malignant tumors of blood vessels: angiosarcomas, hemangioendotheliomas, and hemangioperictyomas

Journal of Surgical Oncology 2008;97:321–329

Malignant Tumors of Blood Vessels:

Angiosarcomas, Hemangioendotheliomas, and Hemangioperictyomas

MORITZ KOCH, MD,1 G. PETUR NIELSEN, MD,2{ AND SAM S. YOON, MD3*

1Department of Surgery, University of Heidelberg, Heidelberg, Germany2Harvard Medical School, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts

3Harvard Medical School, Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts

Sarcomas that arise from or resemble the components of blood vessels are uncommon and include angiosarcomas, hemangioendotheliomas, and

hemangiopericytomas. This article reviews the management of these three types of sarcomas. Diagnosis can sometimes be difficult, with the

diagnosis of hemangiopericytoma versus solitary fibrous tumor currently in debate. Each of these sarcomas subtypes has certain unique clinical

traits. The mainstay of treatment is surgical resection, sometimes combined with radiation therapy. Adjuvant chemotherapy is unproven but can be

considered. For patients with advanced disease, various chemotherapeutic regimens may result in meaningful responses in a minority of patients.

J. Surg. Oncol. 2008;97:321–329. � 2008 Wiley-Liss, Inc.

KEY WORDS: angiosarcoma; hemangioendothelioma; hemangiopericytoma

INTRODUCTION

Blood vessels are normally comprised of an inner layer of

endothelial cells, surrounding pericytes and smooth muscle cells, and

glomus bodies (specialized forms of arteriovenous anastamoses which

function in thermal regulation). Malignant tumors of blood vessels are

classified as sarcomas. Soft tissue sarcomas (STS) and bone sarcomas

constitute a highly heterogeneous group of tumors with respect

to anatomical distribution, histological subtype, and clinical behavior

[1]. Malignant or potentially malignant sarcomas that arise from or

resemble constituents of blood vessels are rare and include angiosarco-

mas, hemangioendotheliomas, and hemangiopericytomas (Table I).

These three subtypes of sarcoma will be discussed in this review.

Kaposi’s sarcomas are vascular tumors that occur in certain clinical

setting such as in the lower extremity of elderly men of Mediterranean

or Jewish descent (classical Kaposi’s sarcoma), patients with AIDS,

and patients who are immunosuppressed. Glomus tumors are usually

benign tumors that occur in the deep dermis or subcutaneous fat of the

extremity in patients between 20 and 40 years old. There are several

good reviews of Kaposi’s sarcomas [2,3] and glomus tumors [4], and

they will not be reviewed here. Benign tumors of blood or lymph

vessel origin such as hemangioma and lymphangioma will also not be

discussed.

ANGIOSARCOMAS

Presentation

Angiosarcomas comprise less than 1% of all sarcomas. An

overview of relatively large, recent series of angiosarcomas including

our own institution’s series is shown in Table II. In these series, the

median age ranges from 60 to 71 years old, and the male:female

distribution is roughly equal. Symptoms and signs at presentation

depend on the location of the tumor. Unlike most sarcomas, which tend

to occur in deep locations, angiosarcomas commonly occur in the skin

or superficial soft tissues [4]. Cutaneous lesions often present as ill-

defined, bruise-like lesions that can progress to nodular and ulcerated

lesions. Noncutaneous tumors can present as an asymptomatic mass.

The most common presenting symptom is pain or discomfort. Median

size ranges from 3 to 6 cm, and over three-quarters of tumors are

intermediate- or high-grade. Metastases are most common to the lung

and liver, with other less common sites including lymph nodes, soft

tissues, and bone. Angiosarcomas occur in distinct clinical settings

with the presentation and behavior linked to specific settings. We will

discuss angiosarcoma in relation to the following clinical settings: (1)

cutaneous angiosarcoma, (2) cutaneous angiosarcoma associated with

radiation or lymphedema, (3) breast angiosarcoma, (4) angiosarcoma

of deep soft tissues and organs, and (5) angiosarcoma of bone.

Etiologic Factors

Genetic and cytogenetics. There are certain familial syndromes

associated with the development of sarcomas including Li Fraumeni

syndrome, neurofibromatosis, and hereditary retinoblastoma. None of

these syndromes are specifically associated with the development of

angiosarcomas [1]. Using cytogenetics, sarcomas segregate into two

major types: those with specific genetic alterations and usually simple

karyotypes, including fusion genes due to reciprocal translocations

(e.g., PAX3-FKHR in alveolar rhabdomyosarcomas) or specific point

mutations (e.g., c-kit mutations in gastrointestinal stromal tumors), and

those with nonspecific genetic alterations and complex, unbalanced

karyotypes, reflected by numerous genetic losses and gains. Angio-

sarcomas are included in the latter category, and the most frequently

described abnormalities are gain in chromosome 5, 8, and 20 and losses

of chromosomes 7, 22, and Y [5].

{Associate Professor of Pathology

*Correspondence to: Sam S. Yoon, MD, Assistant Professor of Surgery,Harvard Medical School, Division of Surgical Oncology, MassachusettsGeneral Hospital, 55 Fruit Street, Boston, MA 02114; Fax: 617-724-3895.E-mail: [email protected]

Received 27 November 2007; Accepted 4 December 2007

DOI 10.1002/jso.20973

Published online in Wiley InterScience (www.interscience.wiley.com).

� 2008 Wiley-Liss, Inc.

Environmental factors. Radiation can cause the development of

sarcomas, including angiosarcomas, of both soft tissue and bone. Cha

et al. [6] reported on 114 patients at Memorial Sloan-Kettering Cancer

Center with radiation-induced sarcomas. The median time between

radiation and the development of sarcoma was 8.6 years. The most

common malignancies for which radiation was given were breast

cancer (295), lymphoma (16%), and prostate cancer (15%). Malignant

fibrous histiocytoma was the most common histological subtype (23%)

followed by angiosarcoma (15%) and fibrosarcoma (15%). The risk of

sarcoma increases with radiation dose and with the post-radiation

observation period [7]. The frequency of radiation-induced malig-

nancies is higher following treatment of children, especially those

receiving both radiation and chemotherapy; the frequency may be as

high as 20–30% at remote times.

Chronic lymphedema and chronic inflammation may lead to the

development of angiosarcomas. Classically, this has been seen in a

lymphedematous arm of a patient with a history of breast cancer

following mastectomy (Stewart–Treves syndrome) [8]. The develop-

ment of angiosarcoma has also been described following chronic

lymphedema due to congenital defects, trauma, and infections

including filarial infection [9]. There are also several case reports of

angiosarcoma developing near defunctionalized arteriovenous fistulas

in patients with renal transplants [10] as well as adjacent to foreign

body material [11].

Angiosarcomas have been described to occur in pre-existing benign

vascular lesions (port-wine stain and lymphangioma) as well as benign

and malignant nerve sheath tumors, neurofibroma (in the setting

of neurofibromatosis), leiomyoma, spindle cell hemangioma (in the

setting of Maffucci syndrome), retinoblastoma (in the setting of Rb1

deletion), Klippel–Trenaunay syndrome, xeroderma pigmentosum,

malignant germ cell tumor, herpes zoster lesion, and Aicardi syndrome

[4]. Several environmental exposures are associated specifically with

angiosarcomas. Thorium dioxide (Thorotrast) used in the past for

cerebral angiography, vinyl chloride used in the production of synthetic

rubber, and arsenic used in pesticides are all associated with hepatic

angiosarcomas [12,13].

