor that gradually tapers out into a thin tail. Compression of the underlying brain is typical (Figure 1A and B). Invasion of the dura, overlying bone, and skin, as well as adjacent structures such as the orbital contents, is common as well (Figure 2A and B). Bony invasion is often associated with hyperostosis, readily seen on standard x-rays and computed tomography scans. Invasion of the brain is the exception. Even in the case of malignant meningiomas, brain invasion tends to be limited to a few millimeters below the pial surface. Adjacent vessels are frequently ensheathed by meningothelial tumors, but the walls of these vessels are rarely broached (Figure 2B).1

Microscopic The similarities between arachnoid villi and these tumors led Cushing and Eisenhardt to coin the term meningioma in their 1938 monograph.11 Hyperplastic clusters of normal arachnoid cap cells are often histologically identical to microscopic fields of grade I meningiomas (Figure 3A and B). They have pale, round nuclei with evenly dispersed chromatin and occasional clear cytoplasmic invaginations. Borders between cells are indistinct because of interdigitation of adjacent cell membranes, which may give the cells a syncytial appearance. Groups of cells form whorls, the

Figure 2 A histologically benign olfactory groove meningioma (A) encases the cavernous sinuses (B, arrows), invades the skull, and grows into the sinuses.

316

Seminars in Diagnostic Pathology, Vol 28, No 4, November 2011

Figure 3

Arachnoid cap cells (A) and the whorls of a meningothelial meningioma (B) share both architecture and cytology.

centers of which may become mineralized, forming psammoma bodies. Since Cushing and Eisenhardt’s delineation of 9 major types and 22 subtypes of meningiomas,11 the classification has gone through several modifications. The current WHO scheme1 (Table 1) recognizes 15 types. Of these, 9 are WHO grade I. They differ in their histologic patterns but have nearly equal biological behavior. Meningothelial tumors are more syncytial in appearance (Figure 4A), fibroblastic meningiomas have elongated fascicular cells (Figure 4B), and transitional meningiomas contain elements of both types (Figure 4C). Psammomatous meningiomas (Figure 4D) are rich in those lamellar calcifications and angiomatous meningiomas in small vessels (Figure 4E). Microcystic meningiomas are notable for a loose, vacuolated background (Figure 4F). The chronic inflammatory infiltrate of lymphoplasmacyte-rich tumors can obscure the meningothelial features, making diagnosis difficult. They are a rare and somewhat controversial entity. The argument has been made that these tumors actually represent primary inflam-

Table 1 The 2007 WHO classification of meningiomas (1) recognizes 15 types, of which 9 are grade I, 3 grade II, and 3 grade III Grade I Meningothelial Fibrous (fibroblastic) Transitional (mixed) Psammomatous Angiomatous Microcystic Secretory Lymphoplasmacyte rich Metaplastic Grade II Chordoid Clear cell Atypical Grade III Papillary Rhabdoid Anaplastic

matory processes that have been misdiagnosed. Metaplastic meningiomas demonstrate focal mesenchymal elements such as bone, cartilage, and fat (Figure 4G). Secretory meningiomas have brightly eosinophilic intracellular inclusions that have been called pseudopsammoma bodies. They differ biologically from the other 8 WHO grade I tumors in that they are more associated with edema of the surrounding central nervous system tissues.12,13 Three subtypes of meningioma are classified as WHO grade II/atypical tumors because of their high rates of recurrence after resection. Chordoid meningiomas14-16 are named for their resemblance to chordomas. These tumors feature zones with a myxoid background containing trabeculae of eosinophilic cells with vacuolated cytoplasm (Figure 5A). These are intermixed with other zones displaying more typical meningothelial features. Clear cell meningiomas17,18 feature cells with glycogen-rich cytoplasm (Figure 5B and C) and often lack many of the common secondary structures of meningiomas, particularly the distinctive whorled pattern. Meningiomas without the features of these 3 subtypes can also be classified as grade II if they exhibit 4 mitotic figures per 10 high-power fields (Figure 6A), microscopic evidence of brain invasion (Figure 6B), or 3 of the following features: patternless growth, hypercellularity, foci of small cells with high nuclear:cytoplasmic ratio, prominent nucleoli, or foci of necrosis (Figure 7A-D).19 Meningiomas classified as WHO grade III/anaplastic or malignant pursue a more aggressive clinical course. Median survival for these tumors is less than 2 years.20 Papillary meningiomas are characterized by a perivascular pseudopapillary growth pattern (Figure 8A and B). They tend to occur in young patients, demonstrate brain invasion, recur frequently, and can metastasize both within the subarachnoid space and outside the nervous system.21 Rhabdoid meningiomas are named for their intracytoplasmic eosinophilic masses of intermediate filaments similar to those found in rhabdoid tumors from other organs, particularly the kidney (Figure 8C). Most rhabdoid meningiomas have high proliferative indexes and other histologic features of malignancy.22 As in the case of atypical meningiomas, tumors need not demonstrate papillary or rhabdoid features to be classified as anaplastic. The findings of either cytologic

