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Human Pathology (2010) 41, 1711–1717

Original contribution

Primary angiosarcomas of the anterior mediastinum:A clinicopathologic and immunohistochemicalstudy of 9 cases

Annikka Weissferdt MDa,⁎, Neda Kalhor MDa, Saul Suster MDb, Cesar A. Moran MDa

aDepartment of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USAbDepartment of Pathology and Laboratory Services, Medical College of Wisconsin, Milwaukee, WI53226, USA

Received 3 March 2010; revised 9 May 2010; accepted 12 May 2010

0d

Keywords:Angiosarcoma;Anterior mediastinum;Thymus;Immunohistochemistry

Summary We report 9 cases of primary angiosarcomas of the anterior mediastinum. Patient ages rangedfrom 25 to 62 years (mean, 40.7 years); 5 patients were male and 4 were female. Main presentingsymptoms included chest pain, dyspnea, and cough. The tumor size ranged from 3 to 12.5 cm.Macroscopically, the lesions were ill-defined hemorrhagic masses. Histologically, the growth patternsranged from large vascular spaces to capillary-like proliferations. These were either lined by bland ormore pleomorphic endothelial cells. The mitotic activity was variable and corresponded to the degree ofdifferentiation. A rim of thymic tissue was observed in 2 cases suggesting a thymic origin of the tumors.No teratomatous components were identified. Immunohistochemical studies showed that all 9 caseswere reactive for vascular markers including factor VIII–related antigen, CD31, and CD34, andnegative for cytokeratin CAM5.2. All cases were treated by complete resection and 3 patients receivedadjuvant chemotherapy. Follow-up information available for 6 patients revealed that 4 were alive andfree of disease at intervals ranging from 6 to 36 months after diagnosis and 1 was alive with recurrenceat 48 months. One patient had died of the disease 10 months after diagnosis. Primary angiosarcomas ofthe anterior mediastinum are rare tumors that need to be added to the differential diagnosis of primaryanterior mediastinal neoplasms. Despite their histologic similarity to angiosarcomas at other sites,primary angiosarcomas of the anterior mediastinum appear to follow a more protracted clinical coursethan their counterparts in other organ systems.© 2010 Elsevier Inc. All rights reserved.

1. Introduction virtually any anatomic site, including the deep soft tissue,

Vascular tumors of the anterior mediastinum are scarceand represent approximately 1% to 2% of all tumors in thislocation [1]. Angiosarcomas are most often encountered assporadic cutaneous lesions, typically in the scalp or face ofan elderly patient. However, angiosarcomas can occur in

⁎ Corresponding author.E-mail address: aweissferdt@doctors.org.uk (A. Weissferdt).

046-8177/$ – see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1016/j.humpath.2010.05.003

breast, visceral organs, and bone. Although most cases aresporadic, important predisposing conditions include radia-tion exposure, chronic lymphedema, exposure to toxins suchas vinyl chloride or thorotrast, or foreign bodies [2]. Primaryangiosarcomas of the anterior mediastinum are extremelyrare and, to date, less than 25 cases of this entity have beendescribed either as isolated case reports or as part of largerstudies investigating angiosarcomas in general [1,3-8].We herein report a series of 9 cases and present the

Table 1 Specifications of antibodies used

Antibody Company Dilution Antigenretrieval

Antibodyincubationtime

FactorVIII

Dako 1:400 Proteasepretreatmentfor 5 min

15 min

CD31 Novocastra,LeicaMicrosystems

1:300 Tris–EDTAbuffer for20 min

15 min

CD34 BDBiosciences

1:40 Citrate bufferfor 20 min

15 min

CAM5.2 BDBiosciences

1:50 Proteasepretreatmentfor 5 min

15 min

Abbreviation: Tris–EDTA, trisaminomethane–ethylenediaminetetra-acetic acid.

1712 A. Weissferdt et al.

clinicopathologic and immunohistochemical features of thistumor. In addition, the differential diagnoses are discussedand the prognosis is compared to angiosarcomas arising innonmediastinal sites.

