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ORIGINAL ARTICLE
Intracranial anaplastic solitary fibrous tumor/hemangiopericytoma:
immunohistochemical markers for definitive diagnosis
Daisuke Yamashita
1
&Satoshi Suehiro
1
&Shohei Kohno
1,2
&Shiro Ohue
1,3
&Yawara Nakamura
1
&Daisuke Kouno
1
&
Yoshihiro Ohtsuka
1
&Masahiro Nishikawa
1
&Shirabe Matsumoto
1
&Joshua D. Bernstock
4
&Shuko Harada
5
&
Yosuke Mizuno
6
&Riko Kitazawa
6
&Takanori Ohnishi
1,7
&Takeharu Kunieda
1
Received: 28 April 2020 /Revised: 15 June 2020 /Accepted: 6 July 2020
#Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
Intracranial anaplastic hemangiopericytoma (AHPC) is arareandmalignantsubsetofsolitaryfibroustumor/
hemangiopericytoma (SFT/HPC) as per the WHO 2016 Classification of Tumors of the Central Nervous System. AHPC
portends a poor prognosis and is associated with higher rates of recurrence/metastasis in comparison with SFT/HPC.
Accordingly, it is critical to continue to define the clinical course of patients with AHPC and in so doing further refine
clinicopathologic/immunohistochemical (IHC) criteria needed for definitive diagnosis. Herein, we describe clinical/
histological characteristics of six patients with AHPC. In addition, we reviewed and analyzed the expression of various IHC
markers reported within the literature (i.e., a total of 354 intracranial SFT/HPCs and 460 meningiomas). Histologically, tumors
from our six patients were characterized by a staghorn-like vascular pattern, mitotic cells, and strong nuclear atypia.
Immunohistochemically, all tumors displayed positive nuclear staining for STAT6; other markers, including CD34 and Bcl-2,
were expressed only in three patients. Analysis of IHC expression patterns for SFT/HPC and meningioma within the literature
revealed that nuclear expression of STAT6 had the highest specificity (100%) for SFT/HPC, followed by ALDH1 (97.2%) and
CD34 (93.6%). Of note, SSTR2A (95.2%) and EMA (85%) displayed a high specificity for meningioma. Anaplastic SFT/HPC is
a tumor with poor prognosis that is associated with higher rates of recurrence and metastasis in comparison with SFT/HPC. Given
that anaplastic SFT/HPC requires more aggressive treatment than meningioma despite of a similar presentation on imaging, it is
crucial to be able to distinguish between these tumors.
Keywords Hemangiopericytoma .Solitary fibrous tumor .Anaplastic .Meningioma .STAT6
Introduction
Hemangiopericytomas (HPC) are tumors derived from
perivascular cells, which predominantly occur within soft tis-
sue and were initially proposed by Stout and Murray in
the 1940s [1,2]. Although such tumors may also occur
intracranially, the incidence is relatively low, accounting
for ~ 0.4% of all primary CNS tumors [3]. In the 2007
WHO Classification of Tumors of the Central Nervous
System, a highly malignant form of HPC was newly
described as anaplastic hemangiopericytoma (AHPC),
with HPC themselves being regarded as different tumor
vs solitary fibrous tumor (SFT) [4]. Interestingly, the
2013 WHO Classification of Tumors of the Soft
Tissue and Bone identified no difference between HPC
and SFT grouping of these tumors under the category of
fibroblastic/myofibroblastic tumors [5].
*Daisuke Yamashita
yamadai551208@gmail.com
1
Department of Neurosurgery, Ehime University Graduate School of
Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan
2
Department of Neurosurgery, Japanese Red Cross Society Himeji
Hospital, Himeji, Hyogo, Japan
3
Department of Neurosurgery, Stroke Center, Ehime Prefectural
Central Hospital, Matsuyama, Ehime, Japan
4
Department of Neurosurgery, Brigham and Women’s Hospital,
Harvard University, Boston, MA, USA
5
Department of Pathology, University of Alabama at Birmingham,
Birmingham, AL, USA
6
Division of Diagnostic Pathology, Ehime University Hospital,
Toon, Ehime, Japan
7
Department of Neurosurgery, Washoukai Sadamoto Hospital,
Matsuyama, Ehime, Japan
Neurosurgical Review
https://doi.org/10.1007/s10143-020-01348-6
Recent discovery of the presence of NGFI-A-binding pro-
tein 2-signal transducer and activator of transcription 6
(NAB2-STAT6) fusion gene in both HPC and SFT suggests
that these two tumors represent a single disease entity [6]. In
line with such thinking, the 2016 WHO Classification of
Tumors of the Central Nervous System described such lesions
using the combined term SFT/HPC; such tumors are charac-
terized by the microscopic HPC-like features, the shared in-
versions at 12q13, and the fusion of the NAB2 and STAT6
genes [3]. Of note, intracranial SFT/HPC displays character-
istic growth patterns that are similar to those of meningioma.
This often makes it extremely difficult to distinguish SFT/
HPC from high-grade meningioma via preoperative imaging.
Critically, WHO grade II and III SFT/HPC are regarded as
malignant tumors secondary of the high rates of recurrence
and metastasis. Current standard of care involves gross total
resection (GTR) of the tumor and the administration of adju-
vant radiotherapy [7,8]. Such clinical treatment paradigms
highlight the importance of making an accurate diagnosis of
grade II or grade III SFT/HPC as early as possible. While the
significance of immunohistochemical (IHC) markers includ-
ing CD34 and vimentin in the diagnosis of SFT/HPC and
meningioma have been described, many of the reports were
based on the studies that were performed before the discovery
of the NAB2-STAT6 fusion gene in HPC and SFT, which led
to reclassification [9–11]. Several recent reports have demon-
strated the utility of both the NAB2-STAT6 fusion gene and
STAT6 with regard to IHC markers of SFT/HPC [12,13].
