Post-Radiation Angio Sarcoma of the Breast
Gal-Combos EC, Esserman LE, Godinez J, Recine MA and Poppiti RJ, Jr.

The first reported case of angiosarcoma (AS) of the breast was in 1887 by G. B. Schmidt. AS represents 0.04% of all malignant tumors of the breast, and 3-9% of sarcomas of the breast. AS is a well recognized but rare complication of radiation therapy. The first case of mammary AS following lumpectomy, axillary lymph node dissection and irradiation was reported by Bodey in 1987. Less than 30 cases were reported from then, mainly sporadic case reports. Initial underdiagnosis from both the radiologic and pathologic perspectives, is not uncommon as is illustrated by the following examples. With the widespread use of conservative surgery and radiation therapy increase in the incidence of postradiation AS is expected.

We reviewed the available clinical histories and imaging and pathologic findings of five cases of histopathologically proven breast angiosarcomas diagnosed from 1994 to 1999 in our institution. Four of them developed in the irradiated field after radiotherapy for breast cancer and one patient had primary AS of the breast.

Patients data:

The five patients, all women, were identified from the search of pathology records. The age at diagnosis was 42-85 years (mean: 63 years).

Interval from irradiation until diagnosis of AS:

The range was 3 11/12 years to 8 2/12 years (mean 6 7/12 years).

Clinical presentation:

The clinical examination showed palpable mass or masses in all the cases with purple discoloration of the skin at the surgical scar in three cases. Two lesions were painful but soft on physical examination. Two cases were clinically misinterpreted as local recurrence of the original breast carcinoma and one case was followed almost for a year as "multiple hematomas, ecchymoses of the breast".

Imaging findings:

Mammography revealed well-defined subcutaneous mass in two cases. In two cases the mammogram revealed only diffuse thickening of the skin. Ultrasound (in one case) showed an irregular hypo-echoic lesion with a thick-walled echogenic rim.

Gross pathologic findings:

Gross examination showed pink, red or purple, hemorrhagic, ill-defined lesions in the subcutaneous breast tissue. One lesion was more solid and white and the vascular nature was seen only microscopically.

Histopathologic findings:

Two features are characteristic: anastomosing vascular channels within the breast parenchyma and prominent, hyperchromatic endothelial cells.

For the classification, three grades (or types) were described by Rosen et. al., based on microscopic features:

Grade I: Low-grade tumor entirely consists of well-formed anastomosing vascular channels that invade the breast parenchyma. The cells tend to be flat and there is little or no papillary endothelial proliferation. Few mitotic figures are seen.

Figure 1A	Figure 1B
Figure 2A	Figure 2B

Fig1A. Vascular proliferation in low grade AS (Case#2) (H and E x200).

Fig 1B. CD 34 (an endothelial marker) was positive, showing that the lesion is vascular (x200)

Grade II: Intermediate grade tumor consists of largely of a Grade I proliferation. Scattered in the lesion are foci of more solid vascular growth that have papillary endothelial and/or solid components.

Grade III: High-grade tumor is characterized by prominent areas of spindle cell sarcoma or papillary and solid endothelial patterns. Focal necrosis, hemorrhage and a numerous mitotic figures occur.

Fig 2A. High grade AS (Case#4) with spindle cells and endothelial proliferation (H and E x100).

Fig 2B. Highly atypical cells with mitotic figures (H and E x200).

Cytologic and histopathologic misdiagnosis:

Rainwater et al reported a recent decrease in underdiagnosis from 64% to 33%. Chen et al stressed that the significant percentage of misdiagnoses of AS of the breast continues with an incidence of as high as 39%.

In this study FNA was performed in two cases. In the first case ultrasound guided fine needle aspiration was positive for "carcinoma" cells. In the other case FNA was negative for malignant cells. The detected clusters of ductal and spindle cells suggested fibroadenoma. Due to this deceptive benign appearance the diagnosis was postponed by 4 months.

Histopathology of the ultrasound guided core biopsy misdiagnosed the AS as infiltrating duct cell carcinoma in one occasion (Case#1). In contrast to this, the mastectomy showed a high-grade angiosarcoma.

Figure 3. (Case#1) 58-year-old woman who presented with pain in the left breast. Prior biopsy of the ipsilateral breast, performed six years ago, revealed a focus of infiltrating carcinoma, duct cell type, with extensive intraductal carcinoma extending to the surgical margin. The patient was treated with lumpectomy and 35 doses of 1.8 Gy whole breast irradiation therapy, the total of 63Gy.

The current physical examination showed a purple discoloration of the skin at the surgical scar and a palpable, mobile mass.

Fig 3A. and B. Mammography and ultrasound studies revealed an irregular subcutaneous mass and a 1.6 x 1.0cm hypo-echoic lesion with a thick-walled echogenic rim respectively. Subsequent ultrasound guided fine needle aspiration and ultrasound-core biopsies were diagnosed as positive for carcinoma cells and infiltrating duct cell carcinoma respectively. A mastectomy was performed.

Fig 3C. and D. In contrast to the previous pathologic findings, the mastectomy showed a 1.4 cm high-grade angiosarcoma with prominent epithelioid features and a high mitotic index (H and E x100 and x400).

Fig 3E. The vascular differentiation of the tumor was confirmed with positive immunohistochemical staining for CD31 (Figure x200), CD34, Factor VIII and Ulex Europeaus and negative staining for cytokeratin markers. Retrospective immunohistochemical staining of the previously mentioned ultrasound-core biopsies showed a similar staining pattern.

Mastectomy provided the diagnosis in the remaining cases.

Size of the AS:

The size of the tumor varied at the time of initial presentation from 1.4 cm to diffuse involvement of the breast, including a huge mass, larger than 22 cm.

Treatment:

Mastectomy was performed in all the cases and the patients received adjuvant chemotherapy. In one case, local radiation therapy was added.

Outcome:

AS of the breast is a rare disease and often has a fatal outcome. Two patients died within 3 years of diagnosis. One of the survivors had subcutaneous recurrence at a distant site (forehead) after 40 months. The other survivor has no evident disease at 17 months.

Several possible explanations have been proposed for the etiology of radiation-associated AS. Malignant change can be induced in a primary benign lesion, such as hemangioma. Alternatively, a new tumor may develop regardless of the primary tumor because of irradiation. The chronic lymphedema caused by extensive axillary node dissection also may be an important risk factor for the onset of AS (Stewart-Treves syndrome).

In AS of the breast there are no definitive diagnostic and treatment clues. Although the diagnostic pitfalls have been mentioned in several previous reports, the problem of misdiagnosis still occurs in the recently reported cases. AS should be included in the differential diagnosis in cases after irradiation of the breast especially when a vascular lesion is associated with any breast mass.

Figure 3A Figure 3D

Figure 3B   Figure 3C Figure 3E

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