1588

Neuro-Oncology
19(12), 1588–1598, 2017 | doi:10.1093/neuonc/nox101 | Advance Access date 20 May 2017

Diagnostic challenges in meningioma

Martha Nowosielski, Norbert Galldiks, Sarah Iglseder, Philipp Kickingereder,

Andreas von Deimling, Martin Bendszus, Wolfgang Wick, and Felix Sahm

University Medical Center, Neurology, and Neurooncology, German Cancer Research Center and German
Consortium for Translational Cancer Research, Heidelberg, Germany (M.N., W.W.); Medical University Innsbruck,
Department of Neurology, Innsbruck, Austria (M.N., S.I.); Institute of Neuroscience and Medicine, Research Center
Jülich, Jülich, Germany (N.G.); Department of Neurology, University of Cologne, Cologne, Germany (N.G.); Center
of Integrated Oncology, Universities of Cologne and Bonn, Cologne, Germany (N.G.); University Medical Center,
Neuroradiology, Heidelberg, Germany (P.K., M.B.); University Medical Center, Neuropathology, Heidelberg, Germany
(A.V.D., F.S.); Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research,
German Cancer Research Center, Heidelberg, Germany (A.V.D., F.S.)

Corresponding Author: Martha Nowosielski, MD, PhD, Neurology Clinic and National Center for Tumor Diseases, University of
Heidelberg and German Cancer Research Center, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany (Martha.Nowosielski@i-
med.ac.at).

Abstract
Advances in molecular profiling and the application of advanced imaging techniques are currently refreshing
diagnostic considerations in meningioma patients. Not only technical refinements but also sophisticated histo-
pathological and molecular studies have the potential to overcome some of the challenges during meningioma
management. Exact tumor delineation, assessment of tumor growth, and pathophysiological parameters were
recently addressed by “advanced” MRI and PET. In the field of neuropathology, high-throughput sequencing and
DNA methylation analysis of meningioma tissue has greatly advanced the knowledge of molecular aberrations
in meningioma patients. These techniques allow for more reliable prediction of the biological behavior and clini-
cal course of meningiomas and subsequently have the potential to guide individualized meningioma therapy.
However, higher costs and longer duration of full molecular work-up compared with histological assessment may
delay the implementation into clinical routine.
This review highlights the diagnostic challenges of meningiomas from both the neuroimaging as well as the neu-
ropathological side and presents the latest scientific achievements and studies potentially helping in overcoming
these challenges. It complements the recently proposed European Association of Neuro-Oncology guidelines on
treatment and diagnosis of meningiomas by integrating data on nonstandard imaging and molecular assessments
most likely impacting the future.

Key words
diagnosis | meningioma | molecular markers | MRI | neuropathology | PET

Meningiomas are the most frequently reported primary guide individualized therapy.2,3 In the updated World Health
CNS tumors, comprising ~36.1% of all CNS tumors, with Organization (WHO) classification of 2016, the grading and
an incidence of 7.61/100 000.1 They originate from arach- classification of meningiomas did not undergo major revi-
noid meningothelial cells and therefore belong to the sions, except for the introduction of brain invasion as a cri-
group of intracranial extra-axial neoplasms. Just as in terion for the diagnosis of an atypical meningioma.4
other neuro-oncologic entities (eg, gliomas), efforts are Recently, guidelines for diagnosis and treatment of
under way to incorporate molecular profiling into the diag- meningiomas have been published by the European
nostic work-up to allow for a better characterization of the Association of Neurooncology (EANO).2 If treatment is
biological behavior of meningiomas and subsequently required, surgery is the first option. However, there is a

© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
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 Nowosielski et al. Diagnostic challenges in meningioma 1589

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significant subset of patients (especially with higher WHO psammomatous calcifications in the tumor, which is seen
grades) who are not successfully managed by surgery in approximately 25% of meningiomas. Best demonstrated
alone or in whom a complete resection is not possible on CT are osseous destructions which were shown to be
due to the location of the tumor to eloquent brain areas. indicative of atypical or malignant meningioma. In con-
In these patients, adjuvant therapy regimens mainly in the trast, hyperostosis of adjacent skull bone, radiologically
form of radiotherapy need to be applied. Various treatment characterized by cortical thickening and hyperdensity, is
concepts combining surgery and radiosurgery or fraction- highly suggestive of benign meningioma.6 Hyperostosis
ated radiotherapy with different radiation schedules as associated with meningiomas has shown to be caused
well as pharmacological approaches are being developed by tumor invasion of the bone.12 On MRI, meningiomas
and prospective randomized trials are currently ongoing.2 present isointense to the cortex on T1- and T2-weighted
Importantly, according to the EANO guidelines, inciden- sequences and with typically a strong homogeneous en-
tally diagnosed and radiologically presumed meningiomas hancement following administration of gadolinium con-
(usually asymptomatic) may be managed with observation trast. An enhancing “dural tail” adjacent to the tumor,
only. In these patients, treatment may be withhold until which in histopathological correlations has occasionally
symptoms develop, sustained growth occurs, or concerns shown a tumor invasion into the dura mater, represents
of entrapment on sensitive structures arises.2,5 In these a hypervascular, nonneoplastic reaction in the majority of
cases, definitive diagnosis including histological classi- cases.13 Benign meningiomas typically derive their main
fication and grading is lacking without tissue diagnosis; blood supply from the external carotid via dural branches.
risk assessment for tumor growth and progression is then These vessels do not contain a blood–brain barrier and are
exclusively based on clinical and standard MRI findings. thus permeable to gadolinium, generating typical time–
Given the number of tumors managed without invasive intensity curves in T2*-weighted MRI, with little or no re-
diagnosis, meningiomas are one of the most important turn to baseline following contrast agent application.14
neuro-oncologic entities requiring highly precise and reli- However, as the meningioma enlarges, it may recruit pial
able non-invasive diagnostic modalities. branches at the periphery of the tumor from the brain par-
This review highlights the daily diagnostic challenges enchyma, which do contain a blood–brain barrier, show-
that arise during clinical management of meningioma ing an elevated relative cerebral blood volume (rCBV) with
patients from both the neuroimaging and the neuropathol- time–intensity curves that return to baseline signal levels.15
ogy point of view and complements the current guidelines MR spectroscopy with the ability to evaluate metabolite
by integrating nonstandard imaging and molecular assess- concentrations within a given region of interest shows a
ments most likely impacting the future. characteristic alanin peak at 1.3–1.5  ppm16 (Fig.  1). These
pathophysiologic backgrounds allow functional imaging
techniques to assess tumor aggressiveness and solve dif-
ferential diagnostic problems as stated below.11,15,17
Meningioma Diagnosis
Imaging Techniques and Findings Histological Features
The majority of cases display a histology that allows identi-
The tentative diagnosis of meningioma can be made by
fication of the entity meningioma upon inspection of hema-
contrast-enhanced MRI,2 which is also used for long-term
toxylin/eosin staining. Typical features include formation of
follow-up because of the superior soft-tissue capabilities
whorls of tumor cells, nuclear pseudo-inclusions, pseudo-
and absence of radiation exposure. In case of contrain-
syncytial growth, and formation of concentric calcifica-
dications (eg, pacemaker), contrast-enhanced CT can be
tions, called “psammoma bodies.”4 Immunohistochemistry
applied as an alternative cross-sectional technique.6 Intra-
for epithelial membrane antigen or SSTR2a,18 which are
arterial cerebral angiography has no routine role in the
usually positive in meningioma, support the histological
diagnostic workup of meningiomas but can be used as an
diagnosis (Fig. 2).
adjunct to treatment planning or preoperative devascu-
larization in selected cases.2 As meningioma cells strongly
express somatostatin-receptor subtype 2 (SSTR2),7 PET-
based imaging using SSTR ligands such as 68Ga-DOTATOC
Challenge I: Differential Diagnoses
(DOTA-(Tyr3)-octreotide) and 68Ga DOTATATE (DOTA-D-
Phe1-Tyr3-octreotate) has shown to be a helpful additional Radiological Aspects
diagnostic tool.8–10
Meningiomas appear as broad-based dural hemispheric A variety of intracranial lesions may radiologically mimic
or oval lesions, attached to the dura mater. They most fre- meningioma. Tumor location and growth pattern, however,
quently occur supratentorially at the calvaria or the skull might be helpful for differential diagnostic considerations
base meninges, along the falx and in the parafalcine lo- (Table 1). If located in the cerebral hemispheres, meningi-
cation, but they can also be found attached to the ten- omas can be difficult to distinguish from dural metastases
torium, in the cerebello-pontine angle, within the optic especially from prostate, lung, kidney, or breast can-
nerve sheath, or occurring intraventricularly.11 On CT, cers,19,20 primary glial tumors that extend into the suba-
meningiomas usually appear isodense but can occasion- rachnoid space,21 and hematopoietic neoplasms such as
ally be hyperdense or slightly hypodense compared with extra-axial non-Hodgkin lymphoma.22 Characteristic imag-
brain tissue.12 CT is more sensitive than MRI in detecting ing changes, suggestive of a meningioma, along the optic
1590 Nowosielski et al. Diagnostic challenges in meningioma