Accordingly, detection of STAT6 nuclear expression and/or
the NAB2-STAT6 fusion protein is recommended to confirm
the diagnosis of SFT/HPC as per 2016 WHO guidelines.
Herein, we examined the clinicopathologic and IHC features
of six cases of grade III SFT/HPC (i.e., AHPC). We also
investigated the expression of various markers in both SFT/
HPC and meningioma via a detailed review of the literature in
an effort to evaluate the significance of IHC in the accurate
diagnosis of SFT/HPC vs other CNS neoplasms such as me-
ningiomas. We also examined the differences in the expres-
sion rates of the markers between low-grade SFT/HPC and
high-grade SFT/HPC.
Materials and methods
Patients
This study was approved by the IRB for Clinical Research of
Ehime University Hospital (Japan) prior to its initiation.
Written informed consent for surgical resection and tissue
sample collection was obtained from patients prior to surgery
in accordance with institutional regulations. Between 2010
and 2015, 6 cases with pathohistological features consistent
with a diagnosis of AHPC were identified at the Ehime
University Hospital. Subsequently, clinical information and
follow-up data were obtained from the University Hospital’s
electronic medical record (EMR) system. These data included
all medical records related to the patient’s disease, preopera-
tive and postoperative imaging (e.g., MRI, CT, angiography,
etc.), operative notes, and tissue pathology. Via retrospective-
ly reviewing the clinical data, we evaluated patient age, gen-
der, initial symptom(s), tumor location/size, pertinent CNS
imaging, extent of resection, adjuvant radiotherapy, and clin-
ical outcomes.
Tumor size was evaluated by measuring the maximum di-
ameter on preoperative MRI scans. The extent of resection
was assessed by examining the operative record and postop-
erative MRIs. GTR was defined as a Simpson grade I or II
resection (i.e., no residual tumor). Subtotal resection (STR)
was defined as a Simpson grade III resection (i.e., total tumor
mass was resected, but a small part of the dura mater to which
the tumor attached was left without performing coagulation),
while partial resection (PR) corresponded to Simpson grade
IV resection. All 6 patients underwent radiation therapy; ste-
reotactic radiotherapy was employed for 5 patients with ex-
tended field radiotherapy having been employed for 1 patient.
After initial treatment was completed, the patients were
followed as outpatients every 2 months. Surveillance MRI
was performed every 4 months with whole-body CT being
performed every 6 months.
Pathology and immunohistochemistry
Tumor specimens were fixed in buffered formalin and embed-
ded in paraffin for routine histologic examination;
hematoxylin-eosin (H&E) staining and IHC were performed
in all 6 cases. For the IHC studies, deparaffinized 4-μm tissue
sections were hydrated in a graded series of alcohol and sub-
jected to heat-activated antigen retrieval. After blocking en-
dogenous peroxidase activity, the tissue was incubated with
the following primary antibodies: STAT6 (sc-621, Santa Cruz
Biotechnology, Santa Cruz, CA), NAB2 (sc-23867, Santa
Cruz Biotechnology, Santa Cruz, CA), vimentin (M0725,
Dako, Carpinteria, CA), Bcl-2 (M0887, Dako, Carpinteria,
CA), CD34 (M7165, Dako, Carpinteria, CA), CD99
(M3601, Dako, Carpinteria, CA), factor XIIIa (FXIIIA-L-U,
Novocastra, Newcastle, UK), CD57 (Leu-7; M7271, Dako,
Carpinteria, CA), laminin (Z0097, Dako, Carpinteria, CA),
smooth muscle actin (SMA; M0851, Dako, Carpinteria,
CA), epithelial membrane antigen (EMA; M0613, Dako,
Carpinteria, CA), cytokeratin (M3515, Dako, Carpinteria,
CA), S-100 (422091, Nichirei, Tokyo, Japan), glial fibrillary
acidic protein (GFAP; IR524, Dako, Carpinteria, CA), desmin
(M0760, Dako, Carpinteria, CA), and Ki-67 (MIB-1; IR626,
Dako, Carpinteria, CA). Subsequently, the sections were
washed and incubated with a biotinylated secondary antibody
for 30 min at room temperature. The reaction complexes were
Neurosurg Rev
visualized with diaminobenzidine and counterstained with he-
matoxylin. Appropriate positive/negative controls were run
for all antibodies utilized.
Electron microscopy (EM)
The tumor tissue was fixed with 2.5% glutaraldehyde in 0.1 M
phosphate buffer (pH 7.4)for 2 h at room temperature,washed
with cacodylate buffer, post-fixed with 1% osmium tetroxide
in cacodylate buffer for 1 h at 4 °C, dehydrated in a graded
series of ethanol, and embedded in an Epon 812 resin (TAAB
Led, England) mixture. Ultrathin sections (< 60 ∼80 nm)
were prepared using an Ultracut S (Leica Led, Germany),
double-stained with uranyl acetate and lead citrate, and exam-
ined using a JEM 1230 (JEOL Ltd., Japan) operating at 80 kV.
The images (2.0 k pixel ×2.0 k pixel) were captured using a
side-entry Orius 200TEM CCD camera (model no 830, Gatan
Led, Pleasanton, CA).
Expression of IHC markers in SFT/HPC
and meningioma
We examined 354 cases of SFT/HPC and 460 cases of me-
ningioma based on pertinent review of the literature [12–27].
We evaluated the expression rate of various IHC markers
within these tumors and in an effort to delineate the
sensitivity/specificity of such markers for SFT/HPC and/or
meningioma.