Alahmadi and Croul

Pathology and Mimetics of Meningiomas

317

Figure 4 WHO grade I histologic subtypes include meningothelial meningiomas (A), fibroblastic meningiomas (B), and transitional meningiomas with elements of both meningothelial and fibroblastic tumors (C). Psammomatous meningiomas (D) have calcifications, angiomatous meningiomas have small vessels (E), and microcystic meningiomas have a vacuolated background (F). Metaplastic meningiomas demonstrate focal mesenchymal elements such as the bone seen here (G). Secretory meningiomas demonstrate eosinophilic intracellular inclusions (H).

malignancy or 20 or more mitotic figures per 10 high-power fields are sufficient to warrant the diagnosis.20 Immunohistochemistry and electron microscopy The majority of meningiomas demonstrate expression of epithelial membrane antigen by immunohistochemistry (Figure 9A).23 Secretory meningiomas show positivity for carcinoembryonic antigen (Figure 9B). The intracytoplasmic masses of rhabdoid meningiomas are positive for vimentin (Figure 9C). Electron microscopy can occasionally be of value in the diagnosis of meningothelial tumors. Large numbers of intermediate filaments, interdigitated membranes, and desmosomal junctions are characteristic of meningiomas. MIB1/Ki-67 immunohistochemistry is currently used by many pathologists to assess the proliferation index of meningiomas. Although absolute values vary between laboratories, the percentage of positive cells tends to be lowest in grade I and highest in grade III tumors. A MIB1/Ki-67 index of 5%-10% in the absence of histologic features of a grade II tumor is a predictor for early tumor recurrence (Figure 10A and B). Two thirds of meningiomas express progesterone receptors (Figure 10C). Progesterone receptor negativity, although not a risk factor by itself, tends to occur more frequently in higher grade meningiomas and may be

an indicator of poor prognosis when combined with increased proliferation index and higher grade. Progesterone receptor–negative tumors also tend to be larger than those that express progesterone receptors.24-26

Genetics Background The contribution of inheritance to the occurrence of meningiomas has been recognized since the clinical association of multiple meningiomas and meningioangiomatosis with neurofibromatosis was made almost a century ago.27,28 Family groups with increased incidence of meningiomas but without the stigmata of neurofibromatosis have also been described.29 Meningiomas may also occur in the context of other inherited diseases, such as Gorlin and Cowden syndromes.30,31 Whereas the current WHO classification system defines the grade of meningothelial tumors solely on histologic criteria, the genetic profile of meningiomas provides further predictive information. Most of this work has grown out of cytogenetic studies and is therefore presented here in the context of chromosomal aberrations and telomeric stability.

318

Seminars in Diagnostic Pathology, Vol 28, No 4, November 2011

Figure 5 Both chordoid (A) and clear cell meningiomas (B, C) are WHO grade II/atypical. The chordoid tumors feature a myxoid background with vacuolated cells, whereas in the clear cell variant, the cytoplasm of the tumor cells is glycogen rich, accounting for the stunning periodic acid-Schiff positivity (C).