Histopathology

The histopathological features of angiosarcomas can be quite

diverse, ranging from well-differentiated to poorly differentiated

lesions [14]. Low-grade, well-differentiated lesions can be composed

of irregular vascular channels. Figure 1 demonstrates a cutaneous

angiosarcoma with an irregular or sinusoidal pattern of vessels.

Vascular spaces can be lined with atypical endothelium in a single row

or several layers thick. Highly cellular lesions can occur as sheets

of cells with obliteration of vascular spaces. High-grade, poorly

differentiated lesions can be comprised of undifferentiated cells,

making them difficult to discern from other histologies. By

immunohistochemistry, these tumors are usually positive for factor

VIII-related antigen, vimentin, CD34, and CD31 positive [4,15].

While angiosarcomas likely arise from either blood or lymphatic

vessels, it is generally not possible to differentiate histologically between

a blood or lymphatic vessel origin [4]. The term lymphangiosarcoma is

Journal of Surgical Oncology

TABLE I. Tumors of Blood and Lymph Vessels

Benign

Hemangioma

Lymphangioma

Malignant or potentially malignant

Angiosarcoma

Hemangiopericytoma

Hemangioendothelioma

Kaposi’s sarcoma

Glomus tumor

TABLEII.SelectedLargeSurgicalSeriesofAngiosarcoma

FirstAuthor,Year

Number

patients

Sites

included

Mostcommon

site

Agea

Percent

male

Size

Grade

Median

follow-up

Top3sitesof

metastasis

5-year

survival

Median

survival

Prognostic

factors

Mark,1996

67

All

Head/neck

62

62

37,<5cm

;

30,>5cm

58high,9low

30

Lung,liver,

lymphnodes

35%

NRb

Size�5cm

,

highgrade

Meis-Kindblom,1998

80

Softtissue

Extrem

ity

60–70

63

5NR

20

Lungs,lymph

nodes,

softtissues

NR

NR

Age>67,

retroperitoneum

location,larger

size

Paw

lik,2003

29

Scalp

Scalp

71

62

5.9

76%

high,

24%

low

18.2

Lung,liver,

lymphnodes

25–30%

28.4

Age>70,

size

>5cm

,

noradiationtherapy

Fury,2005

59

All

Breast

65

42

NR

NR

22.8

Bone,

lung,liver

NR

30.8

Positivemicroscopic

margin

MGH

series,2007

46

All

Cutaneous

63.5

56

357%

high,

20%

int.,

15%

low

38.9

Lung,bone,liver

60%

Not

reached

Radiationor

lymphedem

a

induced,interm

ediate

orhighgrade

aMeanormedian.

bNR,notreported.

322 Koch et al.

often used when an angiosarcoma arises in the setting of lymphedema,

but the majority of angiosarcomas arising in this setting are

indistinguishable from other angiosarcomas [16]. The only feature that

characterizes angiosarcomas arising in lymphedematous areas as

opposed to other angiosarcomas are areas of lymphangiomatosis, which

appear as premalignant changes in small lymphatic vessels [4]. Like

lymphangiosarcomas, cutaneous angiosarcomas arising in radiated fields

are indistinguishable from other cutaneous angiosarcomas.

Of note, benign cutaneous atypical vascular lesions can arise

following radiation, and these lesions must be differentiated from

angiosarcomas. In the series by Fletcher and coworkers [17], radiation-

associated cutaneous atypical vascular lesions were typically small

well-circumscribed brown or erythematous papules. Microscopically,

they were confined to the dermis, and composed of complex

anastamosing and focally dilated vascular spaces. In general, these

lesions behaved in a benign fashion, although one lesion appeared to

progress to angiosarcoma.

Epithelioid angiosarcoma refers to a variant of angiosarcoma

composed of neoplastic cells that have an epithelioid appearance.

These tumors are usually poorly differentiated and biologically

aggressive [18].

Clinical Management/Prognostic Factors

The initial workup of patients suspected of having an angiosarcoma

begins with a thorough history and physical examination, with

particular attention paid to the region of the primary lesion: definition

of size, site of origin (superficial or deep, attached to or fixed to deep

structures), involvement or discoloration of overlying skin, and mass

effect and functional effect on adjacent organs, nerves, blood vessels,

and bone. Laboratory studies need not go beyond a complete blood

count and chemistry panel. For the primary site, the radiographic

evaluation should include a CT scan or MRI. The most useful

radiological modality to evaluate an extremity or trunk primary site is

MRI, but CT scans can provide supplemental information. A chest

CT should be obtained for high-grade tumors to evaluate for lung

metastases. The role of PET scans has yet to be defined, but many

primary tumors and metastatic sites do show increased FDG uptake.

An adequate biopsy is required to determine a histological diagnosis

as to tumor type and grade. Fine needle aspiration is generally

inadequate for initial diagnosis, so either a core needle biopsy or open

biopsy can be performed. Superficial lesions which are readily palpable

can be directly biopsied without imaging, but for tumors which are

located at depth, a CT- or US-guided approach is advocated. For open

biopsies, care should be taken to limit hemorrhage and contamination

of normal surround tissues with tumor cells.

Cutaneous angiosarcomas. Cutaneous angiosarcomas primarily

affect elderly persons and are often located in the head and neck,

especially the scalp. In the data from the Armed Forces Institute of

Pathology of 101 cutaneous angiosarcomas, 52% occurred in the head

and neck and 21% occurred in the extremity [4]. Lesions are often

infiltrative and ill-defined, and local control can be difficult. Optimal

treatment involves aggressive surgery to achieve negative margins.

Skin graft and flaps are often required to close large defects. Radiation

therapy is usually recommended.

In the older series of 72 patients from the United Kingdom, median

survival was only 15 months and only 12% of patients survived beyond

5 years [19]. Size less than 10 cm was associated with better prognosis,

and radiation appeared to help with local control. Pawlik et al. [20]

reported on the University of Michigan experience with 29 scalp

angiosarcomas over a 27-year period. Nearly all patients underwent

surgical excision but negative margins were achieved in only 21% of

patients. Median survival was 28 months, and younger age, size

<5 cm, and radiation therapy were associated with improved survival.

The M.D. Anderson Cancer Center reported their series of 14 head and

neck cutaneous angiosarcomas over 19 years [21]. Eleven patients had

multi-focal disease. The use of radiation combined with surgery

appeared to improve local control, but 63% of patients developed

distant metastases.

Cutaneous angiosarcoma associated with

radiation or lymphedema

Monroe et al. [22] found about 100 cases of angiosarcoma after

breast conservation therapy in their literature review. Fifty-five of 75

patients (73%) with angiosarcomas after breast surgery and radiation

recurred after surgery for their angiosarcoma, usually within 1 year.

