Discussion and conclusions
In terms of breast cancer, invasive carcinoma is by far the most common type. Angiosarcoma of the breast is a rare tumor; it accounts for 0.04% of all primary malignancies of the breast [
1,
2,
5‐
7]. In our case, there was no axillary lymphadenopathy. The mammography showed no evidence of spiculation or suspicious calcifications. A biopsy showed anastomosing vascular spaces. Lining cells were almost bland. These results can be interpreted as a benign lesion. However, this did not correlate with the radiologic findings: 5 cm mass with ill-defined margins.
It may be primary or secondary to breast surgery or irradiation. Primary (
de novo) angiosarcoma usually occurs in younger women [
2,
5,
8] with an average age of 40 years [
1,
8] compared to 67.5 years in secondary angiosarcoma [
8]. The factors involved in carcinogenesis of primary angiosarcoma are exposure to vinyl chloride, arsenic and Thorotrast (thorium dioxide), chronic irritation induced by a foreign body, and local trauma [
5]. Secondary angiosarcoma may occur in the skin and chest wall following radical mastectomy and local radiotherapy, and in the skin and breast parenchyma following breast conserving surgery and radiotherapy [
1]. Furthermore, secondary angiosarcoma may occur in the skin and soft tissues of the arm following radical mastectomy and subsequent lymphedema (axillary dissection) [
1].
It is manifested by a painless mass [
2,
5,
6], sometimes with a pulsating character [
5]. The overlying skin may have a bluish red discoloration, and there is no nipple retraction [
2]. Axillary lymph node involvement is uncommon (0 to 5% of cases) [
5] or even absent [
2]. Mammography shows large, dense, and homogeneous mass, with sharp and sometimes polylobated contours [
7]. There are no calcifications [
5,
7] or spiculation which are often seen in breast carcinomas [
2,
5]. On sonography, angiosarcoma appears as a heterogeneous lesion [
5,
7] with both hyperechoic and hypoechoic appearance [
2,
7]. Hypoechoic areas represent hemorrhagic or necrotic changes [
7]. Color Doppler sonography reveals marked hypervascularity of the lesion [
5,
7]. This hypervascular character is confirmed by computed tomography and magnetic resonance imaging with intravenously administered contrast injection [
7]. The signal on T2-weighted image is hyperintense [
2,
5,
7], suggesting the presence of vascular channels containing slow flowing blood [
2].
The tumors are deeply located in the breast parenchyma [
1]. Size is always > 2 cm [
5] and usually > 4 cm [
2]. It is reported that 12% of patients present with diffuse breast enlargement [
1].
In some cases, diagnosis by fine-needle aspiration cytology and needle core biopsy may be difficult. Chen
et al. reported a percutaneous biopsy false-negative rate of 37% [
9]. Given the vascular nature of these tumors, macrobiopsy is often difficult to perform, hence the need for surgical resection [
2].
On macroscopic examination, angiosarcomas have a spongy hemorrhagic appearance with ill-defined borders [
1]. Poorly differentiated tumors appear as a solid fibrous lesion [
1].
Only a histological examination can confirm the diagnosis. Three groups are defined according to the classification proposed by Donnell
et al. [
10]. Grade I (well differentiated) contains open anastomosing vascular channels invading the breast fat and parenchyma. A single layer of endothelial cells lines these channels. The nuclei of the endothelial cells may be hyperchromatic. Solid areas of spindle cells, hemorrhage (known as “blood lakes”), and necrosis are not present. In grade II (intermediately differentiated) 75% of the tumor is composed of the well-differentiated pattern seen in grade I, but there are additional solid cellular foci or papillary formations scattered throughout the tumor. Slightly increased mitotic activity is present. In grade III, solid areas of spindle cells and papillary formations are prominent. Mitoses are common. Areas of hemorrhage and necrosis are also seen.
The constituent cells show immunoreactivity for endothelial markers: CD31, CD34, and factor VIII [
1,
6]. CD31 remains the most sensitive and the most specific endothelial cell marker. The role of immunohistochemical study is to confirm the vascular nature of tumor proliferation.
