Recurrence of Primary Breast Angiosarcoma 7 Years after Mastectomy in a 17-Year-Old Woman: A Case Report

Breast angiosarcoma is a highly aggressive vascular neoplasm and is estimated to constitute 0.05% of the malignant diseases of the breast [1]. Breast angiosarcomas can be divided into 2 types: primary breast angiosarcoma and secondary angiosarcoma resulting from the preceding breast cancer therapy. The causes of primary breast cancer remain unclear. Primary breast angiosarcomas are most common in women in their 30s and 40s [2]. Here, we present a case of primary breast angiosarcoma in a woman less than 18 years of age, with a follow-up period of over 5 years. The patient is still alive 8 months after her second resection, and no evidence of any local or distant disease is observable.

A 17-year-old woman was admitted to our hospital with a 6.0 × 5.5 cm lump in the upper quadrant of the right breast. No congenital vascular lesion was found in her breast before the breast angiosarcoma was diagnosed. Sonography showed the tumor to be ill-defined, irregular in shape, and hypoechoic in B-mode, with absent color Doppler signals (fig. 1). Histological findings of a needle biopsy specimen revealed the lesion to be an angiosarcoma. She underwent a mastectomy. The pathology findings of the gross specimen were consistent with grade III angiosarcoma. The tumor was observed to invade the surrounding adipose tissue. Endothelial markers (CD31, factor VIII), vascular markers (CD34, Ets-related gene (ERG), vascular endothelial growth factor (VEGF)), the tumor suppressor genes P53 and P16, and the mesenchymal marker vimentin were positively expressed in the tumor. We recommended adjuvant chemotherapy as a safety measure according to the clinical guidelines [3] and clinical studies on soft-tissue sarcoma [4, 5, 6, 7]. However, she refused the option to receive adjuvant chemotherapy.

After 86 months, the right chest wall showed a 5.5 × 4.5 cm rapidly enlarging mass (fig. 2a). No axillary lymphadenopathy was palpated. A computed tomography (CT) scan of the chest showed a solid mass under the skin of the right chest wall (fig. 2b). Sonography showed the mass to be well defined and hypoechoic in B-mode, with hypervascular Doppler signaling. The patient underwent extensive local excision and transplantation of an adjacent skin flap.

Histopathological findings revealed a poorly differentiated soft-tissue angiosarcoma infiltrating into vessels and striated muscle. A papillary and capillary growth pattern formed by anastomosing vascular channels was observed (fig. 3a, b). Necrosis was also found in the tumor. Immunohistochemical examination showed positive expression of the endothelial marker CD31 (fig. 3c), the vascular markers CD34 (fig. 3d), factor VIII (fig. 3e), ERG (fig. 3f), and VEGF (fig. 3g), and of the tumor suppressor genes P53 and P16. The mesenchymal marker vimentin was also positively expressed (fig. 3h). In contrast, the epithelial markers cytokeratin (CK) AE1/AE3, smooth muscle actin (SMA), and epithelial membrane antigen (EMA) were negatively expressed. The proliferation index Ki-67 was positively expressed at 25%. After the second resection, we suggested the patient to undergo chemotherapy based on the current clinical guidelines [8], but she refused. The disease-free interval from the second resection to the publication of this case was 8 months, up until September of 2018.

Breast angiosarcoma, a sarcoma arising from endothelial cells of blood vessels, occurs more often in women between 20 and 50 years [9]. However, the patient was 17 years old when first diagnosed. During physical examination, a painless mass with bluish skin discolorations was palpable, in accordance with the description in the literature [10]. Almost one-third of primary breast angiosarcomas can be determined by mammography [11], but our patient did not undergo mammography due to her young age. At the time of initial diagnosis, ultrasound revealed several honeycomb-like low-echo masses without blood flow in the right breast, which was different from the typical appearance of breast angiosarcoma [12]. However, when the condition recurred, the ultrasound demonstrated a mass with marked vascularity and unclear boundary, which was similar to the typical appearance.

Morphologically, growth patterns of angiosarcoma present as ramifying irregular vascular structures, including vasoformative growth, solid growth, papillary endothelial growth, and capillary-type growth forming anastomosing vascular channels. Atypical endothelial cells, including endothelial shapes that appear plumped, spindled, or epithelioid-like, have hyperchromatic nuclei of varying sizes. Necrosis and blood lakes may be found in the stroma. The diagnosis can be clarified by positive immunohistochemical expression of the endothelial biomarker CD31 in tumor cells, which is the most sensitive and specific indicator of angiogenic proliferation, while vascular markers such as CD34, factor VIII, D2-40, and Fli1 were also positively expressed [13]. Moreover, it is suggested that the proliferative index, Ki-67, is a useful differentiating index when attempting to differentiate benign breast mesenchymal tumors from malignant ones [14]. It has been shown that neither preoperative fine-needle biopsy nor core needle biopsy is reliable enough, since a 37% false-negative rate has been reported [15]. Therefore, a surgical specimen for histological and immunohistochemical examination is necessary.

Surgery plays an indispensable role in the treatment of primary breast angiosarcoma [16]. Generally, mastectomy (including the muscular fascia) is recommended even in combination with postoperative radiotherapy. Lymphadenectomy is not carried out in the absence of clinical evidence of involvement [8]. Although, so far, there are no relevant clinical trials on breast angiosarcomas due to their rarity, it has been demonstrated that grade III primary breast angiosarcoma patients and patients with disease recurrence would benefit from chemotherapy [17]. The chemotherapy regimens refer to soft-tissue sarcomas. For high-risk patients, administering anthracyclines and ifosfamide for at least 3 cycles is an option [8]. In addition, doxorubicin, liposomal doxorubicin, and taxanes are possible choices for monotherapy [18]. As for targeted therapy, bevacizumab is an effective and well-tolerated agent against metastatic or locally advanced angiosarcoma [7]. Considering the high risk of local and systemic relapses, radiation may be used and the timing depends on the wound complications. The recommended regimen is a total dose of 50 Gy in fractions of 1.8-2 Gy, possibly with a boost of up to 66 Gy, depending on the margins at the time of presentation and after resection. Furthermore, re-irradiation should be considered in radiation-induced angiosarcomas [8]. So far, there is no conclusive evidence that radiation increases the risk of secondary angiosarcoma.

In conclusion, primary breast angiosarcoma is a rare malignant sarcoma. It usually presents as a palpable, painless breast mass. Surgery is a necessary treatment option for the early stages of breast angiosarcoma. Chemotherapy and radiation are recommended to decrease the risk of recurrence. Long-term close follow-up is extremely important, regardless of how long after surgery or the status of the surgical margins.

We would like to thank the anonymous reviewers who have helped to improve the paper. W.T. was supported by grants from the National Natural Science Foundation of China (grant no. 81502598) and the Zhejiang Provincial Natural Science Foundation of China (grant no. LQ14H160010). Y.D. was supported by grants from the Zhejiang Provincial Natural Science Foundation of China (grant no. LY14H160020).

The authors have no ethical conflicts to disclose.

None of the authors has conflicts of interest to disclose.