Local recurrences occurred in the tumor bed or along the surgical scar,

and very few reports of surgical salvage after local tumor recurrence

were reported. Distant metastases usually developed at the time of or

after local recurrence, and the authors felt that if local control could be

attained that survival rates may be improved. Since adjuvant radiation

may also reduce the risk of local recurrence, the authors recommended

these patients undergo pre-operative radiation followed by aggressive

surgical resection with the placement of flaps as needed.

There have been about 300 cases of Steward-Treves syndrome

reported world-wide [23]. These patients usually present with purplish,

multicentric lesions in a lymphedematous extremity, often have

aggressive disease, and are thought to carry a poor prognosis. Others

have reported some long-term survival in small series [23].

In a recent review of patients treated at our institution with

angiosarcomas, we found that patients who developed angiosarcomas

in radiation or lymphedema fields were significantly more prone to

local and distant recurrence and death from disease [24]. Of the eight

patients who had localized disease, six patients had local recurrence

between 1 and 63 months after surgical resection, and six patients had


Fig. 1. Cutaneous angiosarcoma. [Color figure can be viewed in theonline issue, available at www.interscience.wiley.com.]

Malignant Tumors of Blood Vessels 323

distant recurrence between 1 and 77 months. At last follow-up, five

patients died of disease 6 months to 7 years after surgery, two patients

were alive with disease 4 months and 4 years after surgery, and only

one patient was alive without disease 5 years after surgery. Thus for

patients with radiation induced angiosarcomas or lymphangiosarcomas

and without metastatic disease, we generally recommend aggressive

surgery which often requires chest wall resection for breast lesions and

amputation of extremity lesions. Radiation therapy can sometimes be

delivered to previously irradiated fields using techniques such as

brachytherapy. Adjuvant chemotherapy is also often recommended.

Breast angiosarcoma. Primary breast sarcomas are rare, and

primary breast angiosarcomas (in the absence of prior radiation) are

even rarer. In the review from the Mayo Clinic of 25 primary breast

sarcomas, 6 were angiosarcomas [25]. In one series of 83 women with

primary breast sarcomas, only 8 of these were angiosarcomas and

angiosarcoma histology was associated with significantly poorer

overall survival compared to other histological subtypes [26]. This is

in contrast to another study of 60 breast sarcomas, where angiosarcoma

histology was associated with improved survival [27]. Treatment

recommendations for primary breast angiosarcoma generally include

simple mastectomy and often radiation therapy, although other

recommendations have ranged from wide local excision to radical

mastectomy. The role of axillary dissection is also unclear. In the series

from M.D. Anderson of 59 patients with any breast sarcoma including

17 angiosarcomas, 59% of patients had axillary dissections and none of

the over 300 lymph nodes examined had evidence of tumor. In this

study, local recurrence occurred in 34% of patients after mastectomy

alone compared to 13% after mastectomy and radiation, although this

difference was not statistically significant.

We generally recommend simple mastectomy for patients with

primary breast angiosarcomas or more extensive resections when there

is involvement of adjacent tissues such as the chest wall. Breast

conservation therapy is avoided given these lesions often have ill-

defined margins and are multifocal. Sentinel lymph node biopsies or

axillary lymph node dissections are not generally performed. Even

with negative surgical margins, radiation therapy is also often

recommended after mastectomy.

Angiosarcoma of deep soft tissues or organs. Angiosarcomas

arising in deep soft tissues or organs may have distinct differences

compared to cutaneous angiosarcoma, with a wider age distribution. In

the review of 80 patients with soft tissue angiosarcoma by Meis-

Kindblom and coworker, these lesions occurred most often in the

seventh decade and primarily in the extremity (54%) and trunk (31%).

Median size was 5 cm, and there was a wide morphologic spectrum.

Fifty three percentage of patients died at a median of 11 months and

31% were alive without disease at a median of 46 months. Local

recurrence occurred in 20% and distant recurrence in 49%, most

commonly to the lungs followed by lymph nodes, soft tissues, bone,

and liver. Poor prognostic factors for survival included older age,

retroperitoneal location, and large size.

There are numerous case reports and small series of angiosarcomas

arising in solid organs including the heart [28], liver [29], spleen [30],

and adrenal gland [31]. Angiosarcomas arising in solid organs often

have a poor prognosis. In one series of 28 splenic angiosarcomas, only

one patient survived without disease for 10 years [30].

Local therapy for angiosarcomas arising in deep soft tissues

or organs involves aggressive surgery. Adjuvant radiation is often

recommended for soft tissue tumors. Adjuvant chemotherapy should

also be considered.

Angiosarcoma of bone. Angiosarcoma of bone is rare and

accounts for less than 1% of primary skeletal malignancies, with very

limited reports in the literature [32]. There can be two different patterns

of presentation [18,32]. One pattern is a tumor presenting as multiple

lesions in a single bone, or multiple lesions presenting in adjacent

bones or even all the bones of a limb. Tumors with this presentation

tend to have a more indolent course. The second pattern is a rapidly

progressive solitary lesion that metastasizes quickly to the lung or to

other distant bones. Epithelioid angiosarcoma refers to a variant of

angiosarcoma composed of neoplastic cells that have an epithelioid

appearance. These tumors are usually poorly differentiated and

biologically aggressive [18].

Radiographically, there is no specific finding associated with

angiosarcoma of bone as opposed to other malignant bone tumors

[33]. They may be solitary or multiple which may be related to the

vascular ancestry of the cells. The lesions are usually highly

destructive, and may grow too fast to invoke a periosteal reaction.

They may be eccentric and may have a purely lytic or mixed lytic-

sclerotic pattern. Complete destruction of the cortex with extension

into soft tissues may be present in high grade lesions. Some lesions,

particularly of the multicentric type, may have a ‘‘soap-bubble’’ type of

appearance extending up and down the cortex of a long bone.

Involvement in the spine may affect several adjacent vertebrae.

In the largest series of 112 cases, angiosarcoma of bone occurred

slightly more commonly in males than females, had a wide age range,

and tended to involve the long tubular bones [34]. However, any bone

can be affected. Multifocal involvement was common, occurring in 25

of 112 cases in one series, but was not associated with poorer survival.

Treatment for localized disease involves surgical resection, often

combined with radiation therapy.

Adjuvant chemotherapy. A meta-analysis of 14 randomized

trials of doxorubicin-based adjuvant chemotherapy versus no chemo-

therapy for STS was performed in 1997 [35]. The adjuvant chemo-

therapy group had a statistically significant higher rate of local

recurrence-free survival (81% vs. 75%, P¼ 0.016), distant recurrence-

free survival (70% vs. 60%, P¼ 0.003), and overall-recurrence-free

survival (55% vs. 45%, P¼ 0.001). However, overall survival differed

only by 4% (54% vs. 50%) and this difference did not attain statistical

significance. The trend towards benefit in the few, under-powered

studies done to date may favor the use of adjuvant chemotherapy for

the highest risk patients. Angiosarcomas generally carry a higher risk

of local recurrence and metastasis than other histological subtypes of

STS, and so adjuvant chemotherapy is more frequently recommended.

Chemotherapy regimens most frequently include doxorubicin, ifosfa-

mide, dacarbazine, and navelbine.

Prognostic factors. Several series have examined prognostic

factors for survival after surgical resection (Table II). Factors

associated with worse prognosis include larger size (>5 cm), high

grade, positive margin resection, difficult location such as the

retroperitoneum, and advanced age.