Results
Clinical features
Clinical features and imaging findings of our 6 patients are
summarized in Table 1. Of the 6 patients, 2 were men and 4
were women; the median age of our patients was 60.0 years
(ranging from 44 to 72 years). All patients had focal neuro-
logic symptoms attributable to their tumors. Other symptoms
included mild disturbances of consciousness (n= 3), headache
(n= 2), and nausea (n= 1). Three tumors were located within
cerebral convexities, two were located around the temporal
fossa, and one involved the cerebellopontine angle and spinal
canal. MRI revealed that three of the tumors had cystic com-
ponents (Fig. 1a). In all patients, the tumors showed a slightly
low- to iso-signal intensity on T1-weighted imagesand an iso-
to high-signal intensity on the T2-weighted images. There was
flow void in three cases and a “corkscrew”finding in one
patient (Fig. 1b–d); in one case (case 6), intratumoral hemor-
rhage was observed at the onset. CT chest/abdomen/pelvis
confirmed that none of patients has metastatic disease at pre-
sentation. Four of the six patients underwent preoperative em-
bolization of the feeding arteries. Ultimately, two patients had
GTR of the tumor, while two patients had a STR; the remain-
ing two patients underwent PR.
Histopathologic features
The histologic features of the resected surgical specimens
proved similar in all cases (Table 2). H&E staining revealed
a staghorn-like vascular pattern (Fig. 2a). Examination of
high-power fields demonstrated spindle-shaped cells with
swollen nuclei, numerous mitotic figures, and relatively strong
nuclear atypia (Fig. 2a); tissue necrosis was also present in
some areas. In addition, silver impregnation staining revealed
intercellular fibrosis in all cases (Fig. 2a). These histopatho-
logical findings met the diagnostic criteria for APHC in all 6
patients.
Results of IHC studies are summarized in Table 2. All
cases displayed strong nuclear expression of STAT6 and
NAB2 (Fig. 2b, c). Although all cases were positive for
vimentin (Fig. 2d), CD34, a common IHC marker employed
for SFT/HPC, was negative in two cases (Fig. 2d).
Additionally, half of the cases were positive for Bcl-2 (3/6),
CD99 (3/6), laminin (3/6), and SMA (4/6). In all cases, EMA,
cytokeratin, S-100 protein, GFAP, and desmin were negative
(Fig. 2d). MIB-1 expression varied and ranged from 4.3 to
42% (Table 2and Fig. 2d). Interestingly, EM demonstrated
accumulation of a basal membrane-like substance in the outer
circumference of the thickened cell membrane, without any
gap junctions in one patient (case 1) (Fig. 2e).
Clinical follow-up
Clinical follow-up information was available for all patients.
The average follow-up duration was 48 months (with a range
from 11 to 80 months). Among the 4 patients, there were no
issues/symptoms secondary to surgery with the exception of
one case which had preoperative hemorrhage and a resulting
cranial nerve palsy. One patient (case 1) received extended field
radiotherapy (60Gy) after resection yet went on to develop local
recurrence 25 months after the first surgery (e.g., a STR); this
patient underwent a second surgery for resection of the recur-
rent tumor and received adjuvant stereotactic radiosurgery (i.e.,
Cyberknife). The remaining five patients received stereotactic
radiotherapy as soon as possible after surgery. Of note, local
recurrence occurred in an additional 3 of the patients, and me-
tastases were diagnosed in two patients (Table 1).
Expression of IHC markers in SFT/HPC
and meningioma as per a detailed review
of the literature
The expression rates of IHC markers in SFT/HPC (grades I–
III) and meningioma are presented in Table 3; stratification of
SFT/HPC by grade is presented in Table 4. Sensitivity/
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Table 1 Clinical features and imaging findings ofsixpatientswithanaplasticSFT/HPC
Case Age Sex Initial symptoms Location Size
(mm)
Cyst Imaging (CT, MRI,
angiography)
Embolization Resection Radiation Follow
up
(month)
Recurrence
(time)
Metastasis
(time)
1 67 F Mild DOC, hemiparesis,
sensory aphasia,
hemianopia
Parietal convexity 70 + CT: iso
MRI:
T1; mild low
T2; high
Gd; +
–1st: STR
2nd: STR
1st: extended field
radiotherapy
2nd: SRS
30 (expired) + (27 months) –
2 53 F Mild DOC, headache,
pain of trigeminal
nerve (V2)
Temporal fossa 55 –CT: mild high
MRI: T1; iso
T2; iso ~ mil d high
Gd; +
Flow void +
+STR1st:SRS
2nd: SRS
80 (alive) + (63 months) –
3 72 M Mild DOC, hemiparesis Frontal convexity 56 –CT: high
MRI:
T1; iso
T2; mild high
Gd; +
Flow void +
Angiography: corkscrew +
+STRSRS 70(alive)–Liver, kidney,
pancreas
(70 months)
4 51 F Ataxia Supratentorium~
occipital convexity
29 + CT: high
MRI:
T1; iso
T2; mild high
Gd; +
–GTR SRS 54 (alive) ––
5 72 M Facial dysesthesia (V1, 2) Temporal fossa~
inflatemporal
fossa
62 + CT: iso
MRI:
T1; low
T2; mild high
Gd; +
+PRSRS 41(alive)+(36months)Lung
(40 months)
6 48 F Headache, nausea,
vertigo, lower nerve
palsy
Cerebellopontine
angle~spinal
canal (C1 level)
53 –CT: mixed density
with hemorrhage
MRI:
T1; iso
T2; iso ~ mil d high
Gd; +
Flow void +
+PRSRS 11(expired)+(3months)–
F, female; M, male; DOC, disturbance of consciousness; CT, computed tomography; MRI, magnetic resonance imaging; STR, subtotal removal; GTR, gross total removal; PR, partial removal; SRS,
stereotactic radiosurgery
Neurosurg Rev
specificity values of the different IHC markers were evaluated
in SFT/HPC and meningioma (Table 5). STAT6 was
expressed very highly within the nucleus in SFT/HPC, while
it was not expressed in meningiomas (Table 3). The high
expression rate of STAT6 was not different in among WHO
grades (i.e., SFT (grade I), HPC (grade II), and AHPC (grade
III)) as per Table 4. The specificity and sensitivity of nuclear
STAT6 for SFT/HPC were 100% and 96.6%, respectively
(Table 5). ALDH1 was also highly expressed in SFT/HPC
with a resultant specificity of 97.2% and sensitivity of
84.2% (Tables 3and 5). GRIA2 was also expressed in SFT/
HPC at a relatively high rate (84%), but did have some ex-
pression within meningiomas (16%) (Table 3), thereby lead-
ing to a moderately high specificity of GRIA2 for SFT/HPC
(83.9%) (Table 5). EMA and SSTR2A were expressed much
more highly in meningioma than SFT/HPC (Table 3). The
sensitivity and specificity of EMA and SSTR2R were 85%
and 89.3% and 92% and 95.2%, respectively (Table 5).
