Case ReportAngiosarcomas of the breast are aggressive tumors of

endovascular origin.1 Although angiosarcomas of the breast are rare, they are being reported with increasing frequency in patients who have previously undergone breast-con-serving therapy.2,3 The molecular mechanisms of radia-tion-induced neoplastic transformation are unknown. It is thought that tumor induction is a result of DNA damage after exposure to ionizing radiation.4 Initial reports were unable to correlate radiation exposure to the development of post–breast-conserving angiosarcomas. However, more recent studies from large national databases indicate that the incidence of post–breast-conserving angiosarcomas is approximately 0.15%.2 Our personal experience suggests that the incidence might be even higher.5

The clinical presentation of post–breast-conserving angio-sarcomas is highly variable, but they commonly present with dermal nodules that clinically resemble recurrent breast

carcinomas.6 In addition, there is often similarity in the cytologic and histologic features of these 2 entities, and misdiagnosis is not uncommon.7,8 An accurate microscopic distinction between post–breast-conserving angiosarcomas and recurrent breast carcinoma often requires the use of immunohistochemical markers. An accurate tissue diagno-sis is essential because the prognosis and treatment of these 2 entities are different. Although the prognosis for angio-sarcoma of the breast after breast conservation is dismal, a recent report suggests that hyperfraction radiation might be more effective in lowering the risk of local recurrence.9 It should be noted, however, that the series was small and the follow-up was short. There have been no published reports to substantiate the value of hyperfractionated therapy compared with standard radiation therapy in post–breast-conserving angiosarcomas.

In an effort to make physicians more aware of this diagnostic dilemma, we present a case of a post–breast-conserving angiosarcoma that was initially misdiagnosed as recurrent breast cancer. Based on our experience and a literature review, recommendations are made for avoiding this diagnostic pitfall.

Case ReportIn the spring of 1997, a 61-year old woman presented with

a 3-cm lump in the upper-outer quadrant of her left breast. Mammogram revealed a spiculated density that was solid on

Submitted: Jan 8, 2007; Revised: Aug 24, 2007; Accepted: Sep 10, 2007

1The Breast Care and Imaging Center of Orange County2Department of Pathology, St. Joseph’s Hospital, Orange3University of California Los AngelesCA

Address for correspondence: John West, MD, The Breast Care and Imaging Center of Orange County, 33 Creek Rd, Ste C300, Irvine, CA 92604 Fax: 714-541-5945; e-mail: jwest@breastcare.com

Angiosarcoma After Breast Conservation: Diagnostic Pitfalls

Angiosarcomas are aggressive tumors of endovascular origin. Although angiosarcomas are relatively rare, they are being reported with increasing frequency in patients who have previously undergone breast con-serving therapy. The initial clinical presentation of angiosarcomas after breast irradiation is often similar to the presentation of recurrent breast carcinomas. In addition, the histologic and cytologic appearance of posttreatment angiosarcomas can be highly suggestive of recurrent breast carcinoma. Immunohistochemical stains are often required to make an accurate distinction between the 2 entities. An accurate diagnosis is essential, because prognosis and treatment are different for each condition. An early and accurate diag-nosis is aided by a high index of suspicion by clinician and pathologist. Herein, a case history is presented that underscores the pitfalls in attempting to achieve an accurate diagnosis.

Clinical Breast Cancer, Vol. 8, No. 1, 94-96, 2008Key words: Cytokeratin staining, Epithelioid growth pattern, Immunohistochemical staining,

Tissue markers, Radiation therapy, Recurrent disease

Abstract

reportcase

John West,1 Shu-Yuan Liao,2 Deborah Cho3

94 • Clinical Breast Cancer February 2008

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Clinical Breast Cancer February 2008 • 95

ultrasound. Core biopsy was positive for infiltrating ductal carcinoma. Breast-conserving surgery was performed. The resection margins were clear, and 3 of 25 nodes were posi-tive. A standard course of postoperative radiation therapy (4600 cGy plus 1400 cGy boost) was given followed by a 5-year course of tamoxifen.

In the fall of 2005, she developed multiple dermal nodules in the region of the previous lumpectomy incision. The clinical impression was recurrent breast cancer. Skin punch biopsy of a dermal nodule was reported as showing solid sheets of pleomor-phic epithelioid cells with high mitotic indexes. Estrogen and progesterone receptors were negative. The histologic interpre-tation was recurrent high-grade breast carcinoma (Figure 1). She underwent a course of doxorubicin plus cyclophosphamide with initial reduction in the bulk of the skin nodules.

In the spring of 2006, she developed recurrent dermal nod-ules with inflammatory changes extending to the right breast (Figure 2). The skin punch biopsy revealed characteristic histologic features of angiosarcoma, which was composed of vascular channels lined by the neoplastic endothelial cells. The neoplastic cells exhibited immunoreactivity for the endo-thelial cell markers, including CD31, CD34, and Factor VIII, but were negative for epithelial cell markers (cytokeratin). An immunohistochemical study was subsequently performed on the first biopsy, which was originally interpreted as recurrent breast cancer, and the results demonstrated identical immu-nostaining patterns to the second biopsy (Figure 3). Thus, the diagnosis of angiosarcoma on the first biopsy was confirmed, and the original diagnosis was amended.

She subsequently underwent bilateral mastectomy. The surgical specimens contained multifocal high-grade angio-

sarcomas. The largest focus measured 6.5 cm, and the final margins were clear. A follow-up course of postoperative hyperfractionated radiation therapy was given. Within 1 year of treatment she died of metastatic disease.

DiscussionAn accurate diagnosis of post–breast-conserving angio-

sarcomas can be a major diagnostic challenge.2-8 The initial clinical presentation of post–breast-conserving angiosarcomas

Original Biopsy Hematoxylin and Eosin StainFigure 1

Initial skin biopsy with epithelioid changes initially interpreted as recurrent breast carcinoma (magnification × 40).