2. Materials and methods

Nine cases of primary angiosarcomas of the anteriormediastinum were identified from the surgical pathologyfiles of MD Anderson Cancer Center, Houston, TX, as wellas from the personal consultation files of 2 of the authors (C.A. M., S. S.). Hematoxylin-eosin–stained sections werereviewed in all cases. Representative paraffin blocks wereavailable from all cases for immunohistochemical studies.Deparaffinized tissue sections were incubated with anti-bodies directed against factor VIII–related antigen (Dako,Carpinteria, CA; 1:400), CD31 (Novocastra, Leica Micro-systems, Bannockburn, IL; 1:300), CD34 (BD Biosciences,San Jose, CA; 1:40), and cytokeratin CAM5.2 (BD

Table 2 Clinical features of 9 patients with angiosarcomas of the an

Case Sex Age (y) Size Clinicalmanifestations

1 M 34 NA Chest pain, dyspnea2 F 39 3 cm Hemorrhagic pericardi3 M 25 5 cm Chest pain, dyspnea4 M 40 NA Pneumonia5 F 30 3.5 cm Swelling face/neck6 F 42 NA Dizziness7 F 45 12.5 cm Chest pain, dyspnea8 M 62 7 cm Cough, fever

9 M 49 NA NA

Abbreviations: M, male; F, female; NA, not available.

Biosciences, San Jose, CA; 1:50) using the polymericbiotin-free horseradish peroxidase method (Bond PolymerRefine Detection Kit; Leica Microsystems, Bannockburn,IL) (Table 1). Appropriate positive and negative controlswere run for all antibodies tested. Clinical and follow-upinformation was obtained from the patients' charts or fromreferral information.

3. Results

3.1. Clinical features

The clinical features are summarized in Table 2. Thepatients comprised 5 men and 4 women with an age rangefrom 25 to 62 years (mean, 40.7 years). Three patientspresented with chest pain and dyspnea, and one each withhemorrhagic pericarditis, pneumonia, swelling of the faceand neck, dizziness, and cough and fever, respectively. Forone patient, no clinical data were available. Radiologically,the tumors presented as anterior mediastinal masses.Treatment consisted of resection in all patients followed byadjuvant chemotherapy in 3 cases. Follow-up informationavailable for 6 patients revealed that 4 were alive and free ofdisease at intervals ranging from 6 to 36 months afterdiagnosis (mean follow-up, 16 months) and 1 was alive withlocal recurrence at 48 months. One patient had died of thedisease 10 months after diagnosis.

3.2. Gross features

The tumor sizes ranged from 3 to 12.5 cm in maximumdimension (mean, 6.2 cm). Grossly, the lesions weredescribed as diffusely infiltrating and intensely hemorrhagicmasses. The tumors were often multinodular and composedof various proportions of solid and cystic areas embedded infatty tissue. To the best of our knowledge, completeresections were achieved in all cases at time of operation.

terior mediastinum

Treatment Follow-up

Resection and chemotherapy Alive at 36 motis Resection Alive at 10 mo

Resection NAResection and chemotherapy Alive at 6 moResection Alive at 12 moResection Deceased at 10 moResection NAResection and chemotherapy Alive with recurrence

at 48 moResection NA

Table 3 Histologic features of 9 patients with angiosarcomas of the anterior mediastinum

Case Grade Histologic characteristics Necrosis a

(%)Growthpattern

Mitotic activity(mitoses/10 HPF)

Thymictissueidentified

Presence ofgerm celltumor

1 High grade Cavernous; focal papillary endothelialhyperplasia pattern

20 Infiltrative 3 No No

2 Low grade Capillary 30 Infiltrative 1 No No3 High grade Capillary and cavernous 10 Infiltrative 3 No No4 High grade Capillary and cavernous; focal epithelioid

features10 Infiltrative 1 No No

5 Low grade Capillary and cavernous 30 Infiltrative 2 No No6 High grade Capillary and cavernous; focal papillary

endothelial hyperplasia; epithelioid features70 Infiltrative 3 No No

7 Low grade Capillary 0 Infiltrative 1 Yes No8 High grade Capillary 10 Infiltrative 5 No No9 Low and high

gradeFocal papillary endothelial hyperplasia;calcification, ossification and cysticdegeneration; stromal tumor giant cells

10 Infiltrative 2 Yes No

Abbreviation: HPF, high-power fields.a Percentage of necrosis in material available for review.

