J Neurosurg 112:978–982, 2010

Intracranial angiomatoid fibrous histiocytoma presenting as

recurrent multifocal intraparenchymal hemorrhage

Case report
Pawel G. Ochalski, M.D.,1 James T. Edinger, M.D., 2 Michael B. Horowitz, M.D.,1
William R. Stetler, B.S.,1 Geoffrey H. Murdoch, M.D., 2 Amin B. Kassam, M.D.,1
and Johnathan A. Engh, M.D.1
1
Departments of Neurological Surgery and 2Pathology, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania

Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue neoplasm that most commonly appears in the
limbs, typically affecting children and young adults. The tumor has a propensity for local recurrence and recurrent
hemorrhage but rarely for remote metastasis. To date, only 2 reports have documented an intracranial occurrence
of the tumor (1 of which was believed to be metastatic disease). This is the second report of primary intracranial
AFH. Additionally, hemorrhage from an intracranial AFH lesion has yet to be reported, and little is known about the
radiographic characteristics and biological behavior of these lesions. In this report, the authors describe the case of a
patient with recurrent hemorrhage due to primary multifocal intracranial AFH. Initially misdiagnosed as a cavernous
malformation and then an unusual meningioma, the tumor was finally correctly identified when there was a large
enough intact resection specimen to reveal the characteristic histological pattern. The diagnosis was confirmed using
immunohistochemical and molecular studies. (DOI: 10.3171/2009.8.JNS081518)

Key Words      •      angiomatoid fibrous histiocytoma      •      intracranial hemorrhage      •

sarcoma

F
irst described by Enzinger5 in 1979, AFH is a rare
soft-tissue sarcoma that infrequently recurs and
rarely metastasizes. Clinically, the tumor most fre-
quently arises within the subcutis or deep dermis of the
extremities or trunk. Less commonly, it can develop in
the head or neck regions. Usually, AFH affects adoles-
cents or young adults in the 2nd or 3rd decade of life with
most patients presenting with local tissue swelling or
pain in the affected area. Constitutional symptoms such
as fevers and nausea can occur in a minority of patients.
Angiomatoid fibrous histiocytomas have been shown to
have approximately a 1–5% rate of remote metastasis,
warranting their classification as a low-grade malignant
tumor.6 A wide local excision is the primary treatment
modality, and a local recurrence rate of ~ 2–12% has
been reported.1,3,5
Angiomatoid fibrous histiocytomas display charac-
teristic microscopic and immunohistochemical features,
allowing identification of this tumor type. Histologically,
the tumor features sheets of histiocytoid cells admixed
with organizing hemorrhage. Typically in an en bloc re-
section, these sheets of tumor cells and zones of hemor-
rhage are surrounded by a dense fibrous pseudocapsule
with inflammatory cells. Because of the secondary hem-
orrhage and inflammation, the rate of misdiagnosis is
high.3 Recently, genetic profiling has identified unique
fusion genes thought to play an important role in sarcom-
agenesis of these tumors.1,7 These genetic markers can be
used to help confirm the pathological diagnosis.
To date, there has been a single pathologically con-
firmed case of primary intracranial AFH.4 In addition,
in a series of 108 patients diagnosed with AFH, one pa-
tient was presumed to have an intracranial metastasis;
however, this was based on imaging findings alone.3 In
the present report, the authors describe the second histo-
logically confirmed case of multifocal intracranial AFH
presenting with recurrent hemorrhages. In this particular
case, the patient presented with multifocal recurrent hem-
orrhages. Although initially these tumors were misdiag-
nosed as cavernous malformations and then an unusual
meningioma, the correct diagnosis was made after utiliz-
ing a combination of histological, immunohistochemical,
and molecular features characteristic of AFH.
Case Report
First and Second Examinations. This 35-year-old

This article contains some figures that are displayed in color

Abbreviations used in this paper: AFH = angiomatoid fibrous on­line but in black and white in the print edition.
histiocytoma; FISH = fluorescence in situ hybridization.

