J Neurosurg 112:978–982, 2010

978 J Neurosurg / Volume 112 / May 2010

First 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

Intracranial angiomatoid fibrous histiocytoma presenting as recurrent multifocal intraparenchymal hemorrhage

Case reportPawel 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

1Departments 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

Abbreviations used in this paper: AFH = angiomatoid fibrous histiocytoma; FISH = fluorescence in situ hybridization.

This article contains some figures that are displayed in color on line but in black and white in the print edition.

J Neurosurg / Volume 112 / May 2010

Intracranial angiomatoid fibrous histiocytoma

979

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 No. Op Approach Op Date

Follow-Up (mos) Lesion Location Pathological Diagnosis

1 lt temporal craniotomy 12/17/2004 0.8 lt pst temporal, lt sup cere bel lum 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-

omy2/08/2007 26.5 rt sup cerebellum organizing granulation tissue

5 GKS 5/17/2007 29.8 lt pst temporal, lt sup cer ebel lum NA 6 occipitoparietal craniotomy

w/ Endoport7/25/2007 32.1 lt pst temporal, lt sup cerebellum AFH

7 redo lt retromastoid craniot-

omy10/19/2007 34.9 lt sup cerebellum AFH

8 redo lt temporal craniotomy w/ Endoport

8/4/2008 44.4 lt pst temporal, lt sup cere bellum AFH

9 GKS 9/17/2007 45.8 lt pst temporal, rt sup cere bellum NA10 lt VP shunt 11/19/2008 47.9 NA NA

11 redo lt retromastoid craniot- omy

12/15/2008 48.8 lt sup cerebellum dense fibrous tissue w/ chronic inflammation

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

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.

P. G. Ochalski et al.

980 J Neurosurg / Volume 112 / May 2010

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-tal of 8 open craniotomies for emergency clot evacuation and/or elective tumor debulking (Table 1). The patient also underwent 2 radiosurgical ablations in an attempt to gain local disease control and limit the need for additional open surgery. Despite these attempts, the patient died of progressive hydrocephalus due to recurrent hemorrhage after 49 months of clinical follow-up. What follows is an expanded discussion on the radiographic and histological characteristics of the tumor.

Imaging Findings. Imaging characteristics have not been previously described for intracranial AFH due to the paucity of reports. Using serial MR imaging, we charac-terized AFH imaging features (Fig. 2).

On precontrast T1-weighted MR imaging, AFH dis-played loculations of T1 signal shortening that appeared isointense or slightly hyperintense compared with normal gray matter. Postcontrast T1-weighted imaging delineated aspects of the tumor capsule, but this modality has lim-ited use when assessing recurrence (Fig. 2A and B); how-ever, with tumor growth the enhancement did become more prominent (Fig. 2B inset). A characteristic MR fea-ture of AFH, in our case, was the presence of a bubbly appearing mass on T2-weighted imaging (Figs. 2C and 3C) surrounded by a thin rim of hypointensity better seen on gradient echo scans and resulting from extracellular methemoglobin and hemosiderin.

Histological, Immunohistochemical, and Genetic Findings. Despite multiple open microsurgical evacua-tions and resections, a confirmatory diagnosis of AFH

was not established until the sixth operation. The patho-logical diagnosis of AFH was made using combined data from histological sections, immunohistochemical stains, and the identification of a rearranged ESWR1 gene inves-tigated using FISH). Histologically, the classic features of AFH were not present collectively in the first several resection specimens because of the fragmented nature of the specimens. Each specimen showed predominantly organizing hemorrhage and glial scar with small foci of probable tumor. The later resection specimens did exhibit classic histological features of AFH including the follow-ing: 1) the presence of a fibrous pseudocapsule; 2) cellular foci of pleomorphic, hyperchromatic, histiocytoid cells; 3) focal areas of hemorrhage and pseudovascular, blood-filled spaces lacking an endothelial lining; and 4) a lym-phohistiocytic inflammatory cuff surrounding the lesion (Fig. 3A and B). Furthermore, extensive hemosiderin and hematoidin pigment deposition was present with numer-

Fig. 2. Follow-up MR imaged acquired 24 months after initial tumor debulking, demonstrating recurrence in the supratentorial compart-ment. The absence of surrounding hemorrhage enables better char-acterization of the lesion on MR imaging. A and B: Precontrast and postcontrast T1-weighted images showing loculations of T1 signal shortening with minimal enhancement (inset in B: higher-magnification contrast-enhanced T1-weighted image of the same lesion at 30 months demonstrating increased tumor enhancement associated with tumor growth). C: Axial T2-weighted image demonstrating the hyperintense bubbly appearance of an AFH surrounded by a rim of hypointensity, better seen at higher magnification (inset) and showing minimal cere-bral edema. D: Gradient echo MR image revealing a large area of magnetic susceptibility consistent with macrohemorrhages.

J Neurosurg / Volume 112 / May 2010

Intracranial angiomatoid fibrous histiocytoma

981

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).

DiscussionWhen 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,

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).

P. G. Ochalski et al.

982 J Neurosurg / Volume 112 / May 2010

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.

ConclusionsWe 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-

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.

References

1. Antonescu CR, Dal Cin P, Nafa K, Teot LA, Surti U, Fletcher CD, et al: EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 46:1051–1060, 2007

2. Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M: EWS-CREB1: a recurrent variant fusion in clear cell sarco-ma–association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res 12:5356–5362, 2006

3. Costa MJ, Weiss SW: Angiomatoid malignant fibrous histio-cytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol 14:1126–1132, 1990

4. Dunham C, Hussong J, Seiff M, Pfeifer J, Perry A: Primary intracerebral angiomatoid fibrous histiocytoma: report of a case with a t(12;22)(q13;q12) causing type 1 fusion of the EWS and ATF-1 genes. Am J Surg Pathol 32:478–484, 2008

5. Enzinger FM: Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer 44:2147–2157, 1979

6. Fanburg-Smith JC, Miettinen M: Angiomatoid “malignant” fi brous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum Pathol 30:1336–1343, 1999

7. Hallor KH, Micci F, Meis-Kindblom JM, Kindblom LG, Bac-chini P, Mandahl N, et al: Fusion genes in angiomatoid fibrous histiocytoma. Cancer Lett 251:158–163, 2007

8. Pratibha R, Ahmed S: Angiomatoid variant of fibrous histio-cytoma: a case report and review of literature. Int J Paediatr Dent 16:363–369, 2006

9. Thway K: Angiomatoid fibrous histiocytoma: a review with recent genetic findings. Arch Pathol Lab Med 132:273–277, 2008

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 Cen ter, 200 Lothrop Street, Suite B-400, Pittsburgh, Pennsylvania 15213. email: enghja@upmc.edu.