Hemangioendothelioma

Intra-axial involvement of the brain by an epithelioid hemangioendothelioma is rare, and biological properties of the tumor are uncertain. Most of the primary brain manifestations are confined to the cerebral hemispheres. We report magnetic resonance imaging and microscopic findings of a case of suprasellar involvement by an epithelioid hemangioendothelioma. The tumor was treated with a subtotal resection only, and no progression of the disease was noted during a 6-month follow-up. Review of the literature suggested that most epithelioid hemangioendotheliomas in the brain are unifocal tumors with a rather favorable clinical outcome.

(Arch Pathol Lab Med. 2004;128:1289-1293)

REPORT OF A CASE

A 49-year-old woman, during the course of a few months, developed a progressive headache projecting onto the center of her forehead. The headache was worse on awakening in the morning and was not associated with nausea. At the same time, her vision deteriorated, especially on the left side. Her medical history was significant for hypertension, non-insulin-dependent diabetes mellitus, hypercholesterolemia, and depression. Neurological examination revealed pallor of the left optic disc. There was no extraocular dysmotility or facial numbness. Her reflexes were brisk and symmetric, and her gait was normal-based and steady. Magnetic resonance imaging revealed a large suprasellar lesion. The mass was isointense with cortex on T1 and T2, associated with a marked vasogenic edema, and displayed homogeneous contrast enhancement (Figure 1, A through C). The patient underwent a subtotal resection of the tumor, which resulted in improved vision and only transient short-term memory deficits. Postoperatively, no radiation therapy or immunotherapy was attempted. She had a short-term memory loss and stable bitemporal hemianopsia. Magnetic resonance imaging 6 months after surgery showed a stable disease.

MATERIALS AND METHODS

The tumor was processed for routine paraffin embedding. For immunohistochemistry, 5-µm-thick sections were deparaffinized, rehydrated, and stained with monoclonal antibodies to glial fibrillary acidic protein, CD31, CD34, and epithelial membrane antigen. The sources for primary antibodies and their dilutions are summarized in Table 1. Subsequently, horseradish peroxidase-conjugated anti-mouse polymer (Dako EnVision+, DakoCytomation, Carpinteria, Calif) was used according to the manufacturer's instructions.

PATHOLOGIC FINDINGS

The suprasellar tumor was soft and focally hemorrhagic, and measured 3.5 × 2.5 × 2.0 cm. Hematoxylin-eosin-stained sections disclosed distinct patterns of growth. Predominant was an epithelioid lobular arrangement of tumor cells showing distinct cell borders and bland nuclei (Figure 2, A). Occasionally, epithelioid cells lined large ductlike spaces (Figure 2, B). A second pattern featured loose fascicles of elongated and spindle-shaped cells streaming in a myxoid background (Figure 2, C). Coalescence of adjacent cells often gave rise to short trabeculae bearing clear vacuoles, some of which contained occasional red blood cells and leukocytes (Figure 1, D). Lymphoplasmacyte-rich infiltrates (Figure 2, D) and areas of intense stromal desmoplasia were conspicuous. The tumor cells were negative for epithelial membrane antigen, glial fibrillary acidic protein, S100, synaptophysin, and CDIa, but showed a strong and uniform immunoreactivity for endothelium-specific marker CD31 and for CD34 (Figure 2, E and F). The tumor nuclei lacked hyperchromasia or pleomorphism. No foci of necrosis or appreciable mitotic activity was detected. Correspondingly, the Ki-67 proliferative index was less than 3%. The findings of a tumor of endothelial cells showing a focally solid pattern of growth, histiocytoid cytology, and lacking aggressive features of angiosarcoma indicated a diagnosis of epithelioid hemangioendothelioma (EHE).

COMMENT

Epithelioid hemangioendothelioma is a rare tumor of intermediate grade between benign hemangioma and a full-blown angiosarcoma.1 Our case is among 29 primary and metastatic tumors with a morphology compatible to EHE found in the literature (Table 2). Morphology of some of the older cases is at variance with currently accepted criteria for EHE. Our case is also the third with suprasellar involvement. In the central nervous system, EHE affects all ages, but so far it has shown a male predilection (20:9). In contrast to the lesions of the bone, lung, or liver, primary EHE of the brain appears to be a unifocal lesion. Consistent imaging characteristics included prominent peritumoral vasogenic edema and homogeneous contrast enhancement.2

Morphologically, EHEs in the central nervous system are similar to their counterparts in soft tissue, lung, or bone,3 and they display a variable mix of histiocytoid or epithelioid and spindle cell areas.4 Their morphologic appearance is quite different from other tumors composed of transformed endothelial cells. Epithelioid hemangioendotheliomas lack dilated vascular spaces of cavernous hemangioma. In fact, in contrast to capillary hemangioma, juvenile, or spindle cell hemangioendothelioma, the vascular lumina in EHE often are not apparent or are only focally apparent. The tumors usually show no gross or significant microscopic hemorrhage or cytologically aggressive features to suggest a diagnosis of angiosarcoma.