Discussion
Although the incidence of intracranial SFT/HPC is relatively
low, accurate diagnosis of such tumors is required in an effort
to optimize clinical decision-making/treatment stratagems. As
previously noted, high-grade SFT/HPC has a propensity for
local recurrence and/or metastasis. Unfortunately, clinical fea-
tures and image findings of SFT/HPC are similar to those of
meningiomas. Characteristically, SFT/HPC tends to occur at a
younger age (with a peak in the 4th–5th decades) as compared
with meningioma and is slightly more common in males than
in females [28]; within our institutional cohort, 2 patients were
over 60 years of age and 4/6 were females.
On image analysis, HPC is characterized by the presence of
cystic/necrotic changes or flow voids within the lesion and the
absence of calcification/bone thickening, which are often seen
in high-grade meningioma. Angiography of HPC may dem-
onstrate tumor feeding vessels that are supplied by meningeal
and cortical vessels, as well as a characteristic “corkscrew”
pattern and/or early venous drainage. Of note, there have been
few studies centered on differences in imaging findings be-
tween HPC and AHPC. Of these, Zhou et al. compared MRI
findings of HPC (grade II) and AHPC (grade III) and reported
that APHC is characterized by lobulated and/or irregular-
shaped masses associated with prominent brain edema and
frequent bone destruction [29]. Interestingly, our cases dem-
onstrated similar findings on imaging studies, yet it proved
difficult to definitively differentiate the AHPC from other
Fig. 1 Neuroimaging findings. a
Gadolinium-enhanced T1-
weighted image showing an
enhanced tumor with cystic
lesion. bT2-weighted image
showing slightly high intensity
mass lesion with flow void and
perifocal edema. c
Gadolinium-enhanced T1-
weighted images showing an
enhanced mass lesion with
enhanced corkscrew artery
(yellow arrow heads). d
Corkscrew finding on
angiography (yellow arrow
heads)
Neurosurg Rev
tumors, particularly high-grade meningioma by image analy-
sis alone.
Given such challenges, histopathological diagnosis plays a
critical role in ensuring both an accurate diagnosis and clinical
decisions for patients with SFT/HPC that subsequently unfold.
Histopathology of HPC (grade II) is characterized by a high
cellular density, abundant blood vessels that branch to form a
staghorn-like (coralloid) vascular pattern, monotonous sheet-
shaped tumor growth, oval to spindle-shaped nuclei, frequent
nuclear atypia, many mitotic figures, and the absence of
intranuclear pseudo-inclusion bodies that are common in menin-
gioma; HPC can be further differentiated from meningioma in
that HPC lacks whorl formation and/or psammoma bodies, while
intercellular fibrosis can be observed via silver impregnation
staining [3]. Electron microscopic features of AHPC have also
been reported and include tumor cells surrounded by a highly
electron dense basal membrane-like substance and a lack of both
desmosome and gap junctions; images display from case 1 in the
present study highlight such findings.
Until the discovery of NAB2 and STAT6 fusion gene,
CD34 and Bcl-2 predominated as IHC markers for SFT/
HPC; however, their expression was not consistent, and they
therefore displayed suboptimal specificity for SFT/HPC [9,
10]. Such utility has also been confirmed by whole-exome
sequencing in which NAB2-STAT6 was identified as a useful
marker for the diagnosis of SFT [15]. Recently, two new
markers for SFT, ALDH1, and GRIA2 were recognized via
analysis of genome expression profiles [30,31]. Table 3pre-
sents the rates of the positive expression of IHC markers in
354 cases with SFT/HPCs and 460 cases with meningiomas
that were obtained via a literature review [12–27]. The high
specificity of STAT6 we again noted is clearly in line with
previous reports [8,12].
Beyond STAT6, Bouvier et al. reported that ALDH1 was
overexpressed in SFT/HPC both at gene and protein levels as
compared with meningiomas. They stated that the specificity and
sensitivity for SFT/HPC were 98.8% and 84%, respectively [30].