978 J Neurosurg / Volume 112 / May 2010

Intracranial angiomatoid fibrous histiocytoma

Fig. 1.  Imaging studies obtained at the patient’s initial presentation.  A: Axial unenhanced CT scan showing a large left
posterior temporal hemorrhage.  B: Contrast-enhanced T1-weighted MR image demonstrating minimal enhancement (arrow-
head).  C: Axial T2-weighted MR image showing the tumor focus surrounded by a rim of hypointensity likely delineating the
tumor capsule.

man initially presented with progressively worsening
headache that had developed over the preceding 2 weeks.
On examination, he exhibited some mild right facial
weakness but no other neurological deficits. A CT scan
of the brain revealed an acute left posterior temporal in-
traparenchymal hemorrhage, measuring 4 × 2 × 4 cm,
with surrounding edema (Fig. 1A). Initial MR imaging
showed a single 0.5 × 0.5–cm lesion, arising in the left
mesial temporal area (Fig. 1B). On the T2-weighted im-
ages, we observed a thin rim of hypointensity consistent
with hemosiderin surrounding the tumor capsule (Fig.
1C). Conventional angiography revealed no sign of vascu-
lar malformations or aneurysms (data not shown). In light
of his stable clinical condition, the patient was managed

TABLE 1: Summary of surgical management and histopathological diagnosis*

Proce-
dure Follow-
No. Op Approach Op Date Up (mos) Lesion Location Pathological Diagnosis
 1 lt temporal craniotomy 12/17/2004 0.8 lt pst temporal, lt sup cere­bel­lum neoplasm; organizing
  hematoma
 2 lt retromastoid craniotomy 1/04/2006 13.4 lt sup cerebellum proliferating meningothelium
  & organizing hemorrhage
 3 rt suboccipital craniotomy 9/21/2006 22 rt sup cerebellum no specimen was analyzed
 4 redo rt suboccipital craniot- 2/08/2007 26.5 rt sup cerebellum organizing granulation tissue
  omy
 5 GKS 5/17/2007 29.8 lt pst temporal, lt sup cer­ebel­lum NA
 6 occipitoparietal craniotomy 7/25/2007 32.1 lt pst temporal, lt sup cerebellum AFH
  w/ Endoport
 7 redo lt retromastoid craniot- 10/19/2007 34.9 lt sup cerebellum AFH
  omy
 8 redo lt temporal craniotomy 8/4/2008 44.4 lt pst temporal, lt sup cere­bellum AFH
  w/ Endoport
 9 GKS 9/17/2007 45.8 lt pst temporal, rt sup cere­bellum NA
10 lt VP shunt 11/19/2008 47.9 NA NA
redo lt retromastoid craniot- 12/15/2008 48.8 lt sup cerebellum dense fibrous tissue w/
11
  omy   chronic inflammation

*  GKS = Gamma Knife surgery; NA = not applicable; pst = posterior; sup = superior; VP = ventriculoperitoneal.