Advanced Disease

Patients with advanced angiosarcomas in general fare poorly.

Several chemotherapeutic regimens have been investigated, with

some recent optimism found for paclitaxel. A retrospective review of

patient receiving paclitaxel for angiosarcoma of the head and neck at

Memorial Sloan-Kettering Cancer Center revealed that 8 of 9 patients

had a major response and 1 patient had a minor response with a median

duration of 5 months [36]. In a subsequent report from the same

institution, 52 patients received chemotherapy for unresectable

disease. Paclitaxel was given as first line therapy in 26 patients and

median progression-free survival was 4.0 months. For 19 patients with

scalp angiosarcoma, median progression-free survival was 4.6 months

and efficacy may have been better with weekly dosing compared to

every 3-week dosing. Mesna, doxorubicin, and ifosfamide (MAI)

administration resulted in a progression-free survival of 5.4 months.

Doxorubicin-based chemotherapy regimens, commonly used for

other sarcoma subtypes, have also been used for angiosarcomas.

Skubitz and Haddad [37] reported their experience with 13 patients

treated initially with either paclitaxel or pegylated-liposomal doxor-


324 Koch et al.

ubicin. Five of 8 patients treated with paclitaxel had either partial or

complete responses, and 3 of 6 patients treated with pegylated-

liposomal doxorubicin had partial responses.

Angiosarcoma growth is often promoted by pro-angiogenic factors.

Some newer biologic therapies including anti-angiogenic therapies

hypothetically may be effective against angiosarcomas but remain

largely untested. D’Adamo et al. [38] combined doxorubicin and

bevacizumab, an anti-VEGF antibody, for patients with metastatic soft

tissue sarcomas and had a 12% response rate, and 35% of patients

developed grade 2 or greater cardiac toxicity. None of the patients had

angiosarcomas, and perhaps this regimen may be more effective

against this specific histological subtype. Vogt et al. reported a regimen

of two anti-angiogenic agents, pioglitazone and rofecoxib, combined

with metronomic dosing of trofosfamide for five patients with

advanced angiosarcomas. Two patients had a complete response, one

had a partial response, and two had stable disease [39].

The treatment of angiosarcomas is often quite challenging

compared with other sarcomas subtypes. Some major challenges in

the treatment of angiosarcomas include characteristics such as ill-

defined borders, long distances of covert extension, frequency of

multifocal disease, and propensity for metastatic disease. Evidence has

accumulated that in addition to surgery, there are important roles for

radiation therapy and possibly chemotherapy in the management of

these patients. Optimal results usually require a multidisciplinary

approach to the overall management of these patients.

EPITHELOID HEMANGIOENDOTHELIOMAS

Presentation

Hemangioendotheliomas are classified as intermediate-grade

malignant or borderline tumors and rank, due to their clinical behavior,

between the benign hemangiomas and more malignant angiosarcomas

[40]. The term hemangioendothelioma includes a variety of tumors

with varying malignant potential. The most aggressive and most

common variant of hemangioendothelioma is epithelioid hemangioen-

dothelioma, first described by Weiss and Enzinger [41]. Other

members of the family of hemangioendotheliomas are Kaposiform

hemangioendothelioma, hobnail (Dabska-retiform) hemangioendothe-

lioma, and polymorphous hemangioendothelioma [42]. Kaposiform

hemangioendothelioma occurs nearly exclusively in children in the

superficial or deep soft tissues [42]. Hobnail hemangioendotheliomas

occur at all ages and have a propensity for spread to regional lymph

nodes [43]. Polymorphous hemangioendotheliomas are rare tumors

that occur primary in lymph nodes [44]. This section will focus on

epithelioid hemangioendotheliomas.

Epithelioid hemangioendotheliomas occur usually in adults with

roughly equal sex distribution [45]. These tumors are rarely seen in

children [46]. The most common location is in the superficial or deep

soft tissues, but they can also be seen in the liver and bone. Numerous

other locations have been described such that these tumors can

essentially occur throughout the body. Soft tissue lesions are usually

unifocal while in the liver, lung, and bone, epithelioid hemangioen-

dotheliomas often are multifocal because of invasive growth along

small vessels. Symptoms and signs on presentation depend on the

location of the tumor. In larger clinical series of patients with epithelioid

hemangioendotheliomas, metastasis has been seen in 21–61% of cases,

depending on the location of the primary tumor [45,47–49].

Histopathology

Since hemangioendothelioma are rare tumors and display various

histomorphological patterns, they are often misdiagnosed [50,51].

Grossly, epithelioid hemangioendotheliomas have variegated, reddish-

white or gray-white color [40]. About half these lesions arise from a

blood vessel, commonly a vein, and in these cases the vessel lumen is

filled with a combination of tumor cells, necrotic debris, and dense

collagen. Tumor cells have small intracellular lumens or vacuoles and

are arranged in short strands or solid nests of rounded to slightly

spindled endothelial cells (Fig. 2). The tumor stroma varies from

highly myxoid to hyaline. Cytologically, the tumor cells usually

display mild atypia and almost no mitotic activity. Some tumors show

an enhanced level of atypia, mitotic activity, and even necrosis, and

these features are thought to indicate a more aggressive clinical course

with metastases. Immunohistochemically, the cells show a vascular

phenotype with positive staining for endothelial markers, most

commonly CD31, CD34, and von Willebrand factor. About one-fourth

of epithelioid hemangioendotheliomas express cytokeratin which may

lead to possible misdiagnosis of nonvascular lesions [45,52]. The main

differential diagnosis of epithelioid hemangioendotheliomas, espe-

cially in deep sites and visceral organs, includes metastatic carcinoma,

melanoma, and epithelioid sarcoma.


Since there are no reliable clinical or radiological signs for a

hemangioendothelioma, definitive diagnosis is usually established

by the pathologist after biopsy or surgical resection. Preoperative

radiological evaluation should include a CT scan or MRI of the

primary site and chest CT scan to search for pulmonary metastases.

Doppler ultrasound and MRI may be helpful in the diagnosis of

primary venous lesions. A recent study showed enhanced FDG-uptake

on PET imaging for pulmonary hemangioendothelioma [53].

Soft tissue tumors. In the series of 30 patients reported by

Mentzel et al., [45] epithelioid hemangioendotheliomas of the soft

tissues usually presented with a solitary and at times painful mass.

These lesions occurred at a median age of 50 and with a slight female

predominance. About half of the lesions were deep to the muscular

fascia and the other half involved subcutaneous fat or dermis. For

isolated soft tissue tumors, curative resection with an adequate tumor-

free resection margin should be performed. The role of adjuvant

radiation is unclear. Given local recurrence can occur in over 10%

patients, we often consider adjuvant radiation, especially with a close

or positive resection margin.

In one of the largest studies of 46 patients by Weiss et al., [49] 31%

of patients with soft tissue hemangioendotheliomas developed

metastases but only half of the patients with metastases died of

disease. This finding was explained by the fact that the majority of

patients only developed regional lymph node metastases. Another


Fig. 2. Epithelioid hemangioendothelioma. [Color figure can beviewed in the online issue, available at www.interscience.wiley.com.]


series of 24 patients with a median follow-up of 39 months found that

13% of patients recurred locally, 21% developed distant metastases,

and 17% died of disease [45]. In this study, negative prognostic factors

included increased mitoses and nuclear atypia, which were associated

with poor survival. No correlation with survival was found with tumor

size. Weiss and Enzinger [41] demonstrated that mitosis >1 per 10

high powered field, necrosis, and extensive spindling were associated

with a higher rate of metastasis.