Critically, their findings coincided with the results obtained from
our detailed literature review. Of note, the authors also reported
that ALDH1 was positive in 84% of SFT, 85.4% of HPC, and
1.2% of meningiomas and further described that ALDH1 had a
specificity and positive predictive value of ~ 100% when associ-
ated with CD34. GRIA2 (glutamate receptor 2) is another marker
of SFT/HPC in which the GRIA2 gene is overexpressed and
present within the cytoplasm of SFT [31]. As GRIA2 is also
expressed within meningiomas and other tumors, it is unclear
whether GRIA2 is useful in constructing a differential diagnosis
(i.e., between SFT/HPC and meningioma); in our review of the
literature, GRIA2 specificity was 83.9%. It is prudent to note that
vimentin, NAB2, and Bcl-2 are expressed in both SFT/HPC and
Table 2 Pathological features of
six patients with anaplastic
SFT/HPC
Case 1 Case 2 Case 3 Case 4 Case 5 Case 6
Mitosis ≧5/10HPF ≧5/10HPF ≧5/10HPF ≧5/10HPF 5–6/10HPF ≧5/10HPF
Necrosis + –+–++
Nuclear atypia + + + + ± –
Cellularity High High Moderate High High High
Reticulin 3+ 3+ 3+ 3+ 3+ 3+
STAT6 3+ 3+ 3+ 2+ 2+ 3+
NAB2 3+ 3+ 3+ 2+ 3+ 3+
Vimentin 3+ 3+ 2+ 3+ 2+ 3+
Bcl-2 2+ ––3+ 2+ –
CD34 3+ –2+ –3+ –
CD99 ––1+ 1+ 1+ –
Factor XIIIa ––––– –
CD57 –1+ ––1+ ND
Laminin 1+ –1+ ––1+
SMA 1+ –1+ 1+ –1+
EMA ––––––
Cytokeratin ––ND –––
S-100 ––––––
GFAP ––––ND –
Desmin ––––––
MIB-1 index 42% 14% 5% 4.3% 32% 30%
STAT6, signal transducer and activator of transcription 6; NAB2, NGFI-A binding protein 2; SMA, smooth
muscle actin; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; ND, not done
Neurosurg Rev
meningioma, so these markers cannot be used to differentiate
between such tumors. Ouladan et al. have also reported that
NAB2 staining was positive in a myriad of mesenchymal soft
tissue tumors including angiosarcoma, liposarcoma, and heman-
gioma [32]. In the present literature review, 77.9% of SFT/HPC
and 6.4% of meningioma are positive for CD34 expression,
Fig. 2 Histopathological findings. aThe lesion showed staghorn
appearance (left, original magnification ×4), dense cellularity (middle,
original magnification ×40), and a rich network of reticulin fibers (right,
original magnification ×10). bTumor cells were nuclear positive for
STAT6 (cases 1–6, original magnification ×40). cTumor cells were
nuclear positive for NAB2 (cases 1–6, original magnification ×40). d
Immunohistochemical findings of case 1. Tumor cells were positive for
vimentin (left upper, original magnification ×10), partial positive for
CD34 (right upper, original magnification ×10), and negative for EMA
(left lower, original magnification ×10). Many tumor cells expressed Ki-
67 (right lower, original magnification ×10). eElectron micrograph of
case 1 showed an absence of gap junction
Neurosurg Rev
yielding a specificity and sensitivity of 93.6% and 77.9%, respec-
tively, for SFT/HPC. However, the expression rate of CD34 in
SFT (grade I), HPC (grade II), and AHPC (grade III) were
90.2%, 76.3%, and 67.7%, respectively (Table 4). In our
AHPC cases, expression rate of CD34 was 50% (3/6 patients).
These data may suggest that the higher the grade of SFT/HPC is,
the lower the sensitivity of CD34 for SFT/HPC is, suggesting
that CD34 may not be as helpful in differential diagnosis of
anaplastic SFT/HPC as has been suggested. Interestingly, among
those IHC markers examined in our review of the literature, only
CD34 displayed s uch a trend when compared with tumor
grade. In the course of our study and literature review,
Table 4 Literature review of immunoreactivities in subtypes of SFT/HPC
All (n= 354) Grade I (n= 112) Grade II (n= 51) Unknown (grade II or III) (n= 110) AHPC (grade III) (n= 81)
STAT6 340 / 352 96.6% 106 / 110 96.4% 47 / 51 92.2% 107 / 110 97.3% 80 / 81 98.8%
NAB2 62 / 62 100% 25 / 25 100% 37 / 37 100%
Vimentin 10 / 10 100% 3 / 3 100% 3 / 3 100% 1 / 1 100% 3 / 3 100%
ALDH1 64 / 76 84.2% 20 / 24 83.3% 17 / 23 73.9% 27 / 29 93.1%
GRIA2 62 / 74 83.8% 20 / 24 83.3% 20 / 23 87.0% 22 / 27 81.5%
Bcl-2 29 / 35 82.9% 9 / 13 69.2% 8 / 8 100% 1 / 2 50.0% 11 / 12 91.7%
CD34 127 / 163 77.9% 55 / 61 90.2% 29 / 38 76.3% 1 / 2 50.0% 42 / 62 67.7%
p16 5 / 7 71.4% 1 / 2 50.0% 2 / 2 100% 2 / 3 66.7%
CD99 9 / 13 69.2% 4 / 4 100% 2 / 3 66.7% 1 / 2 50.0% 2 / 4 50.0%
p21 4 / 8 50.0% 1 / 2 50.0% 2 / 3 66.7% 1 / 3 33.3%
PR 3 / 17 17.6% 2 / 5 40.0% 0 / 5 0% 0 / 1 0% 1 / 6 16.7%
EMA 17 / 113 15.0% 3 / 39 7.7% 2 / 31 6.5% 1 / 2 50.0% 11 / 41 26.8%
CD57 1 / 7 14.3% 0 / 2 0% 1 / 2 50.0% 0 / 3 0%
Cytokeratin 2 / 22 9.1% 0 / 7 0% 0 / 6 0% 1 / 2 50.0% 1 / 7 14.3%
SSTR2A 2 / 25 8.0% 1 / 10 10.0% 1 / 6 16.7% 0 / 9 0%
S-100 2 / 36 5.6% 0 / 15 0% 1 / 8 12.5% 0 / 2 0% 1 / 11 9.1%
GFAP 0 / 35 0% 0 / 13 0% 0 / 9 0% 0 / 1 0% 0 / 12 0%
Desmin 0 / 8 0% 0 / 2 0% 0 / 3 0% 0 / 3 0%
Synaptophysin 0 / 8 0% 0 / 2 0% 0 / 3 0% 0 / 3 0%
ALDH1, aldehyde dehydrogenase 1; GRIA2, glutamate receptor 2; PR, progesterone receptor; SSTR2A, somatostatin receptor 2A
Table 3 Immunoreactivities of IHC markers in SFT/HPC and menin-
gioma: analysis of literature review