For grade I and II breast angiosarcoma, the differential diagnosis includes intramammary hemangioma, angiomatosis, and pseudoangiomatous stromal hyperplasia (PASH) [
4], especially in a core biopsy. Hemangioma is usually 2 cm or less and is sharply defined [
4]. Angiomatosis is a diffuse angioma with hemangioma and lymphangioma-like channels growing diffusely in breast tissue but sparing lobules and without nuclear atypia. Unlike angiomatosis, angiosarcoma infiltrates and dissociates breast lobules [
4]. PASH is a benign lesion comprising stromal myofibroblastic proliferation and having the appearance of anastomosing slit-like pseudovascular spaces lined by spindle-shaped cells [
11]. These spaces do not contain red cells, and have a perilobular concentric arrangement with a densely collagenous stroma [
4]. There is no destruction of the normal breast tissue, no necrosis, and no fat invasion [
11]. The myofibroblasts in PASH are positive for CD34 but are negative for factor VIII and CD31 [
4,
11]. The differential diagnosis of grade I and II breast angiosarcoma is summarized in Table
1.
Table 1
Differential diagnosis of grade I (well-differentiated) and grade II (intermediately differentiated) angiosarcomas of the breast
Lesion | Grade I angiosarcoma | PASH | Hemangioma | Angiomatosis |
Size |
Always > 2 cm
| Variable |
< 2 cm
| Diffuse |
Anastomosing spaces | True vascular channels contain erythrocytes |
Pseudovascular spaces, without erythrocytes
| True vascular channels contain erythrocytes | True vascular channels contain erythrocytes |
Destruction of adjacent breast tissue, invasion of fat | Yes | No | No | No |
Dense hyaline stroma | Absent |
Present
| Absent | Absent |
Lining cells |
Atypical with prominent and hyperchromatic nuclei
| Without atypia (very rarely atypia and hyperchromasia) | Without atypia | Without atypia |
Factor VIII and CD31 | Positive |
Negative
| Positive | Positive |
For grade III, sarcomatoid carcinoma and other types of high-grade sarcomas should always be considered in the differential diagnosis, hence the necessity of cytokeratin antibodies and endothelial markers [
4]. The differential diagnosis of poorly differentiated angiosarcoma is summarized in Table
2.
Table 2
Differential diagnosis of grade III (poorly differentiated) angiosarcoma of breast
Endothelial markers |
Positive
| Negative |
Negative
|
Cytokeratin | Negative |
Positive
|
Negative
|
Angiosarcoma is an aggressive malignancy with high recurrence rates and poor overall survival [
12]. According to Rosen and colleagues’ study [
13], grade is an important prognostic factor. In fact, the 5 years disease-free survival rate was 76%, 70%, and 15% for grade I, grade II, and grade III tumors, respectively. Primary tumor size was not significantly related to the risk of recurrence or to survival. In contrast, Zelek
et al. [
14], by reviewing eight cases of breast angiosarcoma, found that the tumor size was correlated with the rate of disease-free survival at 10 years. The prognosis was even worse when the tumor size was greater than 10 cm. Primary angiosarcoma of the breast gives metastasis mainly to lungs, liver, bones, skin, and the contralateral breast [
1,
2].
There are no treatment standards for breast angiosarcomas because of their rarity [
2]. However, treatment is primarily surgical. Mastectomy with negative margins is the recommended treatment [
2,
5], without axillary dissection [
5,
6]. Complementary radiation therapy is necessary in case of tumorectomy [
5]. Adjuvant radiation and chemotherapy improve survival outcomes in patients with tumor size > 5 cm [
14,
15]. Chemotherapy is beneficial in high-grade lesions [
3,
6] and in the metastatic setting [
3]. Recently, with the exploitation of vascular endothelial growth factor (VEGF)-A and VEGF-C and the receptor VEGF-R1, anti-angiogenic treatment is certainly a highly promising therapeutic approach [
2,
5].
Through this case report, we emphasize the importance of clinicopathological confrontation in angiosarcoma of the breast. This is especially true in cases of biopsy showing a well-differentiated angiosarcoma. It poses a problem of differential diagnosis with benign vascular pathology. It has a poor prognosis and presents therapeutic management difficulties.