Chromosomal aberrations Chromosome 22q Loss of the long arm of chromosome 22, which is usually associated with inactivation of the NF2 gene, is the most common genetic abnormality found in meningiomas (Figure 11A).32-34 NF2, which codes for the merlin (schwannomin) protein, is a tumor suppressor because its inactivation by mutation, methylation of the 5= region, or proteolysis results in the phenotype of peripheral neurofibromas and multiple meningiomas.34,35 Sporadic merlin (schwannomin) inactivation is most common in fibroblastic and transitional meningiomas, but uncommon in meningothelial and secretory meningiomas.35,36 Although NF2 inactivation has been documented in all grades of meningiomas, there is a high frequency of additional complex genetic abnormalities in

the higher-grade tumors. This has led to the hypothesis that NF2 inactivation initiates low-grade tumors followed by the additional genetic events that are responsible for the progression to high-grade tumors.34 Chromosome 1p Loss of heterozygosity for chromosome 1p is associated with increases in both grade and recurrence rate of meningiomas (Figure 11B). The rate of 1p loss increases from a low of 25% in WHO grade I to a high of 85% in grade III meningiomas.37 Meningiomas with loss of 1p have also been reported to be those with the highest risk of recurrence.9 The critical region of chromosomal loss has been narrowed to the 1p32, 1p34, and 1p36 loci.38-43 Although several genes within these regions, including p18, CDKN2C, p73, GADD45A, and EPB41, have been

Figure 6 In the absence of chordoid or clear cell morphologies, either 4 mitoses/10 high-power fields (arrows A) or brain invasion by tumor (B) are sufficient to make the diagnosis of atypical meningioma.

Alahmadi and Croul

Pathology and Mimetics of Meningiomas

319

Figure 7 Tumors demonstrating 3 of the following: patternless growth (A), hypercellularity, foci of small cells (B) with high nuclear:cytoplasmic ratio (C), prominent nucleoli, or foci of necrosis (D), are also considered grade II/ atypical.

examined for mutations and polymorphisms, none has been detected.37,44-46 A few studies have demonstrated promoter methylation of p7347,48 and RASSF1A,48 implying that downregulation of these genes may play a role

in meningioma progression. At the same time, more maps of these loci have generated further lists of candidate genes,40,43 the analyses of which are yet to be reported.

Figure 8 The perivascular growth pattern of papillary meningiomas can be seen with hematoxylin and eosin staining (A) but is even clearer with immunohistochemistry for CD34 (B), which clarifies the structure of the vascular cores. The intracytoplasmic inclusions of rhabdoid meningiomas (C, arrow) are brightly eosinophilic.

320

Seminars in Diagnostic Pathology, Vol 28, No 4, November 2011

Figure 9 Epithelial membrane antigen immunohistochemistry stains the majority of meningiomas (A), whereas carcinoembryonic antigen is positive in secretory meningiomas (B) and vimentin marks the intracytoplasmic filamentous accumulations of rhabdoid meningiomas (C).

Chromosome 14q Loss of 14q is associated with grade II and III meningiomas38,49-53 (Figure 11B). The 14q loss may also be a predictor of early recurrence in grade I meningiomas and poorer outcome in grade III meningiomas.53-55 A candi-

date tumor suppressor gene, NDRG2, located at 14q11.2, has been identified. Decreased expression of its transcripts and protein product have been demonstrated in lower-grade meningiomas with aggressive clinical behavior.56

Figure 10 Meningiomas that are WHO grade I by standard morphologic criteria (A) but have proliferation indexes of 5%-10% by MIB-1 staining (B) have an increased risk of early recurrence. Progesterone receptor expression can be demonstrated by immunohistochemistry in the majority of meningiomas (C).

Alahmadi and Croul

Pathology and Mimetics of Meningiomas

321

Figure 11 Fluorescent in situ hybridization is used to detect chromosomal abnormalities in meningiomas. 22q deletion is demonstrated with a probe for NF2 (22q12) in red and another for BCR (22q11.2) in green. The presence of only 1 of each in most nuclei is consistent with either monosomy of chromosome 22 or a large 22q deletion (A). Loss of both 1p and 14q is demonstrated with a probe for 1p32 labeled in green and another for 14q32 labeled in red. Again, most cells have 1 green and 1 red, consistent with deletions of both chromosomal regions (B). Hemizygous deletion of 9p21 is shown with CEP9 (centromere enumerating probe for chromosome 9) in green (2 signals in most nuclei) and the p16 (CDKN2A) gene region (9p21) in red (1 signal in most cells) (C) (courtesy of Arie Perry, MD, Department of Pathology, University of California San Francisco School of Medicine).