SFT/HPC (n= 354) Meningioma (n= 460)
STAT6 340 / 352 96.6% 0 / 454 0%
NAB2 62 / 62 100% 83 / 87 95.4%
Vimentin 10 / 10 100% 4 / 4 100%
ALDH1 64 / 76 84.2% 5 / 180 2.8%
GRIA2 62 / 74 83.8% 29 / 180 16.1%
Bcl-2 29 / 35 82.9% 100 / 125 80.0%
CD34 127 / 163 77.9% 20 / 312 6.4%
p16 5 / 7 71.4% 4 / 5 80.0%
CD99 9 / 13 69.2% 3 / 5 60.0%
p21 4 / 8 50.0% 3 / 5 60.0%
PR 3 / 17 17.6% 70 / 92 76.1%
EMA 17 / 113 15.0% 117 / 131 89.3%
CD57 1 / 7 14.3% 3 / 4 75.0%
Cytokeratin 2 / 22 9.1% 7 / 116 6.0%
SSTR2A 2 / 25 8.0% 120 / 126 95.2%
S-100 2 / 36 5.6% 46 / 131 35.1%
GFAP 0 / 35 0% 0 / 127 0%
Desmin 0 / 8 0% 0 / 5 0%
Synaptophysin 0 / 8 0% 0 / 5 0%
Table 5 Sensitivity and specificity of IHC markers for SFT/HPC and
meningioma
IHC markers Sample sizes Sensitivity (%) Specificity (%)
For SFT/HPC
STAT6 806 96.6 100
NAB2 149 100 4.6
Vimentin 14 100 0
ALDH1 256 84.2 97.2
GRIA2 254 83.8 83.9
Bcl-2 160 82.9 20
CD34 475 77.9 93.4
For meningioma
PR 109 76.1 82.4
EMA 244 89.3 85
SSTR2A 151 95.2 92
S-100 167 35.1 94.4
Neurosurg Rev
we demonstrated that SSTR2A is a negative marker for
SFT/HPC and was the most highly expressed protein
noted in meningioma with a specificity of 92%.
Another negative marker of SFT/HPC, EMA, was high-
ly expressed in meningioma with only mild levels of
expression in SFT/HPC having been noted. Boulagnon-
Rombi et al. reported that a combination of SSTR2A and/or
EMA positivity reached maximal sensitivity (i.e., 100%) and
co-expression of SSTR2A and EMA was the most specific
(i.e., 94.8%) for the diagnosis of meningioma, regardless of
the grade and/or subtype [24].
Amyriadofstudieshaveshownthatgrosstotalresectionof
tumor is an important prognostic factor for survival and recur-
rence with regard to SFT/HPC [7,8,33]. While it may be diffi-
cult to obtain a definitive pathological diagnosis of SFT/HPC in
the operating room, if suspected it is the authors’contention
that maximal safe resection of the tumor should be
attempted. In addition, when the tumor is high-grade
SFT/HPC and/or has not been completely resected, ra-
diation therapy should be administered shortly after sur-
gery. In the present cohort of cases, three of six patients
(50%) developed local recurrence. Such a high rate of
recurrence is similar to those studies that have previously
been published with 22/27 cases (84.6%) discussed by Mena
et al. [34], 4/12 (33%) reported by Damodaran et al. [35], and
22/52 (42.3%) reported by Gui-Jun Zhang et al. [7] having
been documented to reoccur. Of these recurrent cases, the
majority underwent subtotal resections of tumor, thereby
highlighting the need for accurate diagnosis and surgical plan-
ning centered on total resection of the tumor when faced with
SFT/HPC.
Conclusion
We have presented the core clinicopathological and IHC fea-
tures of 6 cases with AHPC. In addition, we identified highly
useful IHC markers for the differential diagnosis of SFT/
HPCs and meningiomas via a comprehensive review of the
literature. As discussed, AHPC is a tumor that portends an
incredibly poor prognosis and is associated with higher rates
of recurrence and extracranial metastases. As such, it remains
critical to distinguish SFT/HPC from meningioma via the em-
ployment of selected diagnostic markers in an effort to im-
prove outcomes for our patients and their families.
Acknowledgment The authors thank Masachika Shudo, Integrated
Center for Science, Ehime University School of Medicine, for assessing
electron microscopy in this work.
Authors’contributions Conception and design: Yamashita. Acquisition of
data: Yamashita and Suehiro. Analysis and interpretation: Yamashita.
Drafting the article: Yamashita and Bernstock. Critically revising the article:
Harada and Ohnishi. Reviewed submitted version of manuscript: all authors.
Approved the final version of the manuscript on behalf of all authors:
Yamashita. Statistical analysis: Yamashita. Administrative/technical/material
support: Mizuno and Kitazawa. Study supervision: Ohnishi.
Compliance with ethical standards
Conflicts of interest J.D.B. has positions/equity in CITC Ltd. and
Avidea Technologies and is a member of the Scientific Advisory Board
for POCKiT Diagnostics. The remaining authors report no conflicts of
interest related to the data presented.
Ethical approval All procedures performed in this study were in accor-
dance with the ethical standards of the institutional research committee
and with the 1964 Helsinki declaration and its later amendments or com-
parable ethical standards.
Informed Consent Informed consent was obtained from all individual
participants included in the study.
References
1. Stout AP, Murray MR (1942) Hemangiopericytoma: a vascular
tumor featuring Zimmermann's pericytes. Ann Surg 116:26–33
2. Stout AP (1949) Hemangiopericytoma; a study of 25 cases. Cancer
2:1027–1054 illust
3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, World Health
Organization, International Agency for Research on Cancer (2016)
WHO classification of tumours of the central nervous system.