J Neurosurg / Volume 112 / May 2010 979

 P. G. Ochalski et al.

conservatively and discharged with a working diagnosis

of hemorrhage secondary to a cavernous malformation.
He returned 2 weeks later with complaints of headache.
Repeated imaging revealed enlargement of the previously
documented hemorrhage and evidence that it extended
through the tentorium into the left superior cerebellum.
Initial Operation. The patient underwent a left tempo-
ral craniotomy, and the hematoma was evacuated and the
tumor debulked. Intraoperatively, we identified no major
abnormal vascular channels, but the lesion appeared to
originate from the tentorium with some extension into the
infratentorial compartment. A gross-total resection was
attempted. Pathological analysis showed fragments of an
organizing hematoma with entrapped foci of a low-grade
neoplasm composed of bland, round-to-oval nuclei with
focal areas of moderate pleomorphism and a proliferative
index of ~ 10%. Based on vimentin and weak, focal epi-
thelial membrane antigen immunoreactivity, a tentative
diagnosis of possible meningioma was made.
Additional Operations. Over a 49-month period, the
patient experienced multiple intracranial recurrences. Tu-
mor growth was identified within the left mesial temporal
lobe as well as within the right cerebellopontine angle.
A metastatic workup, including serial craniospinal MR
imaging and whole-body CT scanning, did not reveal any
evidence of tumor elsewhere. Furthermore, a number of
hemorrhagic events associated with tumor growth were
observed during this time. The recurrent hemorrhages
were the result of residual tumor growth and de novo in-
tratumoral bleeding. In total, the patient underwent a to- Fig. 2.  Follow-up MR imaged acquired 24 months after initial tumor
tal of 8 open craniotomies for emergency clot evacuation debulking, demonstrating recurrence in the supratentorial compart-
ment. The absence of surrounding hemorrhage enables better char-
and/or elective tumor debulking (Table 1). The patient acterization of the lesion on MR imaging.  A and B: Precontrast and
also underwent 2 radiosurgical ablations in an attempt to postcontrast T1-weighted images showing loculations of T1 signal
gain local disease control and limit the need for additional shortening with minimal enhancement (inset in B: higher-magnification
open surgery. Despite these attempts, the patient died of contrast-enhanced T1-weighted image of the same lesion at 30 months
progressive hydrocephalus due to recurrent hemorrhage demonstrating increased tumor enhancement associated with tumor
after 49 months of clinical follow-up. What follows is an growth).  C: Axial T2-weighted image demonstrating the hyperintense
expanded discussion on the radiographic and histological bubbly appearance of an AFH surrounded by a rim of hypointensity,
better seen at higher magnification (inset) and showing minimal cere-
characteristics of the tumor. bral edema.  D: Gradient echo MR image revealing a large area of
Imaging Findings. Imaging characteristics have not magnetic susceptibility consistent with macrohemorrhages.
been previously described for intracranial AFH due to the
paucity of reports. Using serial MR imaging, we charac-
terized AFH imaging features (Fig. 2). was not established until the sixth operation. The patho-
On precontrast T1-weighted MR imaging, AFH dis- logical diagnosis of AFH was made using combined data
played loculations of T1 signal shortening that appeared from histological sections, immunohistochemical stains,
isointense or slightly hyperintense compared with normal and the identification of a rearranged ESWR1 gene inves-
gray matter. Postcontrast T1-weighted imaging delineated tigated using FISH). Histologically, the classic features
aspects of the tumor capsule, but this modality has lim- of AFH were not present collectively in the first several
ited use when assessing recurrence (Fig. 2A and B); how- resection specimens because of the fragmented nature of
ever, with tumor growth the enhancement did become the specimens. Each specimen showed predominantly
more prominent (Fig. 2B inset). A characteristic MR fea- organizing hemorrhage and glial scar with small foci of
ture of AFH, in our case, was the presence of a bubbly probable tumor. The later resection specimens did exhibit
appearing mass on T2-weighted imaging (Figs. 2C and classic histological features of AFH including the follow-
3C) surrounded by a thin rim of hypointensity better seen ing: 1) the presence of a fibrous pseudocapsule; 2) cellular
on gradient echo scans and resulting from extracellular foci of pleomorphic, hyperchromatic, histiocytoid cells;
methemoglobin and hemosiderin. 3) focal areas of hemorrhage and pseudovascular, blood-
filled spaces lacking an endothelial lining; and 4) a lym-
Histological, Immunohistochemical, and Genetic phohistiocytic inflammatory cuff surrounding the lesion
Findings. Despite multiple open microsurgical evacua- (Fig. 3A and B). Furthermore, extensive hemosiderin and
tions and resections, a confirmatory diagnosis of AFH hematoidin pigment deposition was present with numer-

980 J Neurosurg / Volume 112 / May 2010

Intracranial angiomatoid fibrous histiocytoma

Fig. 3.  Photomicrographic studies of AFH.  A: High-power H & E–stained section showing pleomorphic histiocytoid cells
with abundant eosinophilic cytoplasm and hyperchromatic nuclei.  B: Low-power H & E–stained section showing a fibrous
pseudocapsule with a lymphoplasmacytic cuff and underlying pseudovascular spaces.  C: Specimen strongly positive for vi-
mentin.  D: Specimen strongly positive for desmin.  E: Specimen weakly positive for CD 68 in the tumor cells.  F: Fluo-
rescence in situ hybridization showing EWSR1 (22q12) translocation with a Break Apart probe. Germline EWSR1 genes are
represented by combined red and green probes and appear as a yellow signal when the gene is intact. The presence of separate
red and green signals represents a translocated EWSR1 gene. The specific translocation partner cannot be identified with this
study.  G: Fluorescence in situ hybridization negative for FUS (16p11) translocation using a similar Break Apart probe. All visible
signals are yellow (intact) suggesting that the FUS gene is not translocated. Magnification × 400 (A and C–E), × 100 (B), and
× 1000 (F and G).