Chromosome 9p The frequency of deletions in 9p21 (Figure 11C) is increased proportionally with increased grade of meningioma37,57 and may be an independent predictor of poor outcome in anaplastic meningiomas.57 Several tumor suppressor genes are located on 9p, including CDKN2a, a regulator of the G1/S-phase transition, CDKN2b, which is involved with cell cycle G1 progression, and p14ARF, a regulator of p53 activity. The role that these genes may play in 9p related meningioma progression remains unclear. Whereas in one study37 homozygous deletions of all 3 genes were found in a small percentage of grade II and approximately half of grade III meningiomas, other work58 has reported only promoter methylation not consistently related to changes in gene expression. Chromosome 10 Abnormalities of chromosome 10 are also correlated with meningioma progression from grade I to grades II and III. These include loss of heterozygosity,38,59,60 trisomy,61 and homozygous deletion51,62 of 10q. One recent study,63 which applied both high-density single nucleotide polymorphism arrays and multicolor fluorescence in situ hybridization to single atypical meningioma, reported both loss of heterozygosity at 10q21.1 and a reciprocal translocation involving 10q22: t(10;16)(q2;q12.1).

Chromosome 17 Abnormalities of 17q have also been associated with higher grade meningiomas. Both fluorescent and chromogenic in situ hybridization61,64 showed gains in chromosome 17. Restriction fragment length polymorphism has demonstrated a loss at 17p in malignant meningiomas.65 Comparative genomic hybridization has narrowed this region of interest to 17q22-23.66

Telomere stability Telomere shortening with progressive cell division is involved in the normal regulation of cell division and senescence. Conversely, maintenance of telomere length by the reverse transcriptase telomerase is a common feature of human tumors. Several studies have examined measures of telomere stability in meningiomas. Telomerase activity is detectable in few grade I meningiomas but in most grade II and II tumors.67-73

Radiation The only proven environmental risk factor for meningiomas is ionizing radiation. Evidence for this comes from Tinea capitis patients treated with low-dose radiotherapy prior to the introduction of griseofulvin in the 1960s,74,75

322

Seminars in Diagnostic Pathology, Vol 28, No 4, November 2011

children and teenagers who received full-mouth dental xrays with doses of 1-2.8 Gy or more,76 survivors of the Hiroshima and Nagasaki atomic bombs,77,78 and more recent studies of children receiving high-dose radiation therapy for cancer.79 Although the relative risk in patients who received low-dose radiotherapy was 9.5 times higher than that in the general population, less than 1% of patients treated developed meningiomas.75 Radiation-induced meningiomas are more often multiple and have higher recurrence rates than standard meningiomas.80-82 Most of these tumors are pathologically WHO grade I. One or 2 of the histologic findings associated with grade II tumors (small cell change, nuclear enlargement, hypercellularity, and sheeting) may be found in a greater percentage of the radiation-induced tumors than in standard meningiomas.80,82 Although it is not clear whether a significant proportion of radiation-induced meningiomas are WHO grades II or III at initial presentation, progression in grade is certainly seen in the recurrent tumors.82 It has been suggested that radiation induces meningiomas in individuals with genetic predispositions to radiationinduced tumorigenesis. Support for this notion comes from an epidemiologic analysis that reported an 11% prevalence of meningiomas in first-degree relatives of irradiated patients with meningiomas compared with a less than 1% prevalence of meningiomas in first-degree relatives of irradiated patients without meningiomas.83 In addition, the patients who developed meningioma following irradiation had a higher incidence of other radiation-induced cancers in their siblings. Cytogenetic analyses indicate the most frequent chromosomal loss in radiation-induced meningiomas occurs at 1p followed by 22. Losses of 6q, 7p, 9p, 18q, and 19q as well as gains of 8 and 12 have also been reported, but with less consistency.82,84-89 The increased frequency of chromosome 1p over 22 losses may help explain the more aggressive phenotype of radiation-induced meningiomas. It also brings into question whether these tumors depend on oncogenic pathways that differ from those characterized in meningiomas not associated with radiation. With regard to NF2, the results of studies are variable. Whereas some report a paucity of NF2 mutations and normal merlin expression in radiation-induced meningiomas,88,90 others report underexpression of NF2 transcripts in meningiomas regardless of a history of radiation exposure.82