1713Primary angiosarcomas of the anterior mediastinum

3.3. Histological features

The histologic features are summarized in Table 3. Themorphologic spectrum ranged from low-grade tumorsmimicking benign vascular lesions to high-grade tumorswith prominent cytologic atypia and high mitotic activity.Overall, 5 cases were considered high grade, 3 low grade,and 1 had mixed high- and low-grade histologic features.Growth patterns included large cavernous vascular struc-tures, irregular interanastomosing channels of varying size,small capillary-like proliferations, and slit-like spaces linedby atypical endothelial cells (Figs. 1-3). Vascular spaceformation was more difficult to identify in areas with moresolid growth patterns. The atypical cells had larger and more

Fig. 1 Angiosarcoma composed of large cavernous vascularspaces (case 1).

hyperchromatic nuclei than normal endothelial cells andfocally showed crowding or a prominent hobnailing pattern.In 3 cases, papillary projections resembling endothelialpapillary hyperplasia were noted (Fig. 4). In 2 cases, theendothelial cells showed a prominent epithelioid morphol-ogy characterized by cells with abundant cytoplasm,vesicular nuclei, and small eosinophilic nucleoli (Fig. 5).Isolated pleomorphic tumor giant cells were identified in thestromal background of 1 case (Fig. 6). The stroma wascomposed of fibrous or myxoid tissue and in some areasthe tumor was dissecting the preexisting fat. In 8 cases,necrosis was present ranging from 10% to 70% of the tissueavailable for review and the mitotic rate ranged from 1 to 5mitoses per 10 high-power fields. Foci of hemorrhage, red

Fig. 2 Proliferation of capillary-like vessels in low-gradeangiosarcoma (case 2).

Fig. 3 Angiosarcoma forming irregular slit-like vascular spaces(case 2).

Fig. 5 Solid growth pattern of high-grade angiosarcoma withpleomorphic epithelioid cells and increased mitotic activity (case 6).

1714 A. Weissferdt et al.

blood cell extravasation, and hemosiderin deposition wereevident in most cases. Calcification, ossification, and cysticdegeneration were noted in 1 case. Overall, 7 cases showedthe pattern of conventional angiosarcoma, 1 was classified asan epithelioid type, and 1 demonstrated a mixed pattern. Aperipheral rim of thymic tissue was observed in 2 casessuggesting a thymic origin of these tumors. Teratomatous orother germ cell elements were not identified in any of thecases.

3.4. Immunohistochemical features

The immunohistochemical features are summarized inTable 4. All 9 cases showed at least focal cytoplasmicpositivity for factor VIII–related antigen including low- andhigh-grade areas of differentiation (100%) (Fig. 7). Stainingfor CD31 was performed on 6 tumors, 3 of which showedreactivity for this marker (50%). Staining for CD34performed on 5 cases resulted in positive staining in all 5

Fig. 4 Papillary endothelial hyperplasia-like areas (case 9).

tumors (100%). None of the cases were positive forCAM5.2.

4. Discussion

Angiosarcoma is an uncommon tumor representing lessthan 1% of all sarcomas [9]. Although the most commonclinical presentation is as a cutaneous tumor in the scalp andfacial regions of elderly men, angiosarcomas occur in manylocations including soft tissue, breast, visceral organs, andbone [2]. Apart from the sporadic forms, there is a strongassociation of angiosarcomas occurring with radiation,environmental carcinogens such as vinyl chloride orthorotrast, chronic lymphedema, or foreign bodies [2].Median age at presentation is 52 years and the prognosis isgenerally poor with a median survival of 42 months and a

Fig. 6 Irregular vascular spaces with atypical stromal cells(case 9).