ous pigment-laden macrophages, which is also character-
istic of AFH.
Immunohistochemical stains demonstrated strong,
diffuse vimentin positivity in the cellular areas indicating
a mesenchymal origin. The tumor was strongly desmin
positive, as is seen in nearly 50% of AFH cases, suggest-
ing myoid differentiation of the tumor.8 However, it was
negative for most major skeletal muscle markers, includ-
ing MYOD1, myoglobin, and myogenin. In the tumor
cells, CD 68 was weakly positive, suggesting some de-
gree of histocytic differentiation (Fig. 3C–E).
Discussion
When it was first described in 1979, AFH was thought
to be a histological subtype of malignant fibrous histiocy-
toma.3,5 The WHO subsequently reclassified AFHs as a
distinct clinicopathological entity, a type of fibrous his-
tiocytoma with an intermediate malignancy grade.8 How-
ever, due to the rarity of primary intracranial AFHs, the
lesion was also not classified as a distinct pathological
entity on the WHO 2007 CNS tumor list. Nevertheless,
the diagnosis of AFH is made primarily by histological
examination. Recent molecular studies have identified
several chromosomal translocations that can be reproduc-
ibly seen in these lesions, thus aiding in the diagnosis.1,4,7
Two chromosomal translocations that were initially seen
in AFHs are as follows: 1) fusion of ATF1 from chro-
mosome 12q13 (a leucine-zipper transcription factor)
with FUS from chromosome 16p11 (a TET family RNA
binding protein); and 2) ATF1 to EWSR1 from 22q12
(also a TET family RNA binding protein). Additionally,
Antonescu et al.1 identified a translocation between the
EWSR1 gene and the CREB1 gene and suggested that this
fusion may be the most common in AFH. These fusions
may be detected using either polymerase chain reaction–
based assays or FISH techniques.6,9 While these translo-
cations have been identified in several patients with AFH,

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it should be noted that they are not entirely specific for
this entity. The EWSR1/ATF1 fusion is also commonly
seen in soft-tissue clear cell carcinomas, whereas the
EWSR1/CREB1 fusion has also been described in clear
cell sarcoma of the gastointestinal tract.2 These findings
suggest that the presence of the same translocation and
fusion protein in 2 different precursor cells may explain
the unique and varied phenotypes observed in AFH.
In our case, the tumor was subjected to FISH analy-
sis with EWSR1 and FUS probes to access for possible
EWSR1-ATF1, EWSR1-CREB1, and FUS-ATF1 translo-
cations. The FUS Dual Color Break Apart probe showed
no translocation in any of the 60 tumor cells analyzed.
The EWSR1 Break Apart Rearrangement probe showed a
complex pattern in 56 of the 60 cells involving the disrup-
tion of the EWS region and containing extra fusion sig-
nals. The remaining 4 cells exhibited a classic transloca-
tion pattern (Fig. 3F and G). Detection of this rearranged
EWSR1 gene, in addition to the histological and immuno-
histochemical features, helped establish the diagnosis of
AFH. Fresh tissue for RNA isolation would be necessary
to definitively determine the exact fusion oncogene in this
patient; these studies have not been performed to date.
Conclusions
We have reported the second case of primary mul-
tifocal intracranial AFH with recurrent hemorrhage. We
discussed radiographic and histopathological findings as
well as the clinical course and surgical management op-
tions to treat this unusual neoplasm. Although we suspect
that more cases of intracranial AFH exist, classic histo-
logical features may not be seen in every resection speci-
men and a misdiagnosis of cavernous malformation may
occur. Unfortunately, CT and MR imaging could not eas-
ily distinguish an AFH from a cavernous malformation.
Similar to intracranial cavernous malformation, this AFH
had a “popcorn” or “bubbly” appearance on T2-weighted
imaging and often displayed a variable pattern of hemo-
siderin rim around the tumor. Therefore, an AFH was
not considered and confirmatory molecular testing was
not pursued, delaying the diagnosis. It follows, then, that
without a high index of suspicion these lesions may be
misdiagnosed. For this reason, correlation of the clinical,
radiographic, and pathological features is essential to es-
tablish a timely definitive diagnosis. We recommend that
the diagnosis of AFH be considered in cases of cavernous
malformation in which the lesion recurs following resec-
tion. Furthermore, we recommend attempting a gross-to-
982
P. G. Ochalski et al.
tal resection of the tumor, including its dural attachment,
as this may reduce future hemorrhagic events.
Disclaimer
The authors report no conflict of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper.
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Manuscript submitted November 16, 2008.
Accepted August 5, 2009.
Please include this information when citing this paper: published
online September 4, 2009; DOI: 10.3171/2009.8.JNS081518.
Address correspondence to: Johnathan A. Engh, M.D., Depart-
ment of Neurological Surgery, University of Pittsburgh Medical
Cen­ter, 200 Lothrop Street, Suite B-400, Pittsburgh, Pennsylvania
15213. email: enghja@upmc.edu.
J Neurosurg / Volume 112 / May 2010