References 1. Louis DN, Ohgaki H, Wiestler OD, et al: WHO Classification of Tumours of the Central Nervous System (ed 4). Lyon, France, International Agency for Research on Cancer, 2007 2. Burger PC, Scheithauer BW, Vogel FS: Surgical Pathology of the Nervous System and Its Coverings. New York, Churchill Livingstone,2002 3. Bhatoe HS, Singh P, Dutta V: Intraventricular meningiomas: a clinicopathological study and review. Neurosurg Focus 20:E9, 2006

4. Incarbone M, Ceresoli GL, Di Tommaso L, et al: Primary pulmonary meningioma: report of a case and review of the literature. Lung Cancer 62:401-407, 2008 5. Drummond KJ, Bittar RG, Fearnside MR: Metastatic atypical meningioma: case report and review of the literature. J Clin Neurosci 7:69-72, 2000 6. CBTRUS: Statistical report: Primary Brain Tumors in the United States, 2000-2004. Hinsdale, IL, Central Brain Tumor Registry of the United States, 2008 7. Vernooij MW, Ikram MA, Tanghe HL, et al: Incidental findings on brain MRI in the general population. N Engl J Med 357:1821-1828, 2007 8. Simon M, Boström JP, Hartmann C: Molecular genetics of meningiomas: from basic research to potential clinical applications. Neurosurgery 60:787-798, 2007 9. Ketter R, Henn W, Niedermayer I, et al: Predictive value of progression-associated chromosomal aberrations for the prognosis of meningiomas: a retrospective study of 198 cases. J Neurosurg 95:601-607, 2001 10. Olson S, Law A: Meningiomas and the Polynesian population. ANZ J Surg 75:705-709, 2005 11. Cushing H, Eisenhardt L: Meningiomas: Their Classification, Regional Behavior, Life History, and Surgical Results. Springfield, IL, Charles C. Thomas, 1938 12. Regelsberger J, Hagel C, Emami P, et al: Secretory meningiomas: a benign subgroup causing life-threatening complications. Neurooncology 11:819-824, 2008 13. Jagadha V, Deck JH: Massive cerebral edema associated with meningioma. Can J Neurol Sci 14:55-58, 1987 14. Kepes JJ, Chen WY, Connors MH, et al: “Chordoid” meningeal tumors in young individuals with peritumoral lymphoplasmacellular infiltrates causing systemic manifestations of the Castleman syndrome. a report of seven cases. Cancer 62:391-406, 1988 15. Zuppan CW, Liwnicz BH, Weeks DA: Meningioma with chordoid features. Ultrastruct Pathol 18:29-32, 1994 16. Couce ME, Aker FV, Scheithauer BW: Chordoid meningioma: a clinicopathologic study of 42 cases. Am J Surg Pathol 24:899-905, 2000. Erratum in: Am J Surg Pathol 24:1316-1317, 2000 17. Kubota T, Sato K, Kabuto M, et al: Clear cell (glycogen-rich) meningioma with special reference to spherical collagen deposits. Noshuyo Byori 12:53-60, 1995 18. Zorludemir S, Scheithauer BW, Hirose T, et al: Clear cell meningioma. A clinicopathologic study of a potentially aggressive variant of meningioma. Am J Surg Pathol 19:493-505, 1995 19. Perry A, Stafford SL, Scheithauer BW, et al: Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol 21:1455-1465, 1997 20. Perry A, Scheithauer BW, Stafford SL et al: “Malignancy” in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85:2046-2056, 1999 21. Ludwin SK, Rubinstein LJ, Russell DS: Papillary meningioma: a malignant variant of meningioma. Cancer 36:1363-1373, 1975 22. Kepes JJ, Moral LA, Wilkinson SB, et al: Rhabdoid transformation of tumor cells in meningiomas: a histologic indication of increased proliferative activity: report of four cases. Am J Surg Pathol 22:231-238, 1998 23. Winek RR, Scheithauer BW, Wick MR: Meningioma, meningeal hemangiopericytoma (angioblastic meningioma), peripheral hemangiopericytoma, and acoustic schwannoma. A comparative immunohistochemical study. Am J Surg Pathol 13:251-261, 1989 24. Hsu DW, Efird JT, Hedley-Whyte ET: MIB-1 (Ki-67) index and transforming growth factor-alpha (TGF alpha) immunoreactivity are significant prognostic predictors for meningiomas. Neuropathol Appl Neurobiol 24:441-452, 1998 25. Perry A, Stafford SL, Scheithauer BW, et al: The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. Cancer 82:2262-2269, 1998