International Agency For Research On Cancer, Lyon
4. Louis DN, International Agency for Research on Cancer., World Health
Organization (2007) WHO classification of tumours of the central ner-
vous system. International AgencyforResearchonCancer,Lyon
5. Fletcher CDM, World Health Organization., International Agency
for Research on Cancer (2013) WHO classification of tumours of
soft tissue and bone. IARC Press, Lyon
6. Chmielecki J, Crago AM, Rosenberg M, O'Connor R, Walker SR,
Ambrogio L, Auclair D, McKenna A, Heinrich MC, Frank DA,
Meyerson M (2013) Whole-exome sequencing identifies a recur-
rent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 45:
131–132. https://doi.org/10.1038/ng.2522
7. Zhang GJ, Zhang LW, Li D, Wu Z, Zhang JT (2017) Analysis of
prognostic factors, survival rates, and treatment in anaplastic
hemangiopericytoma. World Neurosurg 104:795–801. https://doi.
org/10.1016/j.wneu.2017.05.092
8. Kim BS, Kim Y, Kong DS, Nam DH, Lee JI, Suh YL, Seol HJ
(2018) Clinical outcomes of intracranial solitary fibrous tumor and
hemangiopericytoma: analysis according to the 2016 WHO classi-
fication of central nervous system tumors. J Neurosurg 129:1384–
1396. https://doi.org/10.3171/2017.7.JNS171226
9. Chaubal A, Paetau A, Zoltick P, Miettinen M (1994) CD34 immuno-
reactivity in nervous system tumors. Acta Neuropathol 88:454–458
10. Perry A, Scheithauer BW, Nascimento AG (1997) The
immunophenotypic spectrum of meningeal hemangiopericytoma:
a comparison with fibrous meningioma and solitary fibrous tumor
of meninges. Am J Surg Pathol 21:1354–1360
11. Okada T, Fujitsu K, Ichikawa T, Mukaihara S, Miyahara K, Tanino S,
Uriu Y, Sakamoto T, Hataoka S, Kubota J, Suzuki K, Niino H,
Yagishita S (2014) A strongly CD34-positive meningioma that was
difficult to distinguish from a solitary fibrous tumor. Ultrastruct
Pathol 38:290–294. https://doi.org/10.3109/01913123.2014.888115
12. Macagno N, Figarella-Branger D, Mokthari K, Metellus P, Jouvet
A, Vasiljevic A, Loundou A, Bouvier C (2016) Differential
Neurosurg Rev
diagnosis of meningeal SFT-HPC and meningioma: which immu-
nohistochemical markers should be used? Am J Surg Pathol 40:
270–278. https://doi.org/10.1097/PAS.0000000000000526
13. Berghoff AS, Kresl P, Bienkowski M, Koelsche C, Rajky U,
Hainfellner JA, Preusser M (2017) Validation of nuclear STAT6
immunostaining as a diagnostic marker of meningeal solitary fi-
brous tumor (SFT)/hemangiopericytoma. Clin Neuropathol 36:
56–59. https://doi.org/10.5414/NP300993
14. Robinson DR, Wu YM, Kalyana-Sundaram S, Cao X, Lonigro RJ,
Sung YS, Chen CL, Zhang L, Wang R, Su F, Iyer MK,
Roychowdhury S, Siddiqui J, Pienta KJ, Kunju LP, Talpaz M,
Mosquera JM, Singer S, Schuetze SM, Antonescu CR,
Chinnaiyan AM (2013) Identification of recurrent NAB2-STAT6
gene fusions in solitary fibrous tumor by integrative sequencing.
Nat Genet 45:180–185. https://doi.org/10.1038/ng.2509
15. Schweizer L, Koelsche C, Sahm F, Piro RM, Capper D, Reuss DE,
Pusch S, Habel A, Meyer J, Gock T, Jones DT, Mawrin C,
Schittenhelm J, Becker A, Heim S, Simon M, Herold-Mende C,
Mechtersheimer G, Paulus W, Konig R, Wiestler OD, Pfister SM,
von Deimling A (2013) Meningeal hemangiopericytoma and solitary
fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed
by nuclear expression of STAT6 protein. Acta Neuropathol 125:651–
658. https://doi.org/10.1007/s00401-013-1117-6
16. Pekmezci M, Vlodavsky E, Perry A (2014) Previously unrecog-
nized pattern of central nervous system hemangiopericytoma with
pseudoglandular spaces. Clin Neuropathol 33:186–189. https://doi.
org/10.5414/NP300721
17. Bruder M, Tews D, Mittelbronn M, Capper D, Seifert V, Marquardt
G (2015) Intramedullary solitary fibrous tumor–a benign form of
hemangiopericytoma? Case report and review of the literature.
World Neurosurg 84:189 e187–189 e112. https://doi.org/10.1016/
j.wneu.2015.02.036
18. Nakada S, Minato H, Takegami T, Kurose N, Ikeda H, Kobayashi
M, Sasagawa Y, Akai T, Kato T, Yamamoto N, Nojima T (2015)
NAB2-STAT6 fusion gene analysis in two cases of meningeal sol-
itary fibrous tumor/hemangiopericytoma with late distant metasta-
ses. Brain Tumor Pathol 32:268–274. https://doi.org/10.1007/
s10014-015-0220-x
19. Trabelsi S, Mama N, Chourabi M, Mastouri MH, Ladib M, Popov
S, Burford A, Mokni M, Tlili K, Krifa H, Jones C, Yacoubi MT,
Saad A, Brahim DH (2015) Meningeal hemangiopericytomas and
meningomas: a comparative immunohistochemical and genetic
study. Asian Pac J Cancer Prev 16:6871–6876
20. Kikuchi A, Fujita T, Takahashi Y, Yokosako S, Yoshimura C,
Akagawa H, Fujibayashi M, Kubo O, Onda H, Kasuya H (2015)
Two cases of primary intracranial solitary fibrous tumor:genetic
examination of <i>NAB2-STAT6</i> fusion and its association
with hemangiopericytoma. No Shinkei Geka 43:641–648. https://
doi.org/10.11477/mf.1436203090
21. Choi J, Park SH, Khang SK, Suh YL, Kim SP, Lee YS, Kwon HS,
Kang SG, Kim SH (2016) Hemangiopericytomas in the central
nervous system: a multicenter study of Korean cases with validation
of the usage of STAT6 immunohistochemistry for diagnosis of
disease. Ann Surg Oncol 23:954–961. https://doi.org/10.1245/
s10434-016-5414-x
22. Fritchie KJ, Jin L, Rubin BP, Burger PC, Jenkins SM, Barthelmess
S, Moskalev EA, Haller F, Oliveira AM, Giannini C (2016) NAB2-
STAT6 gene fusion in meningeal hemangiopericytoma and solitary
fibrous tumor. J Neuropathol Exp Neurol 75:263–271. https://doi.
