Anaplastic Meningioma Versus Meningeal

Hemangiopericytoma: Immunohistochemical
and Genetic Markers
VEENA RAJARAM, MD, DANIEL J. BRAT, MD, PHD,
AND ARIE PERRY, MD
Anaplastic meningiomas (MIIIs) and meningeal hemangiopericy-
tomas (HPCs) display signicant morphologic and immunohisto-
chemical overlap, including occasional cases of otherwise classic
HPC with focal epithelial membrane antigen (EMA) positivity. The
availability of several new biomarkers prompted us to examine the
potential diagnostic roles of ancillary immunohistochemistry (IHC)
and uorescence in situ hybridization (FISH) studies. From the ar-
chival university neuropathology and consult les of 1 of the authors
(A.P.), 19 meningeal HPCs and 19 MIIIs were retrieved for further
study. IHC was performed by using EMA, CAM 5.2, CD99, Bcl-2,
claudin-1 and Factor XIIIa (FXIIIa) antibodies. FISH was performed
with NF2, 4.1B (DAL-1), chromosome 1p32, and 14q32 probes. HPCs
showed strong CD99 (85% of cases), strong bcl-2 (86%), focal EMA
(33%), focal claudin-1 (13%), and scattered individual cell FXIIIa
(100%) positivity. MIIIs showed strong EMA (89%), strong claudin-1
(54%), weak or focal CD99 (15%), weak or focal bcl-2 (31%), and
individual cell FXIIIa (84%) positivity. Focal CAM 5.2 expression was
seen in 26% of HPCs and 15% of MIIIs. Deletions were extremely
common in MIIIs: 1p (94%), 14q (67%), NF2 (100%), and 4.1B (67%).
HPCs showed no 14q or 4.1B deletions, with 1 case each of 1p and
NF2 deletions (6%). The sensitivities and specicities of the 3 most
useful IHC markers (EMA, CD99, bcl-2) were 85%-89% and 67%-
84%, respectively. The sensitivity and specicity of claudin-1 for MIII
were 54% and 86%, respectively. The specicity and positive predic-
tive value of combined CD99 and bcl-2 expression for the diagnosis
of HPC was 95%. The sensitivities of individual genetic markers were
67%-100%, with specicities of 94%-100%. Our 3 conclusions were as
follows: (1) EMA, CD99, bcl-2, and claudin-1 IHC and 1p, 14q, NF2,
and 4.1B FISH are particularly useful for distinguishing anaplastic
meningiomas from meningeal HPCs. (2) Focal EMA expression does
not preclude a diagnosis of HPC. (3) The characteristic FXIIIa stain-
ing pattern reported for HPC also is encountered frequently in
anaplastic meningiomas and therefore is nonspecic in this diagnos-
tic setting. HUM PATHOL 35:1413-1418. 2004 Elsevier Inc. All rights
reserved.
Key words: meningioma, hemangiopericytoma, FISH, immuno-
histochemistry, tumor genetics.
Abbreviations: MIII, anaplastic meningiomas; HPC, meningeal
hemangiopericytomas; EMA, epithelial membrane antigen; FISH, u-
orescence in situ hybridization; FXIIIa, Factor XIIIa.
Anaplastic meningiomas (MIII) and meningeal he-
mangiopericytomas (HPC) are both dural-based tu-
mors with characteristic histologic patterns that can be
distinguished clearly in classic examples. However, oc-
casional cases display sufcient morphologic overlap
such that ancillary tests are necessary to distinguish
between them. MIIIs are World Health Organization
(WHO) grade III tumors that occasionally metastasize
and that have a median survival of less than 2 years,
whereas HPCs are considered primary dural sarcomas
that metastasize outside the CNS in 25%-60% of cases,
typically after 1 or more recurrences. They have a me-
dian survival of 5 to 12 years, predominantly inuenced
by whether they are low grade (WHO grade II) or high
grade (WHO grade III). Currently, the most useful
immunohistochemical and histochemical stains to dis-
tinguish the 2 are the following: (1) epithelial mem-
brane antigen (EMA),
1-4
which is typically positive in
meningiomas and usually negative in HPCs; (2) a char-
acteristic individual cell Factor XIIIa staining pattern
seen in HPCs and not in benign brous meningio-
mas
5,6
; and (3) reticulin, which shows a dense network
of intercellular deposition in HPCs, with most menin-
giomas being relatively reticulin poor. Other stains,
including S100 protein and Leu 7, have been investi-
gated for their utility in distinguishing these tumor
types but were not found to have sufcient sensitivities
and specicities for clinical use.