Table 4 Immunohistochemical features of angiosarcomas ofthe anterior mediastinum

Case Immunohistochemistry of angiosarcomas of theanterior mediastinum

Factor VIII CD31 CD34 CAM5.2

1 + − + −2 + + + −3 + + + −4 + − + −5 + NA NA −6 + − + −7 + NA NA −8 + NA NA −9 + + NA −

Abbreviation: NA, not available.

1715Primary angiosarcomas of the anterior mediastinum

5-year overall survival of 43% [10]. Angiosarcomas are,however, a heterogeneous group of tumors and apart fromstage at diagnosis, an important prognostic factor is theprimary site. Whereas angiosarcomas of the liver, bone, andheart have a particularly bad outcome with 5-year survivalrates ranging from 0% to 36%, tumors of the breast, softtissue, and skin appear to be associated with a slightly betterprognosis as reflected in 5-year survival rates ranging from43% to 74% [10].

Primary angiosarcomas arising in the anterior mediasti-num are very rare. To date, less than 25 cases of this entityhave been described in this location [1,3-8]. The age of thepatients ranged from 5 to 66 years and most tumors werelocated in the anterior mediastinum [5,8]. Chest pain was themain presenting symptom and, from the limited dataavailable, survival ranged from 2 to 36 months from timeof diagnosis [3,7,8,11]. We have studied a further 9 cases ofangiosarcoma arising in the mediastinum. Clinically, thepatients all presented with the typical symptoms of anteriormediastinal masses, namely, chest pain, dyspnea, and cough.The patients' age ranged from 25 to 62 years with a mean ageof 40.7 years. Radiologically, the tumors presented as

Fig. 7 Immunohistochemical staining with CD34 (case 3).

nonspecific anterior mediastinal masses. Histologically, thetumors displayed the typical spectrum of features seen inother locations, ranging from low-grade neoplasms withdefinitive vasoformation to high-grade lesions with a moresolid growth pattern and vast areas of necrosis. Themalignant endothelial cells lining these structures demon-strated variably atypical features ranging from mild nuclearhyperchromasia to highly pleomorphic cells with atypicalmitotic figures. Immunohistochemically, the tumors did notdiffer from their counterparts in other locations. All lesionsshowed at least focal immunoreactivity with the vascularmarkers factor VIII–related antigen, CD34, and CD31, andall were negative for CAM5.2.

Interestingly, follow-up information available for 6patients revealed that 4 were alive and free of disease atintervals ranging from 6 to 36 months after diagnosis (meanfollow up, 16 months). One patient was alive with localrecurrence at 48 months, whereas another patient had died ofthe disease 10 months after diagnosis. Comparing thesesurvival times to those of angiosarcomas in other locationssuch as the deep soft tissue (median survival, 20 months) orthe heart (median survival, 9-12 months) [6,11,12], angio-sarcomas of the anterior mediastinum seem to pursue a lessaggressive clinical course. Because age of presentation,histology, and treatment modalities do not appear to differmuch from tumors in other locations, alternative explana-tions for this improved prognosis will have to be explored[6,11,13]. One possibility may be that the surgical approachof the anterior mediastinum may facilitate complete surgicalresection and avoid local tumor recurrence. Tumor recur-rence is known to occur in at least 20% of cases ofangiosarcomas of the soft tissue [6] and complete surgicalresection may account for the better outcome in patients withmediastinal tumors.