Fig. 1  Standard plus advanced MRI in a large bifrontal meningioma. MR images of a 67-year-old man with a 4-month history of progressive
frontal headaches associated with decreased motivation and personality changes. (A) T1-weighted contrast-enhanced MR image shows a
large meningioma bifrontally with intense, relatively inhomogeneous enhancement. (B) Axial T2-weighted sequence shows high signal intensity
of the tumor with very little peritumoral edema. (C) MR spectroscopy shows a prominent resonance from choline (black arrow) and creatine
(blue arrow) and an inverted doublet peak at 1.45 ppm, corresponding to alanin as a typical marker for meningiomas (red arrow). (D) In MR perfu-
sion there is increased blood volume at the periphery of the lesion due to pial blood supply and heterogeneous blood volume in the tumor center.

nerve sheath or the cavernous sinus may represent glioma Functional imaging techniques including MR perfu-
or even inflammatory (rheumatoid arthritis, Wegener’s sion may differentiate between meningioma and dural
granulomatosis, extra-axial neurosarcoidosis) and infec- metastases from different entities (breast, colon, and
tious diseases (tuberculosis, syphilitic gumma).13,23,24 prostate carcinoma),26 with the exception of metasta-
Pituitary neoplasms like adenomas or craniopharyn- ses from Merkel cell carcinoma, renal carcinoma, or
giomas may also mimic meningiomas. If located at the melanoma, which also represent hypervascular lesions
skull base and especially at the cerebello-pontine angle, with elevated CBV values.26,27 High-grade glioma invad-
meningiomas have to be distinguished from vestibular ing the dura mater may also be difficult to distinguish
schwannomas and neoplastic meningitis; if located within from meningioma, as both lesions show high rCBV val-
ventricles, they need to be differentiated from other ven- ues in perfusion MRI.28,29 In these cases, the evaluation
tricle tumors such as choroid plexus papillomas/carcino- of the time–intensity curve was shown to be a helpful
mas, ependymomas or metastases,11 and solitary fibrous approach14 (Table  2). In MR spectroscopy, an elevated
tumors/hemangiopericytomas.25 As differential diagnoses distinct metabolite peak at 3.8 ppm may allow a differen-
along the spinal cord, metastases, subependymoma, and tiation between meningiomas, high-grade gliomas, and
ependymoma have to be considered. intracranial metastases.30
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Fig. 2  Molecular versus histological diagnosis in meningioma. (A) A meningioma with widely inconspicuous histology and low mitotic activity
may harbor (B) a small area of elevated proliferation. If this area is included in the 10 HPF for assessment of mitotic activity, it might surpass the
threshold for WHO grade II. However, if this area is regarded as nonrepresentative and excluded from assessment of mitotic activity, or not even
present in the section due to sampling bias, the identical tumor might be assigned WHO grade I. (C) Detection of an AKT1 mutation associated
with WHO grade I and slow or no progression, or (D) of a TERT promoter mutation, indicating a higher risk of recurrence, gives additional objec-
tive information on the tumor biology. Scale bar represents 100 µm.

Histological Aspects (such as indistinct tumor–brain interface, positive cap-

sular enhancement, and heterogeneous tumor enhance-
Compared with imaging, differential diagnostic problems ment) were shown to correlate with a higher WHO grade.41
play only a minor role during neuropathological assess- Contradictory results on tumor grading were reported for
ment. If necessary, the most common differential diagno- diffusion-weighted (DW) MRI.42,43 In a retrospective study
ses such as solitary fibrous tumor/hemangiopericytoma of 177 meningioma patients, DW-MRI had no value in both
can be ruled out by staining for signal transducer and determining the histological behavior and differentiating
activator of transcription 6, which is strongly positive in between histopathological subtypes of meningiomas.42
the nucleus of solitary fibrous tumor/hemangiopericy- In contrast, the preoperative assessment of the apparent
toma but confined to the cytoplasm in meningioma31–34 diffusion coefficient (ADC) from DW-MRI showed to be
(Table  2). Once the entity is identified, the meningioma inversely correlated with the histological grade of 77 men-
has to be assigned to one of 15 meningioma subtypes ingioma patients. Studies on MR perfusion for meningi-
which have evolved over decades. This dates back to the oma subtyping are scarce and existing evidence is likewise
1920s when Bailey and Cushing proposed the first clas- contradictory.17,43 In a small pilot study, 24 meningioma
sification schemes of meningioma, establishing the still patients were examined using dynamic O-(2-[18F]-fluoro-
recognized fibroblastic, meningothelial, and angiomatous ethyl)-L-tyrosine (18F-FET) PET and it could be observed that
subtypes.35,36 Importantly, subsequent studies added to different patterns of time–activity curves in combination
the spectrum of subtypes and reported different propensi- with tumor-to-brain ratios are able to differentiate between
ties for recurrence.37–40 high-grade and low-grade meningiomas44 (Table 2).