Hepatic tumors. Less than 500 hepatic epithelioid hemangioen-

dotheliomas have been reported in the literature [54]. The mean age is

42 years old and the male to female ratio is 2:3. Three-quarters of

patients present with symptoms, with the most common symptoms

being right upper quadrant pain, hepatomegaly, and weight loss.

Almost 90% of patients present with multifocal disease in both lobes,

and extrahepatic disease is present at the time of diagnosis in about

one-third of patients.

The tumors are usually imaged with abdominal CT scans or liver

MRI. Hepatic epithelioid hemangioendotheliomas can appear as

discrete nodules of varying sizes or as confluent masses. However

definitive diagnosis requires histopathological examination. Our expe-

rience is that image guided core needle biopsy is usually diagnostic and

laparoscopic or open biopsy is uncommonly needed.

Conventional or extended liver resection is the treatment of choice

when feasible [55,56]. However the majority of patients present with

multiple lesions, and most often, both liver lobes are involved [55].

Orthotropic liver transplantation is a reasonable treatment option for

unresectable, multifocal hepatic disease, offering a 5-year survival

rates of over 50% [57,58]. Other regional therapies have included

radiation therapy and transarterial chemoembolization [48].

In the review article by Mehrabi et al. [54], the most common

treatment of these patients has included liver transplantation (45%), no

treatment (25%), chemotherapy or radiation therapy (21%), and liver

resection (9%). Overall 5-year survival after liver transplantation was

55% compared to 75% after liver resection, 73% after chemotherapy,

30% after radiation therapy, and 4.5% after no treatment.

Bone tumors. In the largest series of 40 patients from the Mayo

Clinic, patients with bone epithelioid hemangioendotheliomas ranged

in age between 11 and 77 and there equal numbers of men and women

[47]. Lesions were multifocal in 22 patients and unifocal in 18 patients.

The most common presentation was local pain or swelling, and three

patients presented with a pathologic fracture. About half of lesions

were in the lower extremity, and appeared radiographically as lytic

lesions near the ends of bones. Common sites of metastasis include the

lung and liver.

Treatment should include resection for unifocal tumors, and

resection and/or radiation therapy can be considered for multifocal

tumors. Some studies have suggested that multifocal tumors have a

better prognosis than unifocal tumors [59], but this has been

contradicted by other studies [47]. Clinical behavior is difficult to

predict based on histological features [47].

Advanced Disease

The most common sites of metastasis are the lungs, liver, lymph

nodes, and bone. The effectiveness of chemotherapy is unknown given

the small number of reports [60]. Interferon alfa has been used in

addition to various conventional chemotherapeutic regimens often

including doxorubicin.

HEMANGIOPERICYTOMAS

Presentation

Hemangiopericytomas were first described and named by Stout and

Murray in 1949 [61]. There is an ongoing discussion between sarcoma

pathologists regarding the term hemangiopericytoma, as solitary

fibrous tumors bear a close histomorphological similarity to heman-

giopericytomas [62]. It is now thought by some experts that the

majority of lesions previously called hemangiopericytomas are, in

fact, essentially indistinguishable from solitary fibrous tumors and do

not show any evidence of pericytic differentiation and are in fact

fibroblastic lesions [63]. Current evolving histopathological concepts

and the new WHO classification of soft tissue tumors acknowledge

these changes and now classify most hemangiopericytomas as solitary

fibrous tumors [62,63]. However, our group continues to diagnose a

small group of tumors as hemangiopericytomas. In the following

section, we will discuss in more detail the histopathology of

hemangiopericytomas and solitary fibrous tumors. Further clinical

details on hemangiopericytomas are based on past studies in which

many hemangiopericytomas were in fact solitary fibrous tumors. Thus

readers are reminded that future studies may differ from the presented

studies, based largely on classification of many more tumors as solitary

fibrous tumors rather than hemangiopericytomas.

Hemangiopericytomas primarily affect adults (median age 45 years)

and are rare in infants and children [64]. Both genders are equally

affected. Many hemangiopericytomas are present for a long time

before they are diagnosed, sometimes as long as several decades, and

many patients present with a slowly growing, often painless mass that

has reached a considerable size [65]. The most common anatomic

locations for hemangiopericytoma are the lower extremity (especially

the thigh), axilla, pelvis, retroperitoneum, and head and neck [66,67].

Other less common locations include the breast, lung, mediastinum,

bone, inguinal region, peritoneum, liver, pancreas, stomach, greater

omentum, mesorectum, uterus, ovary and vagina [25,64,68–71]. The

diagnosis of hemangiopericytoma in uncommon locations should be

viewed with caution as there are many other tumors displaying similar

histomorphological features [62]. Most tumors are deep-seated and

often found in muscle tissue. Dermal and subcutaneous hemangioper-

icytomas are rare except for infantile hemangiopericytomas [62,72].

Most patients present with pain or a mass, but neurological or

vascular symptoms occur in a minority of patients [73]. Other

symptoms include teleangiectasia and elevated temperature of the

overlying skin due to the rich vascularity of hemangiopericytomas

[64]. Hemangiopericytoma in the pelvis and retroperitoneum can be

associated with urinary retention, hydronephrosis, and rarely with

constipation or abdominal distension. Hypoglycemia is associated with

both hemangiopericytoma and solitary fibrous tumor, and is often seen

for tumors located in the pelvis and retroperitoneum [74]. This is

mediated through insulin-like growth factors (IGFs) which are

produced by the tumor, and IGFs and insulin-like growth factor

receptors (IGF-R) can be found in tumor cells even when clinical

symptoms are absent [75]. In patients with hypoglycemia, symptoms

disappear after tumor resection.

Histopathology

Pericytes lack differentiating and characteristic features at the light

microscope level, and the histopathological diagnosis of hemangioper-

icytoma is traditionally based on the presence of a branching pattern of

small and large vessels [66]. As this growth pattern is shared by a

variety of unrelated soft tissue tumors, the exact diagnosis of

hemangiopericytoma is difficult and should be rather an exclusion

diagnosis than a primary diagnosis [64]. Therefore, we will present

typical histopathological features of classic hemangiopericytoma and

solitary fibrous tumor.

The diagnosis of a classic hemangiopericytoma depends initially on

identification of a typical architectural vascular pattern in association

with a population of relatively bland mesenchymal cells that display no

discernible differentiation under light microscopy (Fig. 3) [64]. The

tumor consists of tightly packed, round to fusiform cells with


326 Koch et al.

undefined cytoplasmic borders arranged around an elaborate vascu-

lature. The vessels form a vascular network with branching vessels of

various calibers. As a rule, the dilated vessels divide and communicate

with small vessels that may be partly compressed and obscured by the

surrounding cellular proliferation. Typically, the dividing sinusoidal

vessels have a staghorn configuration. In some hemangiopericytomas,

there exist spindle cell areas, but the spindle cells are never arranged in

long bundles or fascicles as in the solitary fibrous tumor, fibrosarcoma,

or synovial sarcoma. A small subset of hemangiopericytomas contain a

variable amount of fat as an integral part of the tumor [76] and are

now regarded by some as a fat-forming variant of solitary fibrous

tumor [63]. Immunohistochemically, the cells of hemangiopericytoma

usually express muscle-specific actin (HHF-35) and CD34 [77]. The

differential diagnosis of hemangiopericytoma includes solitary fibrous

tumor, synovial sarcoma, fibrous histiocytoma, and mesenchymal

chondrosarcoma [64].