Frontal View of the PatientFigure 2

Frontal view of the patient shows extensive inflammatory changes in the postirradiated left breast and the untreated right breast.

Original Biopsy with CD34 MarkerFigure 3

Initial biopsy stained with CD34 marker. Extensive positive staining for biologic marker supported the diagnosis of angiosarcoma (hematoxylin and eosin staining; magnifica-tion × 40).

is often suggestive of recurrent breast carcinoma, but its appearance can also be suggestive of benign conditions such as hemorrhage, infection, and postradiation skin changes. The histologic appearance of high-grade angiosarcomas can be suggestive of melanoma, high-grade lymphoma, and Kaposi sarcoma in addition to poorly differentiated breast carcinoma. The histologic appearance of low-grade angiosarcomas can be confused with postradiation vascular changes and a variety of benign skin disorders. Imaging studies are usually not helpful in making the diagnosis of post–breast-conserving angiosarco-mas or distinguishing it from other clinical conditions.

An accurate diagnosis of post–breast-conserving angio-sarcomas can sometimes be made with simple office tissue sampling techniques such as punch biopsy and fine-needle aspiration (FNA).5 However, the findings on FNA are often nonspecific, and an accurate diagnosis from fine-needle aspirates requires the use of biologic markers. Because of the heterogeneity of these tumors, the histologic findings on punch biopsies can also be misleading. An accurate tissue diagnosis might require generous tissue sampling.2

There are other factors that add to the challenge of making an accurate diagnosis. Approximately 70% of angiosarcomas have an epithelioid pattern.8,10 The presence of this epithe-lioid pattern and the absence of estrogen and progesterone receptors could be misinterpreted as evidence for a poorly differentiated recurrent breast carcinoma.11 Both factors contributed to the initial misdiagnosis in our case.

In most cases, a simple battery of immunohistochemical markers can be used to differentiate recurrent breast carci-noma from post–breast-conserving angiosarcomas. Standard markers include cytokeratin to identify epithelial components and Factor VIII, CD31, and CD34 to identify endothelial com-ponents. However, in some cases this standard battery of mark-ers will not provide a clear distinction between an epithelial and an endothelial origin. There is considerable variation in the expression of biologic markers among angiosarcomas. In a recent series of angiosarcomas that were not restricted to the breast, all 42 cases studied immunohistochemically stained at least focally for Factor VIII–related antigen, and nearly all stained strongly for vimentin.8 To add to the diagnostic confu-

sion, approximately 30% of angiosarcomas will be positive for cytokeratin, and in rare circumstances, epithelial cells can be positive for endothelial markers.8,12 Thus, if the findings from a standard panel of biologic markers demonstrate inconsisten-cies, a broader panel of markers might be required to establish an accurate tissue diagnosis. In rare cases, ultra-structure analysis might have value.10

An accurate diagnosis of posttreatment angiosarcomas requires a high index of suspicion on the part of clinician and pathologist. The clinician should consider angiosarcomas in the differential diagnosis of any new skin lesions in patients who have previously undergone breast radiation. The clini-cian must communicate this history to the pathologist, who in turn must be alert to the many diagnostic pitfalls in making an accurate diagnosis.

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Philadelphia: Lippencott, Williams, & Wilkins; 2001:813-61. 2. Strobbe LJ, Peterse HL, van Tinteren H, et al Angiosarcoma of the

breast after conservation therapy for invasive cancer, the incidence and outcome. An unforeseen sequela. Breast Cancer Res Treat 1998; 47:101-9.

3. Fodor J, Orosz Z, Szabo E, et al. Angiosarcoma after conservation treatment for breast carcinoma: our experience and a review of the literature. J Am Acad Dermatol 2006; 54:499-504.

4. Little JB. Cancer etiology: ionizing radiation. In: Holland J, Rrei E III, Bast RC, eds. Cancer Medi cine. 4th ed. Baltimore, MD: Williams and Wilkins; 1997:293-306.

5. West JG, Qureshi A, West JE. Risk of angiosarcoma following breast conservation: A clinical alert. Breast J 2005; 11:115-23.

6. Rao J, DeKoven JG, Beatty JD, et al. Cutaneous angiosarcoma as a delayed complication of radiation therapy for carcinoma of the breast. J Am Acad Dermatol 2003; 49:532-8.

7. Gherardi G, Rossi, S, Perrone S, et al. Angiosarcoma after breast-con-serving therapy: fine-needle aspiration biopsy, immunocytochemistry, and clinicopathologic correlates Cancer (Cancer Cytopathol) 2005; 105:145-51.

8. Meis-kindblom JM, Kindblom LG. Angiosarcomas of soft tissue: a study of 80 cases. Am J Surg Path 1998; 22:683-79.

9. Monroe AT, Feigenberg SJ, Mendenhall NP. Angiosarcoma after breast-conserving therapy. Cancer 2003; 97:1832-40.

10. Seo IS, Min KW. Postirradiation epithelioid angiosarcoma of the breast: a case report with immunohistochemical and electron micro-scopic study. Ultrastructural Path 2003; 27:197-203.

11. Vesoulis Z, Cunliffe C. Fine-needle aspiration biopsy of post-radia-tion epithelioid angiosarcoma of breast. Diagn Cytopathol 2000; 22:172-5.

12. Ortiz-Hidalgo C, Torres JE, Cuesta-Mejias T, et al. CD31 with strong membrane immunoreactivity in ductal carcinoma of the breast (letter to the editor). App Immuno Mol Morph 2000; 8:334-5.

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Angiosarcoma After Breast Conservation