Because of the rarity of mediastinal angiosarcomas, theseneoplasms need to be differentiated from a variety of othertumors that can occur in this location. The most importantdifferential diagnosis of the epithelioid type of angiosarcomais epithelioid hemangioendothelioma (Table 5). Epithelioidhemangioendothelioma is a vascular neoplasm of low tointermediate malignant potential that follows a nonaggres-sive clinical course. This tumor has been described in the softtissue as well as in various other organ systems includingbone, liver, and lung [14-16]. The anterior mediastinum isless commonly the site of origin [17]. Epithelioid heman-gioendothelioma, regardless of its primary site, is typicallycomposed of nodules with centrally hypocellular andperipherally hypercellular areas. The tumor cells aremonomorphic and contain round to oval pale nuclei withsmall nucleoli and eosinophilic cytoplasm. Intranuclear orintracytoplasmic vacuoles are often present, sometimescontaining erythrocytes. The stroma shows prominentmyxoid or chondroid changes. Mitotic activity, cellularatypia, and tumor cell necrosis are typically not observed,although in isolated cases, foci of necrosis and infarctionmay be seen [17,18]. Immunohistochemical studies do not

Table 5 Common characteristics of angiosarcomas and epithelioid hemangioendotheliomas of the anterior mediastinum

Angiosarcoma of anterior mediastinum Epithelioid hemangioendotheliomaof anterior mediastinum17

Clinical features Chest pain, dyspnea, cough, hemorrhagic pericarditis, pneumonia,dizziness, fever, swollen face/neck; mean age 40.7 y

Chest pain, cough, dyspnea, many timesasymptomatic; mean age 49.4 y

Radiologic features Anterior mediastinal masses Anterior mediastinal masses;often multifocal process

Gross features Multinodular solid-cystic hemorrhagic masses with infiltrativeborders

Often well circumscribed and encapsulatedmasses, rarely locally infiltrative

Cytologic features Enlarged hyperchromatic endothelial cells; epithelioid endothelialcells with vesicular nuclei and eosinophilic nucleoli

Nests and cords of bland epithelioid cellswith inconspicuous nucleoli

Stroma Myxoid, hyalinized, or fibrous background Prominent myxohyaline backgroundMitoses Variable; average 2.3/10 HPF Few; average 1/10 HPFNecrosis Prominent Absent or focalImmunohistochemicalfeatures

Factor VIII–related antigen, CD34, CD31, CK may be positivein epithelioid subtype

Factor VIII–related antigen, CD34, CD31

Prognosis Aggressive (but less aggressive than angiosarcomas at other sites) Low to intermediate malignant behavior

Abbreviation: HPF, high-power fields; CK, cytokeratin.

1716 A. Weissferdt et al.

differentiate between the lesions as both demonstrate avascular phenotype with immunoreactivity for factor VIII–related antigen, CD31, and CD34 [6,19]. Distinctionbetween the 2 lesions, however, is vital as epithelioidhemangioendothelioma may run a less aggressive clinicalcourse, whereas epithelioid angiosarcoma has a much higherpotential for progression and metastasis [6,14,17].

Epithelioid angiosarcomas also need to be differentiatedfrom carcinoma. Carcinomas, whether primary or metastatic,lack a vasoformative component and express an epithelialimmunohistochemical phenotype; they show no reactivityfor vascular markers. On the other hand, low-gradeangiosarcoma may resemble benign vascular lesions suchas a hemangioma. Cytologic atypia, increased mitoticactivity, and especially infiltrative margins in the formermay be the only features distinguishing these lesions [20].

Another important diagnostic consideration is the possi-bility that angiosarcomas may occur in association withmediastinal germ cell tumors. The presence of this so-calledsarcomatous transformation in these tumors carries a graveprognosis with early local recurrence and metastasis andsurvival times that range from 9 to 33 months [21-23].Distinction of pure mediastinal angiosarcomas from the lattertumors through thorough sampling is therefore vital giventhe difference in outcome.

In summary, we have presented the clinicopathologic andimmunohistochemical features of 9 cases of primaryangiosarcomas of the anterior mediastinum. Despite theaggressive behavior of these tumors in other sites, angio-sarcomas of the anterior mediastinum appear to have a betterprognosis. Whether this is due to easier surgical access at thissite resulting in a higher rate of complete surgical resectionremains to be determined. Primary angiosarcomas need to beincluded in the differential diagnosis of anterior mediastinalneoplasms, and distinction from other tumors at this site isimportant given the potential difference in prognosis.

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