7
Similarly, CD34 was
initially thought to be specic for HPCs,
1,8
but studies
have shown that in contrast to the strong diffuse stain-
ing seen in solitary brous tumors, most HPCs are
either negative or show patchy CD34 positivity, with
60% of meningiomas being similarly positive.
5,8
Diagnostic confusion sometimes results from focal
EMA positivity in otherwise classic HPCs. We therefore
decided to reexplore the issue of ancillary studies in
these 2 tumor types, adding several recently developed
biomarkers. CD99 (O13)
6,9
has been reported to be
frequently positive in HPCs, and bcl-2 is strongly posi-
tive in the closely related solitary brous tumor.
6,10
Claudin-1, an integral structural component of tight
junctions, is a useful marker for perineuriomas and has
now been reported to be positive in meningiomas by
immunohistochemistry.
11-13
Additionally, meningiomas
have characteristic genetic deletions of 1p, 14q, NF2,
and 4.1B (previously known as DAL-1: differentially
expressed in adenocarcinoma of the lung)
14-18
that
can be detected by uorescence in situ hybridization
(FISH). The latter marker, localizing to chromosome
From the Department of Pathology, Washington University
School of Medicine, St. Louis, MO; and the Department of Pathology,
Emory University, Atlanta, GA. Accepted for publication July 29,
2004.
Address correspondence and reprint requests to Arie Perry, MD,
Division of Neuropathology, Box 8118, Washington University School
of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110-1093.
0046-8177/$see front matter
2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.humpath.2004.07.017
1413
18p11.3, was found to have considerable homology to
NF2 and is similarly a member of the protein 4.1 family.
In addition to frequent deletions, its role as a potential
tumor suppressor gene is supported by the fact that
reexpression of 4.1B in 4.1B-decient meningioma cells
reduces cell proliferation.
19
In contrast to meningio-
mas, HPCs currently do not have any well-characterized
or signature genetic alterations.
MATERIALS AND METHODS
Formalin-xed parafn-embedded 5-m-thick tissue sec-
tions were cut or retrieved from previously diagnosed cases of
HPC and MIII in our les at Washington University. These
consisted of both in-house and consultation cases, including
19 cases of HPC and 19 cases of MIII. The histology of these
tumors was rereviewed for diagnostic accuracy. Immunohis-
tochemical stains were performed as summarized in Table 1.
Immunohistochemical results were stratied according to ex-
tent and intensity of staining, respectively, as follows: nega-
tive, focal, or diffuse; and negative, weak, or strong. Although
this represents a subjective approach, it reects the one used
daily in routine diagnostic pathology.
Dual-colored FISH was performed as reported else-
where,
14
and the probes used are summarized in Table 2. The
tissue sections were deparafnized and subjected to target
retrieval by steam cooking in citrate buffer (20 minutes),
cooling (20 minutes), and washing (5 minutes), followed by
pepsin digestion (4 mg/mL at 37C for 30 minutes). The
slides were washed in 2SSC for 5 minutes and air dried. The
probes were diluted 1:25 in DenHyb hybridization buffer
(Insitus Laboratories, Albuquerque, NM) and were paired
(1p/14q, NF2/4.1B). Ten microliters of the hybridization mix
was applied to each slide, and the probe and the target DNA
were simultaneously denatured at 90C for 13 minutes. Over-
night hybridization was performed at 37C in a humidied
chamber. The slides were then washed at room temperature
in 50% formamide1 SSC for 5 minutes, followed by a wash
in 2 SSC for 5 minutes. The slides were air dried and
counterstained with 6-diamino-2-phenylindole (DAPI; 0.5
L/mL; Insitus Laboratories).
Sections were viewed under an Olympus BX60 uores-
cent microscope with appropriate lters (Olympus, Melville,
NY), and those showing 90% nuclei with signals were eval-
uated, with 100 to 200 intact nonoverlapping nuclei scored
for the number of uorescent signals. Cutoffs for deletions
were based on counts from nonneoplastic control specimens
(temporal lobectomy specimens for seizure control) for each
probe. Interpretation of deletion required 50% of nuclei
containing a single signal for the probe.