org/10.1093/jnen/nlv026
23. Yuzawa S, Nishihara H, Wang L, Tsuda M, Kimura T, Tanino M,
Tanaka S (2016) Analysis of NAB2-STAT6 gene fusionin 17 cases
of meningeal solitary fibrous tumor/hemangiopericytoma: review
of the literature. Am J Surg Pathol 40:1031–1040. https://doi.org/
10.1097/PAS.0000000000000625
24. Boulagnon-Rombi C, Fleury C, Fichel C, Lefour S, Marchal Bressenot
A, Gauchotte G (2017) Immunohistochemical approach to the differ-
ential diagnosis of heningiomas and their mimics. J Neuropathol Exp
Neurol 76:289–298. https://doi.org/10.1093/jnen/nlx008
25. Ahmad Z, Tariq MU, Din NU (2018) Meningeal solitary fibrous
tumor/hemangiopericytoma: emphasizing on STAT 6 immunohis-
tochemistry with a review of literature. NeurolIndia 66:1419–1426.
https://doi.org/10.4103/0028-3886.241365
26. Shukla P, Gulwani HV, Kaur S, Shanmugasundaram D (2018)
Reappraisal of morphological and immunohistochemical spectrum
of intracranial and spinal solitary fibrous tumors/
hemangiopericytomas with impact on long-term follow-up. Indian
J Cancer 55:214–221. https://doi.org/10.4103/ijc.IJC_631_17
27. Bertero L, Anfossi V, Osella-Abate S, Disanto MG, Mantovani C,
Zenga F, Rudà R, Garbossa D, Soffietti R, Ricardi U, Papotti M,
Cassoni P (2018) Pathological prognostic markers in central ner-
vous system solitary fibrous tumour/hemangiopericytoma: evi-
dence from a small series. PLoS One 13:e0203570. https://doi.
org/10.1371/journal.pone.0203570 eCollection 2018
28. Sibtain NA, Butt S, Connor SE (2007) Imaging features of central
nervous system haemangiopericytomas. Eur Radiol 17:1685–1693.
https://doi.org/10.1007/s00330-006-0471-3
29. Zhou JL, Liu JL, Zhang J, Zhang M (2012) Thirty-nine cases of
intracranial hemangiopericytoma and anaplastic
hemangiopericytoma: a retrospective review of MRI features and
pathological findings. Eur J Radiol 81:3504–3510. https://doi.org/
10.1016/j.ejrad.2012.04.034
30. Bouvier C, Bertucci F, Metellus P, Finetti P, Maues de Paula A,
Forest F, Mokhtari K, Miquel C, Birnbaum D, Vasiljevic A, Jouvet
A, Coindre JM, Loundou A, Figarella-Branger D (2013) ALDH1 is
an immunohistochemical diagnostic marker for solitary fibrous tu-
mours and haemangiopericytomas of the meninges emerging from
gene profiling study. Acta Neuropathol Commun 1:10. https://doi.
org/10.1186/2051-5960-1-10
31. Mohajeri A, Tayebwa J, Collin A, Nilsson J, Magnusson L, von
Steyern FV, Brosjo O, Domanski HA, Larsson O, Sciot R, Debiec-
Rychter M, Hornick JL, Mandahl N, Nord KH, Mertens F (2013)
Comprehensive genetic analysis identifies a pathognomonic
NAB2/STAT6 fusion gene, nonrandom secondary genomic imbal-
ances, and a characteristic gene expression profile in solitary fibrous
tumor. Genes Chromosomes Cancer 52:873–886. https://doi.org/
10.1002/gcc.22083
32. Ouladan S, Trautmann M, Orouji E, Hartmann W, Huss S, Büttner
R, Wardelmann E (2015) Differential diagnosis of solitary fibrous
tumors: a study of 454 soft tissue tumors indicating the diagnostic
value of nuclear STAT6 relocation and ALDH1 expression com-
bined with in situ proximity ligation assay. Int J Oncol 46:2595–
2605. https://doi.org/10.3892/ijo.2015.2975
33. Ma L, Wang L, Fang X, Zhao CH, Sun L (2018) Diagnosis and
treatment of solitary fibrous tumor/hemangiopericytoma of central
nervous system. Retrospective report of 17 patients and literature
review. Neuro Endocrinol Lett 39:88–94
34. Mena H, Ribas JL, Pezeshkpour GH, Cowan DN, Parisi JE (1991)
Hemangiopericytoma of the central nervous system: a review of 94
cases. Hum Pathol 22:84–91
35. Damodaran O, Robbins P, Knuckey N, Bynevelt M, Wong G, Lee G
(2014) Primary intracranial haemangiopericytoma: comparison of sur-
vival outcomes and metastatic potential in WHO grade II and III var-
iants. J Clin Neurosci 21:1310–1314. https://doi.org/10.1016/j.jocn.
2013.11.026
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