RAAS is a rare type of secondary angiosarcoma with an incidence that varies from 0.05 to 1.11% [1, 8]; the malignancy is often seen in elderly patients [9]. In 1984, Cahan et al. defined RAAS as a sarcoma that arises in an irradiated field of tissue. They also defined RAAS as pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field, in patients with a history of radiation therapy and a latency period of at least 3–4 years from their last radiation therapy [10, 11]. Because the current case met all the above criteria, we diagnosed it as a clinical recurrence of RAAS.
The latency for RAAS occurrence in the irradiated area is 10–12.5 years after the first radiation therapy [9, 12, 13]. Pathologically, angiosarcoma presents as solid sheets of anaplastic endothelial cells that form complex vascular channels. Vascular endothelial markers, for example, CD31, CD34, VIII-related antigen, and Ulex lectin stains, are useful for diagnosis [12]. Sometimes D2-40-reactive lymphatic endothelial markers are seen.
RAAS is associated with high mortality. For example, Colwick et al. reported a 5-year survival rate of 15–20% [12]. Gervais et al. reported that a 5-year OS is 44% and DFS is 23% [6], Torres et al. reported a 10-year OS of 54% [13], and Depla et al. reported a 5-year OS of 43% [7].
RAAS is usually sporadic and spread across multiple sites in the irradiated field and has a high local recurrence rate. With regard to the pattern of the first recurrence of angiosarcoma (including RAAS and sporadic angiosarcoma), Gervais et al. reported that the local recurrence rate was higher than the distant recurrence rate (46% vs. 13%) [6]. Torres et al. reported that local recurrence following R0/R1 resection was observed in 48% of patients compared with 27% of distant metastasis, after a median follow-up of 10.8 (range, 2.4–31.8) years. Additionally, 24% of the patients developed second local recurrences [13]. The authors suggested that this is because microsatellite lesions spread beyond the apparent R0 margins in RAAS in the irradiated area. Ketja et al. also reported the local recurrence rate after R0 resection was 54% [14]. According to their study, the median survival rate in patients who did not develop a local recurrence after R0 resection was higher than those of patients who developed a local recurrence (40.5 months vs. 20 months). From these studies, it is clear that RAAS has a high local recurrence rate even if the surgical margin is negative, and prevention of local recurrence is vital in order to prolong OS.
Although many treatment modalities for RAAS have been proposed, there is no consensus for the optimal treatment because clinical cases are very rare, and this precludes rigorous statistical analysis. Total mastectomy could be considered the current standard treatment for RAAS following breast conservation. However, mastectomy alone is still associated with a high risk of local recurrence; in one report, 73% of patients undergoing mastectomy alone developed further RAAS [1]. In our case, the patient had repeated local recurrence of RAAS, despite the fact that she underwent a mastectomy for her first occurrence of RAAS. These data show that the local control of RAAS is very difficult.
Li et al. reported on surgery-specific risk stratification in the context of RAAS. In this retrospective study, 76 women with RAAS were enrolled and randomized into two groups, the “radical group” and a “conservative group.” The “radical” resection was defined as resection of all the previously irradiated area plus mastectomy. Consequently, the “conservative group” was defined as standard resection such as mastectomy or tumorectomy without total resection of the irradiated area. The radical surgery group had a lower 5-year cumulative local recurrence incidence compared to the conservative surgery group (23% vs. 76%, P < 0.001) and distant metastasis incidence (18% vs. 47%, P = 0.02). Five-year disease-specific survival (DSS) for the radical group was much higher than that for the conservative group (86% vs. 46%, P < 0.001). In addition, patients who underwent conservative surgery with negative margins had a worse DSS than those in the radical group [15]. This study suggests that an extended resection of irradiated area is an effective treatment for RAAS.
Chemotherapy has also been used to treat RAAS. Fujisawa et al. reported that chemoradiotherapy with taxane is superior to conventional surgery and radiation therapy for angiosarcoma. In this retrospective study, the response rate of chemotherapy was 94%, and a 5-year OS for the chemotherapy group was statistically higher than that for the surgery group (56% and 8%, respectively; P < 0.01). However, this study included not only RAAS but also primary angiosarcoma [16]. In contrast, Colwick et al. found that chemotherapy has a minimal benefit (only 17–34% response rates) [12]. Therefore, the true benefit of chemotherapy for RAAS treatment is uncertain. Torres et al. reported on the impact of adjuvant chemotherapy for RAAS and found that it reduces local recurrence rate; however, they concluded that adjuvant chemotherapy was not significantly associated with a better prognosis [13]. Additionally, the optimal chemotherapy regimen is also unclear [2]. Moreover, angiosarcomas overexpress vascular endothelial growth factor (VEGF). Agulnik et al. reported the efficacy of bevacizumab for the treatment of advanced angiosarcoma. They enrolled 32 patients with advanced angiosarcoma which could not be resected surgically, prospectively. The result was that 17% of patients had a partial response and 50% of patients showed stable disease with a mean time to progression of 26 weeks. They concluded that bevacizumab was effective for advanced angiosarcoma [17]. On the contrary, Ray-Coquard et al. reported on a study comparing paclitaxel with or without bevacizumab regimen to treat for advanced angiosarcoma including RAAS. Six-month progression-free survival rate was 54% in the paclitaxel alone group and 57% in the paclitaxel with bevacizumab group. This indicates that paclitaxel with bevacizumab regimen is not superior to paclitaxel alone [18]. Although both studies were prospective and including not only primary angiosarcoma and but also RAAS, it appears that more data is needed to reveal the effectiveness of bevacizumab to treat RAAS.
Although several reports recommend surgery and adjuvant radiation therapy with large doses, no formal radiation therapy trials have been done [19]. Moreover, repeated exposure of the area to radiation is likely to result in local recurrences [12]. Therefore, we consider that the use of radiation therapy for RAAS is also controversial. Additionally, the relationship between RAAS and radiation dose remains unclear. In our case, the patient had been subjected to radiation therapy twice, and RAAS had clearly arisen in the irradiated area of her chest wall. This indicates that the use of radiation therapy to treat RAAS may increase the risk of local recurrence or another new occurrence of RAAS.
In summary, RAAS has a high local recurrence rate even if the surgical margin was negative, because it spreads throughout the irradiated area. In the current case, the patient had repeated local recurrences of RAAS that arose in the irradiated area on three successive occasions. Therefore, we suggest resecting as much as possible of the irradiated area as the most effective treatment for RAAS. Although this patient could not be treated with adjuvant chemotherapy due to her age and history of cerebral infarction, she was completely cured as a result of the “extensive” surgery. We conclude that the resection of the entire irradiated area is the most effective treatment for control of local recurrence and extension of survival time in RAAS patients.
