Breast-conserving treatment (BCT) with radiotherapy has replaced mastectomy as the standard care for early-stage breast cancer in the last few decades.
1 Radiotherapy is usually administered at a maximum of 50 Gy to the operated area, in some cases with an extra booster of 10–20 Gy to the tumor bed. The incidence of breast cancer is increasing; currently, it affects one in ten women in the western world. Accordingly, more secondary angiosarcomas have been reported, with a cumulative incidence of 0.9 per 1,000 breast cancer cases over 15 years.
2 The development of secondary angiosarcoma has been linked to radiotherapy and lymphedema.
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Secondary angiosarcomas after BCT have an observed median latency period of ~4–8 years.
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10 Because of their rarity and seemingly harmless presentation, frequently comprising painless and bruise like skin lesions, both patients and doctors often neglect the initial symptoms and diagnosis is delayed. Patients often have localized, but multifocally growing, disease that is confined to the breast at diagnosis. Surgery is the mainstay of treatment and is usually performed with local resection or mastectomy. The risk of local recurrence and metastasis is high.
9 There have been several studies of (neo-) adjuvant chemotherapy, but the effects remain unclear.
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Discussion
Although secondary angiosarcomas of the breast have an approximate incidence of only 0.9 per 1,000 breast cancer cases
2, they are important because this disease has a very poor prognosis and is related to a previous medical treatment. In this study, two-thirds of the patients with secondary angiosarcoma presented with the typical blue/red discoloration of the skin, sometimes in combination with palpable tumor. The lesions can be single or multiple nodules, and papules or vesicles. One-third of the patients presented solely with a tumor; therefore, suspicion of secondary angiosarcoma should not rest only upon discoloration of the skin. In any patients with discoloration that does not disappear or tumor development within the radiation field, a needle or open biopsy should be performed. Mammography and/or MRI play only a limited role in diagnostics, but MRI may be slightly better at detecting an angiosarcoma.
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19 Since the first case of secondary angiosarcoma of the breast was described in 1987, the prognosis has remained poor, with a median survival of 1–3 years.
5 In our population-based study, we found similar median survivals of 16 and 37 months for DFS and DSS, respectively. Only two of our 35 identified patients presented with metastatic angiosarcoma, both died of the disease within 6 months.
Compared with previously reported population-based studies (Fodor et al. 2006,
n = 8; Hodgson et al. 2007,
n = 31; and Marchal et al. 1999,
n = 9)
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20, our cohort had similar median ages at the time of diagnosis of breast cancer (mean 60 years) and secondary angiosarcoma (mean 68 years). To the best of our knowledge, this is the equal largest study (
n = 31) published for secondary angiosarcoma developing in the irradiated field, but the largest study focusing on surgical treatment and outcome.
Most secondary angiosarcomas present as localized disease without metastasis. Nevertheless, they are difficult to control and often recur locally.
9 In our series, mastectomy achieved R0 margins at higher rates than local resection. In addition, three patients had mastectomy with resection of all irradiated tissue as primary treatment, R0 margins achieved in 2 cases and are alive after 2–9 years without evidence of disease.
Of the 31 patients who underwent surgery, the primary treatment resulted in R0 resections in 23 patients. Despite this, nearly two-thirds of these patients developed a local recurrence. We believe this to be due to the multifocal growth of angiosarcoma and tumor tissue left behind, even if the surgical margins are considered free. In this study, 11 of 19 patients with a local recurrence were considered eligible for surgery. The five patients with metastasis and three patients with locally extensive disease were not considered suitable for surgical treatment. The patients selected for surgery for local recurrence survived longer than those who did not. This difference we believe is due to different stages of tumor, and hence surgery has not necessarily made the difference. However, we conclude that local recurrence per se should not disqualify from aiming at surgery with curative intent.
In addition, four patients with lymph node metastases underwent surgery. Of these, two patients were without evidence of disease at the last follow-up, more than 2 years after surgery. The other two patients died of tumor after 8 and 14 months because of their angiosarcoma.
In other types of soft tissue sarcoma, adjuvant radiotherapy is frequently applied to improve local control. However, since secondary angiosarcomas develop within a field of radiation, usually the surrounding tissue has already received the maximum dose of radiation. In spite of this, one patient was treated with radiotherapy and initially responded well to therapy. After a few months, however, the disease progressed rapidly. A small single-center study (
n = 14) that looked at hyperfractionated and accelerated radiotherapy (HART), with or without surgical resection, found a 64 % 5-year progression-free survival.
9 Other studies reported a good response to (neo-) adjuvant treatment with paclitaxel in some patients.
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22 Interpretation of these results is hampered by the limited number of cases and the heterogeneity of the study populations. Therapies targeting angiogenesis through the vascular endothelial growth factor (VEGF) pathway and VEGF receptors (VEGFR) (e.g., sunitinib, sorafenib, and bevacizumab) have been promising in some patients with angiosarcoma; however, they clearly do not benefit a majority of patients.
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Another important field of study concerns the dose, extent, and duration of radiotherapy as part of breast-conserving therapy. Studies comparing hypofractionated and conventional fractionation of radiotherapy for breast cancer have been conducted, as have studies investigating radiotherapy for a quadrant of the breast instead of the entire breast.
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30 If changes in the dose, extent, and duration of radiotherapy are implemented, the risk of developing secondary angiosarcoma will have to be monitored closely.
In conclusion, the only chance of curative treatment for secondary angiosarcoma is extensive surgery, preferably with resection of all irradiated tissue performed. The rarity of the disease, its complex behavior, and the need for extensive surgery indicates that these tumors should be managed at a tertiary sarcoma center. Despite free margins, two-thirds of the patients in our study developed a local recurrence. Surgical intervention in a selected group improved survival for patients with local recurrence. However, the median DSS was still only 3 years.