Alahmadi and Croul

Pathology and Mimetics of Meningiomas

26. Roser F, Nakamura M, Bellinzona M, et al: The prognostic value of progesterone receptor status in meningiomas. J Clin Pathol 57:10331037, 2004 27. Bassoe P, Nuzum F: Report of a case of central and peripheral neurofibromatosis. J Nerv Ment Dis 42:785-796, 1915 28. Omeis I, Hillard VH, Braun A, et al: Meningioangiomatosis associated with neurofibromatosis: report of 2 cases in a single family and review of the literature. Surg Neurol 65:595-603, 2006 29. Maxwell M, Shih SD, Galanopoulos T, et al: Familial meningioma: analysis of expression of neurofibromatosis 2 protein Merlin. Report of two cases. J Neurosurg 88:562-569, 1998 30. Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 66:98-113, 1987 31. Rimbau J, Isamat F: Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) and its relation to the multiple hamartoma syndrome (Cowden disease). J Neurooncol 18:191-197, 1994 32. Leuraud P, Dezamis E, Aguirre-Cruz L, et al: Prognostic value of allelic losses and telomerase activity in meningiomas. J Neurosurg 100:303-309, 2004 33. Lee JY, Finkelstein S, Hamilton RL, et al: Loss of heterozygosity analysis of benign, atypical, and anaplastic meningiomas. Neurosurgery 55:1163-1173, 2004 34. Seizinger BR, de la Monte S, Atkins L, et al. 1987: Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc Natl Acad Sci USA 84:5419-5423 35. Wellenreuther R, Kraus JA, Lenartz D, et al: Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146:827-832, 1995 36. Hartmann C, Sieberns J, Gehlhaar C, et al: NF2 mutations in secretory and other rare variants of meningiomas. Brain Pathol 16:15-19, 2006 37. Boström J, Meyer-Puttlitz B, Wolter M, et al: Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159:661-669, 2001 38. Simon M, von Deimling A, Larson JJ, et al: Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res 55:4696-4701, 1995 39. Sulman EP, Dumanski JP, White PS, et al: Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. Cancer Res 58:3226-3230, 1998 40. Sulman EP, White PS, Brodeur GM: Genomic annotation of the meningioma tumor suppressor locus on chromosome 1p34. Oncogene 23:1014-1020, 2004 41. Bello MJ, de Campos JM, Vaquero J, et al: High-resolution analysis of chromosome arm 1p alterations in meningioma. Cancer Genet Cytogenet 120:30-36, 2000 42. Murakami M, Hashimoto N, Takahashi Y, et al: A consistent region of deletion on 1p36 in meningiomas: identification and relation to malignant progression. Cancer Genet Cytogenet 140:99-106, 2003 43. Buckley PG, Jarbo C, Menzel U, et al: Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci. Cancer Res 65:2653-2661, 2005 44. Leuraud P, Marie Y, Robin E, et al: Frequent loss of 1p32 region but no mutation of the p18 tumor suppressor gene in meningiomas. J Neurooncol 50:207-213, 2000 45. Lomas J, Bello MJ, Arjona D, et al: Analysis of p73 gene in meningiomas with deletion at 1p. Cancer Genet Cytogenet 129:88-91, 2001 46. Piaskowski S, Rieske P, Szybka M, et al: GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis. Cancer Genet Cytogenet 162:63-67, 2005 47. Lomas J, Amiñoso C, Gonzalez-Gomez P, et al: Methylation status of TP73 in meningiomas. Cancer Genet Cytogenet 148:148-151, 2004 48. Nakane Y, Natsume A, Wakabayashi T, et al: Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A. J Neurosurg 107:398-404, 2007