Histological Features
Challenge II: Meningioma Subtyping
As stated above, the challenge in the neuropathological
and Grading work-up of meningioma is usually not the identification of
Imaging Features the entity, but subtyping and grading. The WHO classifica-
tion recognizes 15 subtypes of meningioma4: 9 are allot-
Up to now, the value of meningioma grading on the ted to WHO grade I, and 3 each to WHO grades II and III.4
basis of neuroimaging has been low. In a retrospective The criteria for consecutive subtyping and grading are
study of 120 meningioma patients, distinct MRI features based purely on histology. Among grade I meningiomas,
1592 Nowosielski et al. Diagnostic challenges in meningioma

the presence of any of the histological patterns found in

Table 1  Differential diagnoses11,13,21,25,89–94 grade I  tumors. As a threshold for increased mitotic ac-
tivity, the current classification recommends using either
Localization Differential Diagnoses
≥4 mitotic figures in 10 microscopic high-power fields
Cerebral -Dural metastases (prostate, lung, kidney, (HPF) (ie, about 0.16  mm2 each) or ≥5 mitotic figures in
hemispheres breast cancer, neuroblastoma)
-Glioma
10 HPF if the tumor has markedly increased cellularity.
-Non Hodgkin lymphoma Moreover, a catalogue of alternative criteria exists: high
-Primary Hodgkin disease cell density, pleomorphism, necrosis, “sheeting”-like
-Solitary fibrous tumor/hemangiopericytoma growth, high core/nucleus ratio. If 3 of these are present,
-Pleomorphic xanthoastrocytoma
atypical meningioma can be diagnosed in the absence of
-Hemangioblastoma
-Cavernoma increased mitotic activity. Finally, histological evidence for
-Mucosa-associated lymphoid tissue brain invasion is another independent criterion for atypical
lymphoma (MALT) meningioma WHO grade II, newly introduced in the recent
-Histiocytosis update of the WHO classification.4
Optic nerve -Optic glioma Besides these manifold criteria for atypical meningioma
sheath -Optic neuritis WHO grade II, clear cell histology and cord-like growth pat-
Cavernous -Glioma tern in a mucoid matrix also render a grade II diagnosis,
sinus -Inflammatory (rheumatoid arthritis, Wegener namely clear cell or chordoid meningioma WHO grade II.
granulomatosis, neurosarcoidosis)
Observations that meningioma with these features tend to
-Infectious disease (tuberculosis, syphilitic
gumma) have more aggressive behavior lead to their general des-
-Erdheim–Chester disease and eosinophilic ignation as WHO grade II.4,37,40 However, these variants are
granuloma so rare that studies investigating the prognostic relevance
Nasal cavity -Adenoid cystic carcinoma had to rely on limited case numbers. Similarly, grade III
-Chloroma meningioma is defined by “overtly malignant histology”
-Esthesioneuroblastoma and “markedly elevated mitotic activity,” usually regarded
Spinal cord -Glioma as ≥20 mitotic figures per 10 HPF, then termed anaplastic
-Ependymoma meningioma WHO grade III. Formation of perivascular
-Subependymoma
pseudopapillary growth or rhabdoid cells can also qualify
-Schwannoma
-Embryonal tumor for grade III, termed papillary or rhabdoid meningioma
-Meningeal melanoma WHO grade III.4,38,39,46,47
Cerebello- -Schwannoma Recent studies have questioned the reliability of several
pontine -Neoplastic meningitis of these criteria. Brain invasion, a criterion for atypical men-
angle -Papillary middle-ear tumor ingioma WHO grade II, was not associated with increased
-Metastases risk of recurrence in 3 recent reports.48–50 In another recent
-Plasmacytoma
-Teflon granuloma following microvascular
study, rhabdoid cytology was not indicative of increased
decompression risk of recurrence when other criteria of malignancy were
lacking.51 Accordingly, the updated WHO classification rec-
Ventricles -Choroid plexus papillomas/carcinomas
-Ependymomas ommends to diagnose rhabdoid meningioma WHO grade
-Metastases III only if these cytological features are accompanied by
Pituitary -Pituitary adenoma increased proliferation. Although the concordance for histo-
gland -Adenohypophysitis logical grading was up to 87.2% in a comparative Radiation
-Pituitary apoplexy Therapy Oncology Group study,45 the high subjectivity
-MALT95 of evaluation criteria is a matter of ongoing debates. Risk
-Craniopharyngioma
stratification based on biomarkers is anticipated to increase
Arterial mal- -Arterial aneurysm the prediction power of the classification (Table 2).
formations -Dural cavernous angioma

Molecular Profiles
the 9 variants are defined by cytological or histoarchi- Meningiomas were among the first tumors in which
tectonic features. Examples are presence of secretory cytogenetic aberrations were identified: loss of a copy of
granula, yielding the diagnosis of secretory meningioma 22q52 frequently accompanied by mutations of the remain-
WHO grade I, or spindle cells in a collagen-rich matrix ing NF2 allele affects 60%–80% of meningiomas.53–57
in fibrous meningioma WHO grade I.  Yet, several of the Subsequent studies identified that an accumulation of
various histological patterns can occur in the same tumor cytogenetic aberrations, most frequently losses of 1p,
to varying extent, making subtyping prone to a consider- 10, and 14q, is associated with malignancy and risk of
able interobserver and sampling bias.45 The lack of exact recurrence.58–60 Thus, novel grading algorithms were pro-
delineation of subtypes might be of limited clinical rele- posed that take chromosomal aberrations into account.61
vance among WHO grade I tumors. However, the diagnosis However, their advantage over the WHO classification in
of a higher grade is based on similar, purely histological prognostic accuracy and the cost of cytogenetic analyses
criteria. Atypical meningioma WHO grade II is diagnosed rendered this approach unfeasible for routine diagnostic
if increased mitotic activity is detected, independently of application.
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Table 2  Challenges during menigioma management and recent study results on how to overcome them