Radiographically, hemangiopericytomas are rounded, sharply out-

lined homogenous densities or masses [66]. These tumors appear

on CT scan as well-circumscribed masses, which often displace

neighboring structures and organs such as urinary bladder, colon, and

ureter. Cystic changes in the tumor are often detected, but calcification

is rare and usually occurs only in large tumors. One study suggested

that PET imaging may be useful for the detection of recurrent

hemangiopericytoma during follow-up [78]. Angiography, although

now uncommonly performed, shows a characteristic picture with a

richly vascularized mass, dilated arteries, and a diffuse capillary blush.

Sometimes, early visualization of veins suggests an arteriovenous

shunt. MRI provides several characteristic features suggesting a

diagnosis of solitary fibrous tumor: T1 signal isointensity to gray

matter with heterogeneous gadolinium contrast enhancement and often

T2 hypointensity [79]. However, only after tumor removal or biopsy

with careful examination by an experienced pathologist can diagnosis

of hemangiopericytoma be made. Staging studies include a chest CT

and abdomen/pelvis CT [80].

Management of the primary tumor involves surgery and sometimes

radiation therapy. Local recurrence occurred in one-third of patients in

one series, and local recurrence was more common in difficult

locations such as the epidural space, retroperitoneum, and pelvis [73].

Surgical resection remains the treatment of choice for hemangioper-

icytoma, ideally with negative microscopic margins when feasible.

Radiation likely reduces local recurrence as shown for other soft tissue

sarcomas [81,82]. Spitz et al. [73] recommended adjuvant radiotherapy

for patients with hemangiopericytoma greater than 5 cm in size or

when resection margins are inadequate. Preoperative radiation therapy

can be utilized in locations such as the retroperitoneum or pelvis [83].

The role of adjuvant chemotherapy is controversial for patients with

soft tissue sarcomas in general [35], and even less defined in patients

with hemangiopericytomas.

The difficulty of predicting the prognosis and clinical behavior of

hemangiopericytoma has been repeatedly stressed in the literature [62].

Moreover, pathologists have considerable difficulties in defining

malignant characteristics in hemangiopericytoma. Weiss and Enzinger

proposed a combination of increased mitotic activity (�4 mitoses/10

high powered field), large size of the lesion (>5 cm), a high degree of

cellularity, the presence of immature and pleomorphic tumor cells, and

foci of hemorrhage and necrosis to be characteristic for a malignant

hemangiopericytoma [66]. The rate of metastasis reported for

hemangiopericytoma varies significantly from 10–60% and likely

reflect variations in the application of the diagnosis of hemangioper-

icytoma [67]. In the largest study of hemangiopericytomas from the

Armed Forces Institute of Pathology (AFIP), metastasis rate was

17.2% [66]. A study from the M.D. Anderson Cancer Center found

metastasis in about 30% of the patients with a 5-year actuarial survival

rate of 71% [73]. Another recent study of patients with hemangioper-

icytoma showed a metastasis rate of 20%, and a 5-year overall survival

of 86% [67].

Follow-up of patients with hemangiopericytoma should include

regular clinical examination and further radiological examination in

patients with deep-seated tumors or in patients with suspicion of tumor

recurrence and/or metastasis. Long term follow-up of patients with

these tumors should be maintained as some tumors display late

recurrence and metastasis, even beyond 5 years [73,84].

Advanced Disease

Common sites of metastasis include the lung, bone, and liver. For

patients with advanced or unresectable hemangiopericytoma, treat-

ment remains undefined [85,86]. The effectiveness of chemotherapy is

debatable. Wong and Yagoda [87] reported a 50% complete or partial

remission rate in 16 patients treated with doxorubicin alone or in

combination with other agents, but another more recent study found

only one in six patients responding to doxorubicin-based chemother-

apy [73]. A more aggressive approach with tandem high-dose

chemotherapy and subsequent autologous peripheral blood stem cell

transplantation has been reported in one patient with recurrent

abdominal hemangiopericytoma [88]. Adams et al. [89] described a

successful and curative liver transplantation in a patient with diffuse

liver metastasis and persistent hypoglycemia from malignant heman-

giopericytoma.

REFERENCES

1. Brennan MF, Lewis JL: Diagnosis and management of soft tissuesarcoma. London: Martin Dunitz; 2002.

2. Schwartz RA: Kaposi’s sarcoma: An update. J Surg Oncol 2004;87:146–151.

3. Pantanowitz L, Dezube BJ: Advances in the pathobiology andtreatment of Kaposi sarcoma. Curr Opin Oncol 2004;16:443–449.

4. Weiss SW, Goldblum JR: Malignant vascular tumors. In: WeissSW, Goldblum JR, editors. Enzinger and Weiss’s soft tissuetumors. St. Louis: Mosby; 2001. pp. 917–954.

5. Schuborg C, Mertens F, Rydholm A, et al.: Cytogenetic analysisof four angiosarcomas from deep and superficial soft tissue.Cancer Genet Cytogenet 1998;100:52–56.


Fig. 3. Hemangiopericytoma. [Color figure can be viewed in theonline issue, available at www.interscience.wiley.com.]


6. Cha C, Antonescu CR, Quan ML, et al.: Long-term results withresection of radiation-induced soft tissue sarcomas. Ann Surg2004;239:903–909.

7. Robinson E, Neugut AI, Wylie P: Clinical aspects of postirradia-tion sarcomas. J Natl Cancer Inst 1988;80:233–240.

8. Stewart FW, Treves N: Classics in oncology: Lymphangiosar-coma in postmastectomy lymphedema: A report of six cases inelephantiasis chirurgica. CA Cancer J Clin 1981;31:284–299.

9. Muller R, Hajdu SI, Brennan MF: Lymphangiosarcoma associ-ated with chronic filarial lymphedema. Cancer 1987;59:179–183.

10. Wehrli BM, Janzen DL, Shokeir O, et al.: Epithelioid angiosar-coma arising in a surgically constructed arteriovenous fistula: Arare complication of chronic immunosuppression in the setting ofrenal transplantation. Am J Surg Pathol 1998;22:1154–1159.

11. Jennings TA, Peterson L, Axiotis CA, et al.: Angiosarcomaassociated with foreign body material. A report of three cases.Cancer 1988;62:2436–2444.

12. Popper H, Thomas LB, Telles NC, et al.: Development of hepaticangiosarcoma in man induced by vinyl chloride, thorotrast, andarsenic. Comparison with cases of unknown etiology. Am J Pathol1978;92:349–369.