323 49. Menon AG, Rutter JL, von Sattel JP, et al: Frequent loss of chromosome 14 in atypical and malignant meningioma: identification of a putative “tumor progression” locus. Oncogene 14:611-616, 1997 50. Tse JY, Ng HK, Lau KM, et al: Loss of heterozygosity of chromosome 14q in low- and high-grade meningiomas. Hum Pathol 28:779-785, 1997 51. Lamszus K, Kluwe L, Matschke J, et al: Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer Genet Cytogenet 110: 103-110, 1999 52. Leone PE, Bello MJ, de Campos JM, et al: NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas. Oncogene 18:2231-2239, 1999 53. Cai DX, Banerjee R, Scheithauer BW, et al: Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications. J Neuropathol Exp Neurol 60:628-636, 2001 54. Tabernero MD, Espinosa AB, Maíllo A, et al: Characterization of chromosome 14 abnormalities by interphase in situ hybridization and comparative genomic hybridization in 124 meningiomas: correlation with clinical, histopathologic, and prognostic features. Am J Clin Pathol 123:744-751, 2005 55. Maillo A, Orfao A, Espinosa AB, et al: 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. Neurooncology 9:438-446, 2007 56. Lusis EA, Watson MA, Chicoine MR, et al: Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65:7121-7126, 2005 57. Perry A, Banerjee R, Lohse CM, et al: A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 12:183-190, 2002 58. Tse JY, Ng HK, Lo KW, et al: Analysis of cell cycle regulators: p16INK4A, pRb, and CDK4 in low- and high-grade meningiomas. Hum Pathol 29:1200-1207, 1998 59. Rempel SA, Schwechheimer K, Davis RL, et al: Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression. Cancer Res 53:2386-2392, 1993 60. Mihaila D, Gutiérrez JA, Rosenblum ML, et al; NABTT CNS Consortium: Meningiomas: analysis of loss of heterozygosity on chromosome 10 in tumor progression and the delineation of four regions of chromosomal deletion in common with other cancers. Clin Cancer Res 9:4435-4442, 2003 61. Scholz M, Gottschalk J, Striepecke E, et al: Intratumorous heterogeneity of chromosome 10 and 17 in meningiomas using non-radioactive in situ hybridization. J Neurosurg Sci 40:17-23, 1996 62. Ozaki S, Nishizaki T, Ito H, Sasaki K: Comparative genomic hybridization analysis of genetic alterations associated with malignant progression of meningioma. J Neurooncol 41:167-174, 1999 63. Krupp W, Holland H, Koschny R, et al: Genome-wide genetic characterization of an atypical meningioma by single-nucleotide polymorphism array-based mapping and classical cytogenetics. Cancer Genet Cytogenet 184:87-93, 2008 64. Kasai H, Kawamoto K: Cytogenical analysis of brain tumors by FISH (fluorescence in situ hybridization) and FCM (flow cytometry). Noshuyo Byori 12:75-82, 1995 65. Kim JH, Lee SH, Rhee CH, et al: Loss of heterozygosity on chromosome 22q and 17p correlates with aggressiveness of meningiomas. J Neurooncol 40:101-106, 1998 66. Büschges R, Ichimura K, Weber RG, et al: Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas. Brain Pathol 12:145-153, 2002 67. Langford LA, Piatyszek MA, Xu R, et al: Telomerase activity in ordinary meningiomas predicts poor outcome. Hum Pathol 28:416420, 1997