CHALLENGE Diagnostic Approach

Differential MRI Standard MRI—tumor location might be helpful (Table 1)
diagnosis MR perfusion14,26 to differentiate between meningioma and dural metastases, CAVE—
tumors with elevated blood perfusion
MRS peak at 3.8 ppm in meningiomas.30
PET -
Neuropathology STAT6 staining31–34 to differentiate between meningioma and solitary fibrous tumor/
hemangiopericytoma
Subtyping and MRI Anatomical features41 to distinguish between WHO grades
grading Contradictory results on DW-MRI42,43 and perfusion MRI17 for meningioma subtyping
PET Dynamic 18F-FET PET44 to distinguish between high-grade and low-grade meningiomas
Neuropathology Histological features4: brain invasion as new additional criterion to diagnose atypical
meningioma WHO grade II
Molecular pathology62–67:
-AKT1/TRAF7 and SMO mutations mostly in basal meningioma with meningothelial
histology
-KLF4/TRAF7 mutation in secretory meningiomas WHO grade I
Assessment of MRI Follow-up imaging according to WHO grade2
tumor growth and -WHO grade I: 1x/year for 5 years, afterward every 2 years
risk of recurrence -WHO grade II: every 6 months for 5 years, afterward 1x/year
-WHO grade III: every 3–6 months indefinitely
PET 68Ga-DOTATATE PET75: SUVmax predicts faster growth in WHO grade I and II meningioma,
not in WHO grade III
11C-MET PET76,77: contradictory results on predicting tumor growth

Neuropathology TERT promoter region mutation3,68,69 is associated with increased risk of recurrence and
shorter progression-free survival, present in only 6%–8% of meningiomas
Delineation of MRI Standard MRI has difficulties in differentiating meningioma from adjacent anatomical
tumor extent structures (skull base) and postoperative changes.
PET 68Ga-DOTATATE PET10 to discriminate meningioma from tumor-free tissue uptake (SUVmax
threshold, 2.3) and to improve target volume definition in radiation planning8,82–84 in the
vicinity of bony skull base or after complex surgical procedures
Neuropathology Histological assessment of dura invasion and of other surrounding structures.

Abbreviations: ADC = apparent diffusion coefficient, MRS = magnetic resonance spectroscopy, ppm = parts per million, STAT6 = signal transducer
and activator of transcription 6, 18F-FET = O-(2-[18F]-fluoro-ethyl)-L-tyrosine, 11C-MET = [11C]Methionine,68 Ga-DOTATATE = DOTA-(Tyr3)-octreotide,
TERT = telomerase reverse transcriptase. SUV = standardized uptake value.

High-throughput sequencing of meningiomas have novel therapy approaches in meningioma. First clinical tri-
significantly advanced the knowledge of molecular aber- als have already been initiated (eg, NCT02523014).
rations in meningioma during the past 4  years. Besides As stated above, cytogenetic aberrations have shown to
NF2 mutations, recurrent mutations in AKT1, SMO, be associated with malignancy and risk of recurrence.58–60
PIK3CA, KLF4, TRAF7, POLR2A, PRKAR1A, and SUFU were However, none of these markers has been demonstrated
detected.62–67 Except for SUFU, they occur mutually exclu- to be of prognostic relevance. In contrast, mutations in
sively to NF2 mutations in most cases. Moreover, activat- the promoter region of TERT are strongly associated with
ing hotspot mutations in AKT1 and KLF4 usually coincide increased risk of recurrence and shorter progression-free
with mutations in TRAF7. No exact hotspot was detected survival compared with meningiomas with identical his-
for TRAF7. Instead, the mutations are distributed through- tology but TERT wild-type status.3,68,69 Thus, TERT might
out the sequence that codes for the WD40 domain of the emerge as the first molecular biomarker of more aggres-
TRAF7 protein. Intriguingly, several of these mutations or sive meningioma. While TERT mutations affect only about
combinations of mutations are associated with distinct 6%–8% of meningiomas, further studies and trials are
tumor localizations or histological subtypes. AKT1/TRAF7 warranted to identify reliable markers for the full range of
and SMO mutations mostly affect basal meningioma with meningioma subtypes (Table 2).
meningothelial histology. KLF4/TRAF7 mutant meningi- Recent studies on genome-wide DNA methylation profil-
omas are virtually always associated with occurrence of ing distinguished 6 distinct molecular classes associated
secretory granula in the tumor and, therefore, molecularly with a more homogeneous clinical course. The methylation-
define secretory meningiomas of WHO grade I. These find- based classification system allows prognostication with
ings might have both a diagnostic as well as a therapeutic higher power than the WHO classification, which is mor-
impact. With inhibitors of mutant AKT, SMO, and PIK3CA phology based. Specifically, patients with WHO grade I his-
available, this novel insight might soon be applied for tology but a high risk of recurrence and patients at lower
1594 Nowosielski et al. Diagnostic challenges in meningioma

risk of recurrence among WHO grade II tumors are better for the radiolabeled amino acid 11C-methyl-L-methionine
differentiated. In addition, the number of relevant subtypes (11C-MET).76,77 However, a recently reported 10-year fol-
may be reduced from the currently recognized 15 histologi- low-up evaluation of proton beam irradiated meningioma
cal variants to 6 clinically relevant molecular classes, each patients using 11C-MET PET78 showed that in cases where
with a characteristic molecular profile70 (Fig. 2). tumor remnants showed progression (n = 2), the 11C-MET
uptake ratio increased considerably earlier than the vol-
ume increase on MRI.78