Ultrastructurally, the tumor cells have features of endothelium with caveolae, Weibel-Palade bodies, an abundance of intermediate filaments (responsible for a histiocytoid plump appearance), and are surrounded by a basal lamina.5 Tumor cells are embedded in extracellular matrix, which varies from myxomatous and rich in hyaluronic acid6 to hyalinized.7,8 It appears that endothelial differentiation of an EHE is aborted at the intracellular level; for example, tumor cells form intracellular lumina rather than being capable of forming canalized, blood-filled vessels.3 Cells retain a secretory signature of vascular endothelium, as evidenced by the deposition of a sulfated acid mucin, like that of a ground substance of vessel wall.6 An accompaniment of chronic inflammatory cells, eosinophils, and mast cells is frequently detected.6

Similar to epithelioid hemangioendotheliomas of bone, soft tissue, and parenchymal organs, the primary brain tumors range from indolent and slowly growing to somewhat more aggressive examples. Whereas most of these tumors show only rare mitoses, some can demonstrate a quite brisk mitotic count (up to 6/10 ×400 fields) and foci of necrosis.9 Tumors amenable to a complete surgical re section are associated with a favorable prognosis.9 However, some examples showed focal recurrence5 and seeding of the neuraxis.8 Radiation therapy was attempted to control growth of incompletely excised tumors.4,7,8,10 Treatment with α-interferon became a commonly used modality capable of controlling the growth in most of the cases.10-14

Most primary EHEs of the brain appear to carry a rather favorable prognosis. Only 2 cases of tumor-related deaths have been reported,8 1 of which had a primary extradural mass and involvement of a liver 2 years later.15 In such cases, it is not always possible to conclude based on clinical data whether the brain mass was a metastasis of a slow-growing malignancy elsewhere. Additionally, EHE of bones, and to a lesser degree other organs, is commonly multifocal.3 Similarly, a few cases of intra-axial EHEs show concomitant tumors in other sites (Table 2). Although this might represent a multicentric origin of the tumors, they also can be construed as an original site of the tumor with subsequent brain or skull metastases.5,16 Clonal studies of such cases are needed to resolve this question. Prognostically, the concomitant involvement of other sites, wherein the brain lesions might represent metastatic spread of the somatic disease, fare worse.14 With the exception of this category of patients with a guarded prognosis, only a single report of tumor-related death has been documented for unicentric brain EHEs.8

The differential diagnosis of stroma-rich tumors in the suprasellar area includes a chordoid meningioma, chordoma, chordoid glioma of the third ventricle, yolk sac tumor, and myxoid chondrosarcoma. Immunohistochemical profiling is useful because chordoma is immunopositive for S100 and cytokeratin, chordoid glioma of the third ventricle stains for glial fibrillary acidic protein, and meningioma is at least focally immunoreactive with epithelial membrane antigen. Diffuse staining of epithelioid cells for endothelial cell markers, such as CD31, factor VIII-related antigen, or CD34, proves the endothelial nature of the neoplasm.

The origin of EHEs in the central nervous system is uncertain, but they clearly represent a clonal growth, rather than a reactive process. The nature of the involved genes and alterations in signaling leading to the tumor growth is unknown, but a recent report found translocation t(1; 3)(p36.3;q25) in 2 of 2 cases of EHE.17 The authors suggested an involvement of PAX7 in the pathogenesis of the EHE.17 An alternative chromosomal rearrangement in the region 11q23 t(11;1)(q21;q23) was identified,18 but the role of these genetic alterations in the tumor pathogenesis is unknown.

References

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Joachim M. Baehring, MD; Phillip S. Dickey, MD; Sergei I. Bannykh, MD, PhD

Accepted for publication July 8, 2004.

From the Departments of Neurology (Dr Baehring), Neurosurgery (Dr Dickey), and Pathology (Dr Bannykh), Yale University School of Medicine, New Haven, Conn.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Sergei I. Bannykh, MD, PhD, Department of Pathology, Yale University School of Medicine, 310 Cedar St, BML, R150, New Haven, CT 06510 (e-mail: serguei.bannykh@yale.edu).

Copyright College of American Pathologists Nov 2004
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