Hybridizations were digitally photographed with a high-
resolution black and white charged couple device (CCD)
camera (Cohu Inc., San Diego, CA), with a Z-stack motor
programmed to capture images at sequential DAPI (1 level),
FITC (5 levels), and rhodamine (5 levels) lter settings. Re-
construction into a single superimposed image with blue,
green, and red pseudocolors was accomplished by software
from the CytoVision basic workstation (Applied Imaging,
Santa Clara, CA).
RESULTS
Microscopically, the MIIIs fullled WHO criteria
for anaplasia,
20
including a mitotic count of 20 per 10
high-power elds or pleomorphic spindled or epithe-
lioid malignant cells whose differential diagnosis in-
cluded carcinoma, sarcoma, or melanoma (Figs1A and
2A). The HPCs contained monomorphic oval to spin-
dled cells arranged as dense hypercellular sheets, often
interrupted by pale hypocellular islands, as well as
abundant thin-walled, gaping vessels, some with the
characteristic arborizing (staghorn) pattern (Figs 1B
and 3A).
The immunohistochemical and FISH results are
summarized in Tables 3 and 4. Almost all of the MIIIs
showed diffuse or focal membranous positivity for EMA
(16/18), whereas less than one third of the cases
showed focal or weak staining with CD99 (3/19) or
bcl-2 (6/19; Figs 2B, D, and E). Most of the HPCs
showed diffuse or focal, strong membranous positivity
for CD99 (18/19) and cytoplasmic positivity for bcl-2
(16/19), and most were EMA negative, though a few
cases showed focal, usually weak positivity (7/19) (Fig
3B, D, and E). The characteristic pattern of scattered
single cells with delicate Factor XIIIa (FXIIIa)positive
processes was seen in all the HPCs (19/19) and in the
majority of the MIIIs (16/19; Figs 2C and 3C). Diffuse
or focal membranous positivity was seen for claudin-1
TABLE 1. Antibodies and Methods
Antigen Antibody and Manufacturers Dilution Automated Staining Method Antigen Retrieval
EMA Dako, clone E29, Carpinteria, CA 1:2000 Envision mouse Citrate HIER pH 6.0
Factor XIIIA Calbiochem, polyclonal, La Jolla, CA 1:400 Envision Rabbit Citrate HIER pH 6.0
CAM5.2 BD, monoclonal, San Diego, CA 1:80 Envision mouse EDTA HIER pH 8.0
CD99 Signet, clone O13, Dedham, MA 1:100 Envision mouse Citrate HIER pH 6.0
bcl-2 Dako, clone 124, Carpinteria, CA 1:200 Envision mouse EDTA HIER pH 8.0
Claudin-1 Zymed, rabbit polyclonal, South San
Francisco, CA
1:70 Envision labeled polymer horseradish
peroxidase
Steaming for 15 min
Abbreviation: EDTA, ethylenediaminetetraacetic acid; HIER, heat induced epitope retrieval.
TABLE 2. DNA Probes and Sources
Probe Clone or Product Source
1p32 (green) RP11-260I23 Genome Sequencing
Center, Washington
University, St. Louis, MO
14q32 (red) RP11-299G2 Research Genetics, CIT978
SK-A, Huntsville, AL
NF2 (red) E2 and E15 cosmids Mia MacCollin, MGH,
Boston, MA
4.1B (green) PI-8297 Irene Newsham, Henry Ford
Hospital, Detroit, MI
HUMAN PATHOLOGY Volume 35, No. 11 (November 2004)
1414
FIGURE 1. Representative hematoxylin and eosin staining. (A) Anaplastic meningioma with epithelioid cells, intranuclear clear-
ing, moderate amount of cytoplasm, and mitoses. (B) Hemangiopericytoma with identical monomorphic cells and a single dilated
staghorn vessel (original magnication, 400).
FIGURE 2. Representative anaplastic meningiomas. (A) Hematoxylin and eosin, epithelioid cells with clear cytoplasmand mitoses
imparting a carcinoma-like appearance. (B) Epithelial membrane antigen. (C) Factor XIIIa. (D) CD99. (E) Bcl-2. (F) Claudin-1.