Challenge III: Assessment of

Tumor Growth
Challenge IV: Delineation of
Imaging Features Tumor Extent
A major challenge in meningioma management is the early Following surgery, conventional neuroimaging with CT
prediction of tumor recurrence or progression (ie, the iden- or MRI has limitations in distinguishing between tumor
tification of meningioma patients with progressive tumor remnants and adjacent anatomical structures, postopera-
growth). Given the generally slow growth rate of benign tive changes (eg, scars),79 or bone involvement.80 This con-
meningiomas, the tumor must reach a substantial size stitutes a major challenge in delineating tumor borders,
before regrowth and progression can be diagnosed, and which is particularly important for subsequent treatment
it is critical to select an appropriate time point for therapy planning such as (re-)resection or radiation therapy (ie,
initiation, especially in regions difficult to access, such as definition of the target volume).
the skull base. Recommended intervals of follow-up imag- Data on ultra-high-field MRI were recently reported for 4
ing by standard MRI currently depend on the WHO grade.2 meningioma patients. The advantages of 7.0 Tesla MRI over
WHO I grade tumors require annual MRI assessments for 1.5 Tesla MRI were a more detailed depiction of the peri-
5 years followed by biannual follow-ups. Follow-up imag- and intratumoral vasculature and a clear delineation of
ing of WHO grade II meningiomas should be done every the tumor–brain interface useful for surgical planning. The
6 months, then annually after 5 years, and WHO grade III authors, however, reported an impaired image quality in
tumors require follow-up every 3–6  months indefinitely. skull base lesions at 7.0 Tesla due to susceptibility artifacts.81
The most important factor to estimate tumor recurrence is PET studies have shown to be of more value to overcome
the grade of surgical resection as defined by Simpson.71,72 this challenge. Rachinger and colleagues observed impor-
Further risk factors for progression and recurrence of men- tant findings for the understanding of the 68Ga-DOTATATE
ingiomas are not fully understood and it therefore is of PET signal.10 In a study with neuronavigated tissue sam-
great interest to find methods that can predict tumor pro- pling, they found that an increased 68Ga-DOTATATE uptake
gression earlier than solely when there is a radiological (SUVmax threshold, 2.3) in PET imaging discriminates men-
increase in size. In this context, the natural history of 273 ingioma and tumor-free tissue with higher sensitivity than
intracranial meningiomas being managed purely conserv- standard MRI (90% vs 79%)10 (Fig. 3).
atively was studied, and factors associated with a higher A PET-based imaging approach with SSTR2 ligands has
annual growth rate were male sex, initial tumor diameter therefore been investigated for high-precision radiother-
greater than 25  mm, T2 signal hyperintensity and edema apy planning of subtotally resected or recurring complex
on MRI, and the presence of symptoms.73 skull base meningioma8,82–84 with the goal to spare as
An imaging-based approach in 144 meningioma patients much critical tissue as possible without missing tumor. In
following surgery showed that DW-MRI including ADC these studies, radiation planning with 68Ga-DOTATOC-PET
maps outperformed WHO grading for the prediction of pro- showed an improvement of target volume definition by
gression after initial treatment.74 In this retrospective study providing additional information in around two thirds of
the authors were able to stratify the patients into 3 risk cases,8,82–84 with most adaptations being necessary in the
groups and showed that patients with non-Simpson grade vicinity of bony skull base or after complex surgical pro-
I  resection and low ADC values have a significant risk of cedures. Similar findings could be observed in other PET
progression or recurrence and may benefit from adjuvant studies using 11C-MET.85,86
radiotherapy and/or additional surgery.
Promising results for the identification of an increased
growth rate were recently reported by Sommerauer et al,75
who showed that a high expression of SSTR2 in 64 men- Future Directions and Prospects
ingioma patients as measured by maximum standardized
uptake value (SUVmax) in 68Ga-DOTATATE PET predicts Future attempts to understand meningioma may combine
faster growth in WHO grades I and II meningioma, whereas imaging, histological, and molecular features. Similar
WHO grade III meningioma did not show an association of to parenchymal brain tumors, the concept of an “inte-
tumor growth rate with tracer binding. The authors stated grated diagnosis” will be adopted also for meningiomas.87
that these data may help in planning the optimal time point Integrated diagnoses consider the histological appear-
for surgery and for follow-up imaging and may especially ance and genetic and epigenetic aberrations and provide
be valuable for newly diagnosed meningioma in critical a more precise prediction of risk of recurrence in order to
locations such as the skull base.75 Contradictory findings well advise patients, guide management decisions, and
on the assessment of the tumor growth rate were reported stratify for clinical trials. A  further step in this context,
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Fig. 3  68Ga-DOTATATE PET for the differentiation of meningioma from tumor-free tissue and postoperative changes. (A) Preoperative imaging.
MR and PET images of a 55-year-old male patient who presented with therapy-resistant left frontal headache for the past 6 months. T1-weighted
MR images show subtle contrast enhancement at the skull base without exact delineation of tumor borders. The fluid attenuated inversion
recovery sequence shows diffuse signal changes. In contrast, 68Ga-DOTATATE PET (DOTA-(Tyr3)-octreotide) is able to differentiate between
meningioma and tumor-free tissue with an excellent tumor-to-background contrast. Fusion images were used for surgical planning. (B) Imaging
at recurrence. Histological grading revealed a WHO grade II meningioma. After subtotal surgical resection (Simpson grade IV), the patient
underwent radiation therapy. Follow-up imaging after 2 years revealed further tumor growth/recurrence. The T1-weighted image shows diffuse
contrast enhancement at the skull base, difficult to be differentiated from postoperative changes. 68Ga-DOTATATE PET in contrast is consistent
with meningioma tissue in this region with additional retrobulbar tumor growth.

complementing the evolving landscape of genetic analy- respect to tumor delineation and the evaluation of tumor
sis (“genomics”), can be “radiomics”—the extraction of growth rate. Research on molecular genetic alterations in
a large number of quantitative imaging features and rec- meningiomas is currently ongoing with the goal to incor-
ognition of imaging phenotypes/patterns by automated porate molecular markers into WHO classification and
data characterization.88 Linkage of these radiomic features allow for a more precise assessment of prognosis, risk of
to genomic data (“imaging-genomics” or “radiogenom- recurrence, and guidance of therapy.
ics”) is currently an evolving research field that hopefully
will also address meningioma challenges such as tumor
growth kinetics and differential diagnoses as outlined Acknowledgments
above. Ultimately, it will be the goal not only to character-
The authors confirm the originality of this manuscript. Parts of
ize meningioma tissue and give prognostic information
this review have been presented at the EANO meeting 2016 in
but to offer potential therapeutic strategies—in the form
Mannheim at the educational day.
of targeted therapies (eg, NCT02523014) or recently also in
the form of immunologic approaches (eg, NCT02648997).

Conflict of interest statement. M.B. has received research

funding from Siemens, Novartis, Bayer, Stryker, Medtronic,
Summary Codman, and Guerbet. He has received speaker honoraria from
Codman, Roche, Bayer, Novartis, Teva, and Guerbet. He has a
In summary, neuroimaging with standard MRI is the consultant relationship with B. Braun, Boehringer Ingelheim,
imaging modality of choice for the initial diagnosis and Codman, Vascular Dynamics, and Guerbet. W.W. has par-
follow-up of meningioma patients. Functional imaging ticipated in a speaker’s bureau for and has received research
approaches such as perfusion MRI may help in differen- funding from MSD. He has received research funding from
tial diagnostic problems, and PET imaging especially with Apogenix, Boehringer Ingelheim, Genentech Roche, and Pfizer.
SSTR2 ligands may overcome diagnostic challenges with
1596 Nowosielski et al. Diagnostic challenges in meningioma