13. Lee FI, Smith PM, Bennett B, et al.: Occupationally relatedangiosarcoma of the liver in the United Kingdom 1972–1994. Gut1996;39:312–318.

14. Mark RJ, Poen JC, Tran LM, et al.: Angiosarcoma. A report of 67patients and a review of the literature. Cancer 1996;77:2400–2406.

15. Meis-Kindblom JM, Kindblom LG: Angiosarcoma of soft tissue:A study of 80 cases. Am J Surg Pathol 1998;22:683–697.

16. Karpeh MS Jr, Caldwell C, Gaynor JJ, et al.: Vascular soft-tissuesarcomas. An analysis of tumor-related mortality. Arch Surg1991;126:1474–1481.

17. Brenn T, Fletcher CD: Radiation-associated cutaneous atypicalvascular lesions and angiosarcoma: Clinicopathologic analysis of42 cases. Am J Surg Pathol 2005;29:983–996.

18. Deshpande V, Rosenberg AE, O’Connell JX, et al.: Epithelioidangiosarcoma of the bone: A series of 10 cases. Am J Surg Pathol2003;27:709–716.

19. Holden CA, Spittle MF, Jones EW: Angiosarcoma of the face andscalp, prognosis and treatment. Cancer 1987;59:1046–1057.

20. Pawlik TM, Paulino AF, McGinn CJ, et al.: Cutaneousangiosarcoma of the scalp: A multidisciplinary approach. Cancer2003;98:1716–1726.

21. Morrison WH, Byers RM, Garden AS, et al.: Cutaneousangiosarcoma of the head and neck. A therapeutic dilemma.Cancer 1995;76:319–327.

22. Monroe AT, Feigenberg SJ, Mendenhall NP: Angiosarcoma afterbreast-conserving therapy. Cancer 2003;97:1832–1840.

23. Roy P, Clark MA, Thomas JM: Stewart-Treves syndrome—Treatment and outcome in six patients from a single centre. Eur JSurg Oncol 2004;30:982–986.

24. Abraham JA, Hornicek FJ, Kaufman AM, et al.: Treatment andoutcome of 82 patients with angiosarcoma. Ann Surg Oncol2007;14:1953–1967.

25. Adem C, Reynolds C, Ingle JN, et al.: Primary breast sarcoma:Clinicopathologic series from the Mayo Clinic and review of theliterature. Br J Cancer 2004;91:237–241.

26. Zelek L, Llombart-Cussac A, Terrier P, et al.: Prognostic factorsin primary breast sarcomas: A series of patients with long-termfollow-up. J Clin Oncol 2003;21:2583–2588.

27. Gutman H, Pollock RE, Ross MI, et al.: Sarcoma of the breast:Implications for extent of therapy. The M.D. Anderson experi-ence. Surgery 1994;116:505–509.

28. Janigan DT, Husain A, Robinson NA: Cardiac angiosarcomas. Areview and a case report. Cancer 1986;57:852–859.

29. Neshiwat LF, Friedland ML, Schorr-Lesnick B, et al.: Hepaticangiosarcoma. Am J Med 1992;93:219–222.

30. Neuhauser TS, Derringer GA, Thompson LD, et al.: Splenicangiosarcoma: A clinicopathologic and immunophenotypic studyof 28 cases. Mod Pathol 2000;13:978–987.

31. Kruger S, Kujath P, Johannisson R, et al.: Primary epithelioidangiosarcoma of the adrenal gland case report and review of theliterature. Tumori 2001;87:262–265.

32. Evans HL, Raymond AK, Ayala AG: Vascular tumors of bone: Astudy of 17 cases other than ordinary hemangioma, with anevaluation of the relationship of hemangioendothelioma ofbone to epithelioid hemangioma, epithelioid hemangioendothe-lioma, and high-grade angiosarcoma. Hum Pathol 2003;34:680–689.

33. Wenger DE, Wold LE: Malignant vascular lesions of bone:Radiologic and pathologic features. Skeletal Radiol 2000;29:619–631.

34. Wold LE, Unni KK, Beabout JW, et al.: Hemangioendothelialsarcoma of bone. Am J Surg Pathol 1982;6:59–70.

35. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapyfor localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 1997;350:1647–1654.

36. Fata F, O’Reilly E, Ilson D, et al.: Paclitaxel in the treatment ofpatients with angiosarcoma of the scalp or face. Cancer 1999;86:2034–2037.

37. Skubitz KM, Haddad PA: Paclitaxel and pegylated-liposomaldoxorubicin are both active in angiosarcoma. Cancer 2005; 104:361–366.

38. D’Adamo DR, Anderson SE, Albritton K, et al.: Phase II study ofdoxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005;23:7135–7142.

39. Vogt T, Hafner C, Bross K, et al.: Antiangiogenetic therapy withpioglitazone, rofecoxib, and metronomic trofosfamide in patientswith advanced malignant vascular tumors. Cancer 2003;98:2251–2256.

40. Weiss SW, Goldblum JR: Hemangioendothelioma: Vasculartumors of intermediate malignancy. In: Weiss SW, GoldblumJR, editors. Enzinger and Weiss’s soft tissue tumors. St. Louis:Mosby; 2001. pp. 891–915.

41. Weiss SW, Enzinger FM: Epithelioid hemangioendothelioma: Avascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–981.

42. O’Hara CD, Nascimento AG: Endothelial lesions of soft tissues:A review of reactive and neoplastic entities with emphasis on low-grade malignant (‘‘borderline’’) vascular tumors. Adv Anat Pathol2003;10:69–87.

43. Argani P, Athanasian E: Malignant endovascular papillaryangioendothelioma (Dabska tumor) arising within a deep intra-muscular hemangioma. Arch Pathol Lab Med 1997;121:992–995.

44. Chan JK, Frizzera G, Fletcher CD, et al.: Primary vascular tumorsof lymph nodes other than Kaposi’s sarcoma. Analysis of 39 casesand delineation of two new entities. Am J Surg Pathol 1992;16:335–350.

45. Mentzel T, Beham A, Calonje E, et al.: Epithelioid hemangioen-dothelioma of skin and soft tissues: Clinicopathologic andimmunohistochemical study of 30 cases. Am J Surg Pathol1997;21:363–374.

46. Sharif K, English M, Ramani P, et al.: Management of hepaticepithelioid haemangio-endothelioma in children: What option?Br J Cancer 2004;90:1498–1501.

47. Kleer CG, Unni KK, McLeod RA: Epithelioid hemangioendo-thelioma of bone. Am J Surg Pathol 1996;20:1301–1311.

48. Makhlouf HR, Ishak KG, Goodman ZD: Epithelioid heman-gioendothelioma of the liver: A clinicopathologic study of 137cases. Cancer 1999;85:562–582.

49. Weiss SW, Ishak KG, Dail DH, et al.: Epithelioid hemangioen-dothelioma and related lesions. Semin Diagn Pathol 1986;3:259–287.

50. Al Shraim M, Mahboub B, Neligan PC, et al.: Primary pleuralepithelioid haemangioendothelioma with metastases to the skin.A case report and literature review. J Clin Pathol 2005;58:107–109.

51. d’Annibale M, Piovanello P, Carlini P, et al.: Epithelioidhemangioendothelioma of the liver: Case report and review ofthe literature. Transplant Proc 2002;34:1248–1251.