(Original magnication, 200).
1415
in slightly more than half the MIIIs (7/13), whereas
only 2 of 15 HPCs showed focal or weak positivity (Figs
2F and 3F). Cytoplasmic staining with CAM5.2 was focal
and generally weak to equivocal in rare MIIIs (2/13)
and HPCs (5/17).
By FISH (Fig 4), all the MIIIs had NF2 deletions
(15/15), and the majority had 1p32 (17/18), 14q32
(12/18), and 4.1B (10/15) deletions. In the HPCs, only
1 of 15 cases each had deletion for 1p32 or NF2. There
were no deletions of 14q32 or 4.1B.
The sensitivity for EMA as a marker for MIII was
89%, and the specicity was 67%. FXIIIa was not found
to be useful, given positivity in 84% in MIIIs and 100%
of the HPCs, with an identical staining pattern in both
the tumors. CD99 (O13) was a very sensitive marker of
HPC (95%), with a specicity of 84%. Similarly, bcl-2
was a sensitive marker of HPC (84%), with a specicity
of 68%. When used in combination, positivity of both of
the latter 2 markers yielded a sensitivity of 84%, speci-
city of 95%, and a positive predictive value of 93% for
the diagnosis of HPC. Claudin-1 was not a highly sen-
sitive marker of MIII (54%) but had a specicity of
86%. FISH studies for 1p32, NF2, DAL-1, and 14q32
were highly associated with the diagnosis of MIII, yield-
ing sensitivities of 67%-100% and specicities of 94%-
100% (Table 4). The positive predictive value of having
a single deletion was 94%.
DISCUSSION
Meningeal HPC was initially described as the
angioblastic variant of meningiomas, but as the differ-
ences in its clinicopathologic, immunohistochemical,
3,21
and ultrastructural features
22
from meningiomas be-
came apparent, it has come generally to be considered
a dural-based sarcoma, analogous to its soft tissue coun-
terpart.
23
EMA, FXIIIa, and reticulin have been touted
as the most useful ancillary stains for the distinction of
HPC from MIII, with S100 protein and Leu-7 generally
considered unreliable because of low sensitivities and
specicities.
In our study, EMA remained a highly sensitive
meningothelial marker but was also reactive in more
than a third of the HPCs, albeit weak and focal in most.
EMA expression has similarly been reported in rare
HPCs elsewhere,
1,5,21
emphasizing that focal EMA ex-
FIGURE 3. Representative hemangiopericytomas. (A) Hematoxylin and eosin. Characteristic staghorn vasculature and oval to
spindled cells with high N/C ratios. (B) Epithelial membrane antigen. (C) Factor XIIIa. (D) CD99. (E) Bcl-2. (F) Claudin-1 (Original
magnication, 200).
TABLE 3. Immunohistochemistry Results
Variable HPC (n) MIII (n)
EMA 19 18
Weak focal 6 2
Weak diffuse 0 0
Strong focal 1 10
Strong diffuse 0 4
CD99 19 19
Weak focal 1 2
Weak diffuse 0 0
Strong focal 5 0
Strong diffuse 12 1
bcl-2 19 19
Weak focal 6 4
Weak diffuse 0 1
Strong focal 2 1
Strong diffuse 8 0
Claudin-1 15 13
Weak focal 1 2
Weak diffuse 0 0
Strong focal 1 1
Strong diffuse 0 4
FXIIIa 19 19
Positive 19 16
CAM5.2 18 13
Positive 5 2
HUMAN PATHOLOGY Volume 35, No. 11 (November 2004)
1416
pression does not entirely exclude the diagnosis of
HPC. Surprisingly, the characteristic FXIIIa staining
pattern, which is useful in differentiating HPCs from
brous meningiomas,
5
was not very useful in the differ-
ential with MIII, because most of them had an identical
pattern of FXIIIa staining. In fact, given the individual
cell pattern of reactivity and the cytology of positive
cells, it has been suggested that they represent en-
trapped or recruited dendritic cells, rather than the
actual tumor cells. CAM5.2 was focally positive in both
MIIIs and HPCs, but only in rare cases.