18. Menke JR, Raleigh DR, Gown AM, Thomas S, Perry A, Tihan T.
F.S. has received research support and/or travel bursaries from Somatostatin receptor 2a is a more sensitive diagnostic marker of
Roche, Agilent, and Illumina. No other authors report a conflict meningioma than epithelial membrane antigen. Acta Neuropathol.
of interest. 2015;130(3):441–443.
19. Tagle P, Villanueva P, Torrealba G, Huete I. Intracranial metastasis or
meningioma? An uncommon clinical diagnostic dilemma. Surg Neurol.
2002;58(3-4):241–245.
20. Bendszus M, Warmuth-Metz M, Burger R, Klein R, Tonn JC, Solymosi L.
Diagnosing dural metastases: the value of 1H magnetic resonance spec-
References troscopy. Neuroradiology. 2001;43(4):285–289.
21. Wilms G, Lammens M, Marchal G, et  al. Prominent dural enhance-
ment adjacent to nonmeningiomatous malignant lesions on contrast-
1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: pri- enhanced MR images. AJNR Am J Neuroradiol. 1991;12(4):761–764.
mary brain and central nervous system tumors diagnosed in the United 22. Bourekas EC, Wildenhain P, Lewin JS, et al. The dural tail sign revisited.
States in 2008–2012. Neuro Oncol. 2015;17(Suppl 4):iv1–iv62. AJNR Am J Neuroradiol. 1995;16(7):1514–1516.
2. Goldbrunner R, Minniti G, Preusser M, et  al. EANO guidelines 23. Johnson MD, Powell SZ, Boyer PJ, Weil RJ, Moots PL. Dural lesions
for the diagnosis and treatment of meningiomas. Lancet Oncol. mimicking meningiomas. Hum Pathol. 2002;33(12):1211–1226.
2016;17(9):e383–e391. 24. Sandhu FA, Schellinger D, Martuza RL. A vascular sarcoid mass mimick-
3. Sahm F, Schrimpf D, Olar A, et al. TERT promoter mutations and risk of ing a convexity meningioma. Neuroradiology. 2000;42(3):195–198.
recurrence in meningioma. J Natl Cancer Inst. 2016;108(5):pii: djv377. 25. Chiechi MV, Smirniotopoulos JG, Mena H. Intracranial heman-
4. Louis DN, Perry A, Reifenberger G, et  al. The 2016 World Health giopericytomas: MR and CT features. AJNR Am J Neuroradiol.
Organization classification of tumors of the central nervous system: a 1996;17(7):1365–1371.
summary. Acta Neuropathol. 2016;131(6):803–820. 26. Kremer S, Grand S, Rémy C, et  al. Contribution of dynamic contrast
5. Sughrue ME, Rutkowski MJ, Aranda D, Barani IJ, McDermott MW, MR imaging to the differentiation between dural metastasis and men-
Parsa AT. Treatment decision making based on the published nat- ingioma. Neuroradiology. 2004;46(8):642–648.
ural history and growth rate of small meningiomas. J Neurosurg. 27. Kremer S, Grand S, Berger F, et  al. Dynamic contrast-enhanced MRI:
2010;113(5):1036–1042. differentiating melanoma and renal carcinoma metastases from
6. Saloner D, Uzelac A, Hetts S, Martin A, Dillon W. Modern meningioma high-grade astrocytomas and other metastases. Neuroradiology.
imaging techniques. J Neurooncol. 2010;99(3):333–340. 2003;45(1):44–49.
7. Reubi JC, Schaer JC, Waser B, Mengod G. Expression and localiza- 28. Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of glio-
tion of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger mas: comparison with tumor grade and histologic findings. Radiology.
RNAs in primary human tumors using in situ hybridization. Cancer Res. 1994;191(1):41–51.
1994;54(13):3455–3459. 29. Hakyemez B, Erdogan C, Bolca N, Yildirim N, Gokalp G, Parlak M.
8. Gehler B, Paulsen F, Oksüz MO, et al. [68Ga]-DOTATOC-PET/CT for men- Evaluation of different cerebral mass lesions by perfusion-weighted MR
ingioma IMRT treatment planning. Radiat Oncol. 2009;4:56. imaging. J Magn Reson Imaging. 2006;24(4):817–824.
9. Henze M, Dimitrakopoulou-Strauss A, Milker-Zabel S, et  al. 30. Kousi E, Tsougos I, Fountas K, et  al. Distinct peak at 3.8  ppm
Characterization of 68Ga-DOTA-D-Phe1-Tyr3-octreotide kinetics in observed by 3T MR spectroscopy in meningiomas, while nearly ab-
patients with meningiomas. J Nucl Med. 2005;46(5):763–769. sent in high-grade gliomas and cerebral metastases. Mol Med Rep.
10. Rachinger W, Stoecklein VM, Terpolilli NA, et  al. Increased 2012;5(4):1011–1018.
68Ga-DOTATATE uptake in PET imaging discriminates meningioma and 31. Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing
tumor-free tissue. J Nucl Med. 2015;56(3):347–353. identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat
11. Zimny A, Sasiadek M. Contribution of perfusion-weighted magnetic Genet. 2013;45(2):131–132.
resonance imaging in the differentiation of meningiomas and other 32. Koelsche C, Schweizer L, Renner M, et al. Nuclear relocation of STAT6
extra-axial tumors: case reports and literature review. J Neurooncol. reliably predicts NAB2-STAT6 fusion for the diagnosis of solitary fibrous
2011;103(3):777–783. tumour. Histopathology. 2014;65(5):613–622.
12. Pieper DR, Al-Mefty O, Hanada Y, Buechner D. Hyperostosis associated 33. Robinson DR, Wu YM, Kalyana-Sundaram S, et  al. Identification of
with meningioma of the cranial base: secondary changes or tumor inva- recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integra-
sion. Neurosurgery. 1999;44(4):742–746; discussion 746. tive sequencing. Nat Genet. 2013;45(2):180–185.
13. Guermazi A, Lafitte F, Miaux Y, Adem C, Bonneville JF, Chiras J. The dural 34. Schweizer L, Koelsche C, Sahm F, et al. Meningeal hemangiopericytoma
tail sign—beyond meningioma. Clin Radiol. 2005;60(2):171–188. and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be
14. Cha S, Knopp EA, Johnson G, Wetzel SG, Litt AW, Zagzag D. Intracranial diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol.
mass lesions: dynamic contrast-enhanced susceptibility-weighted echo- 2013;125(5):651–658.
planar perfusion MR imaging. Radiology. 2002;223(1):11–29. 35. Bailey P, Cushing H, Eisenhardt L. Angioblastic meningiomas. Arch
15. Zhang H, Rödiger LA, Shen T, Miao J, Oudkerk M. Perfusion MR im- Pathol Lab Med. 1928;6:453–490.
aging for differentiation of benign and malignant meningiomas. 36. Bailey P, Bucy PC. The origin and nature of meningeal tumors. Am J
Neuroradiology. 2008;50(6):525–530. Cancer. 1931;15:15–54.
16. Majós C, Cucurella G, Aguilera C, Coll S, Pons LC. Intraventricular men- 37. Couce ME, Aker FV, Scheithauer BW. Chordoid meningioma: a clinico-
ingiomas: MR imaging and MR spectroscopic findings in two cases. pathologic study of 42 cases. Am J Surg Pathol. 2000;24(7):899–905.
AJNR Am J Neuroradiol. 1999;20(5):882–885. 38. Kepes JJ, Moral LA, Wilkinson SB, Abdullah A, Llena JF. Rhabdoid
17. Zhang H, Rödiger LA, Shen T, Miao J, Oudkerk M. Preoperative sub- transformation of tumor cells in meningiomas: a histologic indication of
typing of meningiomas by perfusion MR imaging. Neuroradiology. increased proliferative activity: report of four cases. Am J Surg Pathol.
2008;50(10):835–840. 1998;22(2):231–238.
 Nowosielski et al. Diagnostic challenges in meningioma 1597