328 Koch et al.

52. Gray MH, Rosenberg AE, Dickersin GR, et al.: Cytokeratinexpression in epithelioid vascular neoplasms. Hum Pathol1990;21:212–217.

53. Ergun EL, Lim E: Increased FDG uptake in pulmonary epitheloidhemangioendothelioma. Rev Esp Med Nucl 2006;25:188–192.

54. Mehrabi A, Kashfi A, Fonouni H, et al.: Primary malignanthepatic epithelioid hemangioendothelioma: A comprehensivereview of the literature with emphasis on the surgical therapy.Cancer 2006;107:2108–2121.

55. Lauffer JM, Zimmermann A, Krahenbuhl L, et al.: Epithelioidhemangioendothelioma of the liver. A rare hepatic tumor. Cancer1996;78:2318–2327.

56. Leowardi C, Hinz U, Hormann Y, et al.: Malignant vasculartumors: Clinical presentation, surgical therapy, and long-termprognosis. Ann Surg Oncol 2005;12:1090–1101.

57. Belghiti J: Transplantation for liver tumors. Semin Oncol 2005;32:29–32.

58. Madariaga JR, Marino IR, Karavias DD, et al.: Long-term resultsafter liver transplantation for primary hepatic epithelioidhemangioendothelioma. Ann Surg Oncol 1995;2:483–487.

59. Tsuneyoshi M, Dorfman HD, Bauer TW: Epithelioid heman-gioendothelioma of bone. A clinicopathologic, ultrastructural,and immunohistochemical study. Am J Surg Pathol 1986;10:754–764.

60. Kelly H, O’Neil BH: Response of epithelioid haemangioendo-thelioma to liposomal doxorubicin. Lancet Oncol 2005;6:813–815.

61. Stout AP: Hemangiopericytoma; a study of 25 cases. Cancer1949;2:1027–1054 illust.

62. Gengler C, Guillou L: Solitary fibrous tumour and haemangio-pericytoma: Evolution of a concept. Histopathology 2006;48:63–74.

63. Fletcher CD: The evolving classification of soft tissue tumours:An update based on the new WHO classification. Histopathology2006;48:3–12.

64. Weiss SW, Goldblum JR: Perivascular tumors. In: Weiss SW,Goldblum JR, editors. Enzinger andWeiss’s soft tissue tumors. St.Louis: Mosby; 2001. pp. 985–1035.

65. Stout AP, Himadi GM: Solitary (localized) mesothelioma of thepleura. Ann Surg 1951;133:50–64.

66. Enzinger FM, Smith BH: Hemangiopericytoma: An analysis of106 cases. Hum Pathol 1976;7:61.

67. Espat NJ, Lewis JJ, Leung D, et al.: Conventional hemangioper-icytoma: Modern analysis of outcome. Cancer 2002;95:1746–1751.

68. Chnaris A, Barbetakis N, Efstathiou A, et al.: Primary mediastinalhemangiopericytoma. World J Surg Oncol 2006;4:23.

69. Durr HR, Nerlich A, Lienemann A, et al.: Malignant hemangio-pericytoma of the bone. Langenbecks Arch Surg 2000;385:207–212.

70. Kim BW, Wang HJ, Jeong IH, et al.: Metastatic liver cancer: Arare case. World J Gastroenterol 2005;11:4281–4284.

71. Vennarecci G, Boschetto A, Esposito A, et al.: Malignanthaemangiopericytoma of the mesorectum. Chir Ital 2004;56:865–868.

72. Mentzel T, Calonje E, Nascimento AG, et al.: Infantilehemangiopericytoma versus infantile myofibromatosis. Study of

a series suggesting a continuous spectrum of infantile myofibro-blastic lesions. Am J Surg Pathol 1994;18:922–930.

73. Spitz FR, Bouvet M, Pisters PW, et al.: Hemangiopericytoma: A20-year single-institution experience. Ann Surg Oncol 1998;5:350–355.

74. Paullada JJ, Lisci-Garmilla A, Gonzales-Angulo A, et al.:Hemangiopericytoma associated with hypoglycemia. Metabolicand electron microscopic studies of a case. Am J Med 1968;44:990–999.

75. Pavelic K, Spaventi S, Gluncic V, et al.: The expression and roleof insulin-like growth factor II in malignant hemangiopericyto-mas. J Mol Med 1999;77:865–869.

76. Nielsen GP, Dickersin GR, Provenzal JM, et al.: Lipomatoushemangiopericytoma. A histologic, ultrastructural and immuno-histochemical study of a unique variant of hemangiopericytoma.Am J Surg Pathol 1995;19:748–756.

77. Schurch W, Skalli O, Lagace R, et al.: Intermediate filamentproteins and actin isoforms as markers for soft-tissue tumordifferentiation and origin. III. Hemangiopericytomas and glomustumors. Am J Pathol 1990;136:771–786.

78. Kim JY, Chang BC, Ha JW: Images in cardiology. Intimalangiosarcoma of the descending aorta as an unusual cause ofsevere upper extremity hypertension. Heart 2006;92:306.

79. O’Donovan DA, Bilbao JM, Fazl M, et al.: Solitary fibrous tumorof the orbit. J Craniofac Surg 2002;13:641–644.

80. Daigeler A, Lehnhardt M, Langer S, et al.: Clinicopathologicalfindings in a case series of extrathoracic solitary fibrous tumors ofsoft tissues. BMC Surgery 2006;6:10.

81. Pisters PW, Harrison LB, Woodruff JM, et al.: A prospectiverandomized trial of adjuvant brachytherapy in the management oflow-grade soft tissue sarcomas of the extremity and superficialtrunk. J Clin Oncol 1994;12:1150–1155.

82. Yang JC, Chang AE, Baker AR, et al.: Randomized prospectivestudy of the benefit of adjuvant radiation therapy in the treatmentof soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203.

83. Munoz AK, Berek JS, Fu YS, et al.: Pelvic hemangiopericytomas:A report of five cases and literature review. Gynecol Oncol 1990;36:380–382.

84. McMaster MJ, Soule EH, Ivins JC: Hemangiopericytoma. Aclinicopathologic study and long-term followup of 60 patients.Cancer 1975;36:2232–2244.

85. Combs SE, Thilmann C, Debus J, et al.: Precision radiotherapy forhemangiopericytomas of the central nervous system. Cancer2005;104:2457–2465.

86. Galanis E, Buckner JC, Scheithauer BW, et al.: Managementof recurrent meningeal hemangiopericytoma. Cancer 1998;82:1915–1920.

87. Wong PP, Yagoda A: Chemotherapy of malignant hemangioper-icytoma. Cancer 1978;41:1256–1260.

88. Kozuka T, Kiura K, Katayama H, et al.: Tandem high-dosechemotherapy supported by autologous peripheral blood stem celltransplantation for recurrent soft tissue sarcoma. Anticancer Res2002;22:2939–2944.

89. Adams J, Lodge JP, Parker D: Liver transplantation for metastatichemangiopericytoma associated with hypoglycemia. Transplan-tation 1999;67:488–489.



malignant tumors of blood vessels: angiosarcomas, hemangioendotheliomas, and hemangioperictyomas

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