Bcl-2, which has been very useful in the diagnosis
of SFT, was also a sensitive marker for HPC, with only
occasional MIIIs showing weak or focal staining. CD99
is another marker that has been reported to be positive
in SFT, and in our study, it similarly proved to be a
sensitive marker, further highlighting the extensive
overlap between SFT and HPC. In fact, the majority of
HPCs strongly coexpressed CD99 and bcl-2, with this
pattern being highly specic because it was generally
not encountered in the MIIIs.
Claudin-1, a component of intercellular tight junc-
tions, has been shown to be positive in meningiomas. In
our study, only slightly more than half of the MIIIs
showed claudin-1 expression. Nonetheless, only a few of
the HPCs were positive, making claudin-1 a fairly spe-
cic, albeit not very sensitive, marker for MIII.
In most cases, MIII can be differentiated from HPC
by IHC or by the ultrastructural ndings of interdigi-
tating cell processes and desmosomal intercellular junc-
tions in MIII and basal lamina-like amorphous material
in HPC. On rare occasions, the IHC staining pattern
may be equivocal and electron microscopy noncontrib-
utory, necessitating additional molecular studies. Loss
of 1p, NF2, 4.1B, and 14q have been frequently identi-
ed in meningiomas, whereas no consistent chromo-
somal losses or gains have been seen in HPCs. Homozy-
gous deletions of the CDKN2A on 9p21 have been
reported in both HPCs and MIIIs.
24-26
Alterations on
6p, 7p, and 19q and t(12;19)(q13;q13.3) have been
reported in occasional HPCs.
27,28
In our study, dele-
tions for 1p32, 14q32, NF2, and 4.1B by FISH were
extremely common in MIIIs and were exceptionally
rare in HPCs, supporting the notion that these tumors
are genetically and biologically distinct. Thus, it corrob-
orates the current view that HPC is a dural-based sar-
coma, rather than a variant of meningioma. The sensi-
tivities and specicities of these markers were also
sufciently high that they provide rm evidence of
meningothelial origin when 2 or more deletions are
detected and virtually exclude the possibility of MIII
when all 4 are absent. Therefore, they are particularly
useful as an ancillary diagnostic aid in the most poorly
differentiated dural-based neoplasms.
In conclusion, EMA, CD99, and bcl-2 by IHC and
1p32, 14q32, NF2, and 4.1B deletions by FISH are use-
ful ancillary markers in distinguishing MIIIs from
HPCs. Focal EMA positivity may occasionally be seen in
HPCs and therefore does not exclude the diagnosis.
FXIIIa does not appear to be a useful marker in this
differential, because it is seen in the majority of both
HPCs and MIIIs. Additional studies are needed to iden-
tify specic molecular markers for meningeal HPC and
to clarify its relationship with solitary brous tumor.
Acknowledgment. The authors thank all the referring
pathologists who have contributed their cases in consultation;
Ruma Banerjee for assistance with FISH; Rodney Brown,
Alma Johnson, Kevin Keith, Kevin Selles, and Lisa Snipes for
technical support and immunohistochemistry performance;
and Diane Lawson for claudin-1 immunohistochemistry.
FIGURE 4. Representative uorescence in situ hybridizations.
(A) Metaphase III (MIII) with 1p and 14q deletions (1 green and
1 red signal in most nuclei). (B) Meningeal hemangiopericyto-
mas (HPC) showing normal number of 1p/14q signals (up to 2
green and 2 red in most nuclei). (C) MIII with NF2/4.1B deletions
(1 green and 1 red signal in most nuclei). (D) HPC showing
normal number of NF2/4.1B signals (up to 2 green and 2 red in
most nuclei). Some signals are beyond the planes of focus in
the photographs and there is also some truncation artifact,
resulting in fewer signals than expected, because of the sec-
tioning of nuclei (original magnication, 1000).
TABLE 4. Fluorescence In Situ Hybridization Results
Variable
1p32
Deletion,
n (%)
14q32
Deletion,
n (%)
NF2
Deletion,
n (%)
4.1B
Deletion,
n (%)
HPC 1/15 (7) 0/15 1/15 (7) 0/15
MIII 17/18 (94) 12/18 (67) 15/15 (100) 10/15 (67)
Abbreviations: HPC, meningeal hemangiopericytomas; MIIIs,
anaplastic meningiomas.
MENINGIOMA VS. HEMANGIOPERICYTOMA (Rajaram et al)
1417
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