Oncology
Neuro-
39. Perry A, Scheithauer BW, Stafford SL, Abell-Aleff PC, Meyer FB. genomic hybridization in 124 meningiomas: correlation with clinical, histo-
“Rhabdoid” meningioma: an aggressive variant. Am J Surg Pathol. pathologic, and prognostic features. Am J Clin Pathol. 2005;123(5):744–751.
1998;22(12):1482–1490. 59. Sayagués JM, Tabernero MD, Maíllo A, et al. Intratumoral patterns of
40. Zorludemir S, Scheithauer BW, Hirose T, Van Houten C, Miller G, clonal evolution in meningiomas as defined by multicolor interphase
Meyer FB. Clear cell meningioma. A  clinicopathologic study of a fluorescence in situ hybridization (FISH): is there a relationship between
potentially aggressive variant of meningioma. Am J Surg Pathol. histopathologically benign and atypical/anaplastic lesions? J Mol
1995;19(5):493–505. Diagn. 2004;6(4):316–325.
41. Lin BJ, Chou KN, Kao HW, et  al. Correlation between magnetic res- 60. Maillo A, Orfao A, Espinosa AB, et al. Early recurrences in histologically
onance imaging grading and pathological grading in meningioma. J benign/grade I meningiomas are associated with large tumors and coex-
Neurosurg. 2014;121(5):1201–1208. istence of monosomy 14 and del(1p36) in the ancestral tumor cell clone.
42. Sanverdi SE, Ozgen B, Oguz KK, et al. Is diffusion-weighted imaging use- Neuro Oncol. 2007;9(4):438–446.
ful in grading and differentiating histopathological subtypes of meningi- 61. Domingues PH, Sousa P, Otero Á, et  al. Proposal for a new risk
omas? Eur J Radiol. 2012;81(9):2389–2395. stratification classification for meningioma based on patient age,
43. Azizyan A, Eboli P, Drazin D, Mirocha J, Maya MM, Bannykh S. WHO tumor grade, size, localization, and karyotype. Neuro Oncol.
Differentiation of benign angiomatous and microcystic meningiomas 2014;16(5):735–747.
with extensive peritumoral edema from high grade meningiomas with 62. Strickland MR, Gill CM, Nayyar N, et al. Targeted sequencing of SMO
aid of diffusion weighted MRI. Biomed Res Int. 2014;2014:650939. and AKT1 in anterior skull base meningiomas. J Neurosurg. 2016:1–7.
44. Cornelius JF, Stoffels G, Filß C, et al. Uptake and tracer kinetics of O-(2- 63. Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2
(18)F-fluoroethyl)-L-tyrosine in meningiomas: preliminary results. Eur J meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.
Nucl Med Mol Imaging. 2015;42(3):459–467. Science. 2013;339(6123):1077–1080.
45. Rogers CL, Perry A, Pugh S, et al. Pathology concordance levels for men- 64. Clark VE, Harmancı AS, Bai H, et  al. Recurrent somatic mutations
ingioma classification and grading in NRG Oncology RTOG Trial 0539. in POLR2A define a distinct subset of meningiomas. Nat Genet.
Neuro Oncol. 2016;18(4):565–574. 2016;48(10):1253–1259.
46. Kros JM, Cella F, Bakker SL, Paz Y Geuze D, Egeler RM. Papillary men- 65. Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing
ingioma with pleural metastasis: case report and literature review. Acta of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat
Neurol Scand. 2000;102(3):200–202. Genet. 2013;45(3):285–289.
47. Pasquier B, Gasnier F, Pasquier D, Keddari E, Morens A, Couderc P. 66. Sahm F, Bissel J, Koelsche C, et al. AKT1E17K mutations cluster with
Papillary meningioma. Clinicopathologic study of seven cases and re- meningothelial and transitional meningiomas and can be detected by
view of the literature. Cancer. 1986;58(2):299–305. SFRP1 immunohistochemistry. Acta Neuropathol. 2013;126(5):757–762.
48. Baumgarten P, Gessler F, Schittenhelm J, et al. Brain invasion in other- 67. Reuss DE, Piro RM, Jones DT, et al. Secretory meningiomas are defined
wise benign meningiomas does not predict tumor recurrence. Acta by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol.
Neuropathol. 2016;132(3):479–481. 2013;125(3):351–358.
49. Pizem J, Velnar T, Prestor B, Mlakar J, Popovic M. Brain invasion assess- 68. Abedalthagafi MS, Bi WL, Merrill PH, et  al. ARID1A and TERT pro-
ability in meningiomas is related to meningioma size and grade, and can moter mutations in dedifferentiated meningioma. Cancer Genet.
be improved by extensive sampling of the surgically removed meningi- 2015;208(6):345–350.
oma specimen. Clin Neuropathol. 2014;33(5):354–363. 69. Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M.
50. Spille DC, Heß K, Sauerland C, et  al. Brain invasion in meningiomas: High incidence of activating TERT promoter mutations in meningiomas
incidence and correlations with clinical variables and prognosis. World undergoing malignant progression. Brain Pathol. 2014;24(2):184–189.
Neurosurg. 2016;93:346–354. 70. Sahm F, Schrimpf D, Stichel D, et al. DNA methylation-based classifi-
51. Vaubel RA, Chen SG, Raleigh DR, et  al. Meningiomas with rhabdoid cation and grading system for meningioma: a multicentre, retrospective
features lacking other histologic features of malignancy: a study of analysis. Lancet Oncol. 2017;18(5):682–694.
44 cases and review of the literature. J Neuropathol Exp Neurol. 71. SIMPSON D. The recurrence of intracranial meningiomas after surgical
2016;75(1):44–52. treatment. J Neurol Neurosurg Psychiatry. 1957;20(1):22–39.
52. Dumanski JP, Carlbom E, Collins VP, Nordenskjold M. Deletion mapping 72. Gousias K, Schramm J, Simon M. The Simpson grading revisited:
of a locus on human chromosome 22 involved in the oncogenesis of aggressive surgery and its place in modern meningioma management. J
meningioma. Proc Natl Acad Sci U S A. 1987;84(24):9275–9279. Neurosurg. 2016;125(3):551–560.
53. Meese E, Blin N, Zang KD. Loss of heterozygosity and the origin of men- 73. Oya S, Kim SH, Sade B, Lee JH. The natural history of intracranial menin-
ingioma. Hum Genet. 1987;77(4):349–351. giomas. J Neurosurg. 2011;114(5):1250–1256.
54. Schneider G, Lutz S, Henn W, Zang KD, Blin N. Search for putative sup- 74. Hwang WL, Marciscano AE, Niemierko A, et al. Imaging and extent of
pressor genes in meningioma: significance of chromosome 22. Hum surgical resection predict risk of meningioma recurrence better than
Genet. 1992;88(5):579–582. WHO histopathological grade. Neuro Oncol. 2016;18(6):863–872.
55. Wellenreuther R, Kraus JA, Lenartz D, et  al. Analysis of the neurofi- 75. Sommerauer M, Burkhardt JK, Frontzek K, et al. 68Gallium-DOTATATE
bromatosis 2 gene reveals molecular variants of meningioma. Am J PET in meningioma: a reliable predictor of tumor growth rate? Neuro
Pathol. 1995;146(4):827–832. Oncol. 2016;18(7):1021–1027.
56. Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encod- 76. Ikeda H, Tsuyuguchi N, Kunihiro N, Ishibashi K, Goto T, Ohata K. Analysis
ing a putative membrane-organizing protein causes neuro-fibromatosis of progression and recurrence of meningioma using (11)C-methionine
type 2. Nature. 1993;363(6429):515–521. PET. Ann Nucl Med. 2013;27(8):772–780.
57. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, 77. Arita H, Kinoshita M, Okita Y, et al. Clinical characteristics of meningi-
radixin-like gene is a candidate for the neurofibromatosis 2 tumor sup- omas assessed by ¹¹C-methionine and 18F-fluorodeoxyglucose positron-
pressor. Cell. 1993;75(4):826. emission tomography. J Neurooncol. 2012;107(2):379–386.
58. Tabernero MD, Espinosa AB, Maíllo A, et al. Characterization of chromo- 78. Ryttlefors M, Danfors T, Latini F, Montelius A, Blomquist E,
some 14 abnormalities by interphase in situ hybridization and comparative Gudjonsson O. Long-term evaluation of the effect of hypofractionated
1598 Nowosielski et al. Diagnostic challenges in meningioma