324

Seminars in Diagnostic Pathology, Vol 28, No 4, November 2011

68. Hiraga S, Ohnishi T, Izumoto S, et al: Telomerase activity and alterations in telomere length in human brain tumors. Cancer Res 58:21172125, 1998 69. Carroll T, Maltby E, Brock I, et al: Meningiomas, dicentric chromosomes, gliomas, and telomerase activity. J Pathol 188:395-399, 1999 70. Chen HJ, Liang CL, Lu K, et al: Implication of telomerase activity and alternations of telomere length in the histologic characteristics of intracranial meningiomas. Cancer 89:2092-2098, 2000 71. Boldrini L, Pistolesi S, Gisfredi S, et al: Telomerase in intracranial meningiomas. Int J Mol Med 12:943-947, 2003 72. Maes L, Kalala JP, Cornelissen R, et al: Telomerase activity and hTERT protein expression in meningiomas: an analysis in vivo versus in vitro. Anticancer Res 26:2295-2300, 2006 73. Maes L, Van Neste L, Van Damme K, et al: Relation between telomerase activity, hTERT and telomere length for intracranial tumours. Oncol Rep 18:1571-1576, 2007 74. Modan B, Baidatz D, Mart H, et al: Radiation-induced head and neck tumours. Lancet 1:277-279, 1974 75. Ron E, Modan B, Boice JD Jr, et al: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319:1033-1039, 1988 76. Preston-Martin S, Paganini-Hill A, Henderson BE, et al: Case-control study of intracranial meningiomas in women in Los Angeles County, California. J Natl Cancer Inst 65:67-73, 1980 77. Shibata S, Sadamori N, Mine M, et al: Intracranial meningiomas among Nagasaki atomic bomb survivors. Lancet 344:1770, 1994 78. Shintani T, Hayakawa N, Hoshi M, et al: High incidence of meningioma among Hiroshima atomic bomb survivors. J Radiat Res Tokyo 40:49-57, 1999 79. Musa BS, Pople IK, Cummins BH: Intracranial meningiomas following irradiation—a growing problem? Br J Neurosurg 9:629-637, 1995

80. Rubinstein AB, Shalit MN, Cohen ML, et al: Radiation-induced cerebral meningioma: a recognizable entity. 1. J Neurosurg 61:966-971, 1984 81. Soffer D, Pittaluga S, Feiner M, et al: Intracranial meningiomas following low-dose irradiation to the head. J Neurosurg 59:1048-1053, 1983 82. Lillehei KO, Donson AM, Kleinschmidt-DeMasters BK: Radiationinduced meningiomas: clinical, cytogenetic, and microarray features. Acta Neuropathol 116:289-301, 2008 83. Flint-Richter P, Sadetzki S: Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol 8:403-410, 2007 84. Al-Mefty O, Topsakal C, Pravdenkova S, et al: Radiation-induced meningiomas: clinical, pathological, cytokinetic, and cytogenetic characteristics. J Neurosurg 100:1002-1013, 2004 85. Pagni CA, Canavero S, Fiocchi F, et al: Chromosome 22 monosomy in a radiation-induced meningioma. Ital J Neurol Sci 14:377-379, 1993 86. Rajcan-Separovic E, Maguire J, Loukianova T, et al: Loss of 1p and 7p in radiation-induced meningiomas identified by comparative genomic hybridization. Cancer Genet Cytogenet 144:6-11, 2003 87. Rienstein S, Loven D, Israeli O, et al: Comparative genomic hybridization analysis of radiation-associated and sporadic meningiomas. Cancer Genet Cytogenet 131:135-140, 2001 88. Shoshan Y, Chernova O, Juen SS, et al: Radiation-induced meningioma: a distinct molecular genetic pattern? J Neuropathol Exp Neurol 59:614-620, 2000 89. Zattara-Cannoni H, Roll P, Figarella-Branger D, et al: Cytogenetic study of six cases of radiation-induced meningiomas. Cancer Genet Cytogenet 126:81-84, 2001 90. Joachim T, Ram Z, Rappaport ZH, et al: Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas. Int J Cancer 94:218221, 2001