high-energy proton treatment of benign meningiomas by means of (11) delineation in stereotactic radiotherapy of skull base meningiomas. Int J
C-L-methionine positron emission tomography. Eur J Nucl Med Mol Radiat Oncol Biol Phys. 2008;72(4):1161–1167.
Imaging. 2016;43(8):1432–1443. 87. Louis DN, Perry A, Burger P, et  al.; International Society Of
79. Afshar-Oromieh A, Giesel FL, Linhart HG, et al. Detection of cranial men- Neuropathology–Haarlem. International Society of Neuropathology–
ingiomas: comparison of 68Ga-DOTATOC PET/CT and contrast-enhanced Haarlem consensus guidelines for nervous system tumor classification
MRI. Eur J Nucl Med Mol Imaging. 2012;39(9):1409–1415. and grading. Brain Pathol. 2014;24(5):429–435.
80. Pieper DR, Al-Mefty O. Management of intracranial meningiomas sec- 88. Gillies RJ, Kinahan PE, Hricak H. Radiomics: images are more than pic-
ondarily involving the infratemporal fossa: radiographic characteristics, tures, they are data. Radiology. 2016;278(2):563–577.
pattern of tumor invasion, and surgical implications. Neurosurgery. 89. Guermazi A, De Kerviler E, Zagdanski AM, Frija J. Diagnostic imaging of
1999;45(2):231–237; discussion 237. choroid plexus disease. Clin Radiol. 2000;55(7):503–516.
81. Song SW, Son YD, Cho ZH, Paek SH. Experience with 7.0 T MRI in 90. Fukui MB, Meltzer CC, Kanal E, Smirniotopoulos JG. MR imaging of the
patients with supratentorial meningiomas. J Korean Neurosurg Soc. meninges. Part II. Neoplastic disease. Radiology. 1996;201(3):605–612.
2016;59(4):405–409. 91. Stevens KL, Carlson ML, Pelosi S, Haynes DS. Middle ear meningiomas:
82. Milker-Zabel S, Zabel-du Bois A, Henze M, et  al. Improved target a case series reviewing the clinical presentation, radiologic features,
volume definition for fractionated stereotactic radiotherapy in patients and contemporary management of a rare temporal bone pathology. Am J
with intracranial meningiomas by correlation of CT, MRI, and [68Ga]- Otolaryngol. 2014;35(3):384–389.
DOTATOC-PET. Int J Radiat Oncol Biol Phys. 2006;65(1):222–227. 92. Tan ZG, Zhou Q, Cui Y, Yi L, Ouyang Y, Jiang Y. Extra-axial isolated cer-
83. Graf R, Nyuyki F, Steffen IG, et al. Contribution of 68Ga-DOTATOC PET/CT ebral varix misdiagnosed as convexity meningioma: A case report and
to target volume delineation of skull base meningiomas treated with ste- review of literatures. Medicine (Baltimore). 2016;95(26):e4047.
reotactic radiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(1):68–73. 93. Lavinsky J, Aaron KA, Christian E, et al. Solitary plasmacytoma in the
84. Nyuyki F, Plotkin M, Graf R, et al. Potential impact of (68)Ga-DOTATOC internal auditory canal and cerebellopontine angle mimicking meningi-
PET/CT on stereotactic radiotherapy planning of meningiomas. Eur J oma. Otol Neurotol. 2016;37(10):e400–e401.
Nucl Med Mol Imaging. 2010;37(2):310–318. 94. Deep NL, Graffeo CS, Copeland WR 3rd, et al. Teflon granulomas mim-
85. Grosu AL, Weber WA, Astner ST, et al. 11C-methionine PET improves the icking cerebellopontine angle tumors following microvascular decom-
target volume delineation of meningiomas treated with stereotactic frac- pression. Laryngoscope. 2017;127(3):715–719.
tionated radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(2):339–344. 95. Lee JH, Lee HK, Choi CT, Huh J. Mucosa-associated lymphoid tissue
86. Astner ST, Dobrei-Ciuchendea M, Essler M, et  al. Effect of lymphoma of the pituitary gland: MR imaging features. AJNR Am J
11C-methionine-positron emission tomography on gross tumor volume Neuroradiol. 2002;23(5):838–840.