Primary and secondary breast angiosarcoma: single center report and a meta-analysis

Breast sarcomas are a heterogenous group of tumors, accounting for < 1% of all breast malignancies and < 5% of all soft tissue sarcomas [1]. With an annual incidence of 4.6 cases per million, it is considered an extremely rare type of malignancy [2]. Angiosarcomas of the breast account for < 1% of all of soft tissue tumors, but represent the major histological subtype of all breast sarcomas [3]. Despite mimicking breast adenocarcinoma clinically, breast angiosarcoma is a more aggressive malignant tumor of the vascular endothelium, with rapid proliferation and infiltration into surrounding connective tissues and is associated generally with worse prognosis [4, 5]. Based on the etiology, breast angiosarcoma can be divided into two categories: primary (de novo) and secondary (therapy-related).

Breast primary angiosarcoma (PAS) develops de novo with no prior breast radiation. It typically occurs in younger females between ages of 30 to 50, and often presents as a large mass that arises within the breast parenchyma, typically without any skin changes [6]. Secondary angiosarcoma (SAS) has been traditionally linked to two clinical scenarios. More commonly, SAS occurs in the setting of radiation therapy typically given for treatment of breast cancer [7]. SAS can also occur in the setting of chronic lymphedema typically post breast surgery and lymph node dissection (also called Stewart–Treves syndrome) [8]. Typical presentation of SAS is ecchymotic skin lesions with or without ulceration [6], appearing on average 6 years following radiation to the breast and/or chest wall, and occurring mostly in older females between ages 60 and 70. While the incidence of SAS secondary to lymphedema has significantly decreased due to improved surgical techniques [6], the incidence of SAS secondary to radiation therapy has been increasing with the increased use of breast conservation surgical approach [6]. On FISH analysis, SAS exhibits frequent amplification of cMyc and FLT4, not usually seen with PAS [9]. Furthermore, compared to SAS of the breast, patients with PAS historically have had significantly longer survival, and are less prone to regional recurrence and distant metastasis [10]. Previous studies have demonstrated the role of grade in prognosis [11]. Grading is based on patterns of growth, histological markers of atypia and proliferation indices. They are classified into low, moderate and high grade, with SAS having higher percentage of high grade tumors as compared to PAS [6]. Staging is based on AJCC guidelines, and follows other soft tissue sarcomas; it incorporates both tumor grade as well as size, nodal involvement and presence or absence of distant metastasis.

Due to rarity of these tumors, most available literature consists of case reports and single institution retrospective cohorts, with very limited number of published studies. Previous meta-analysis was published which only included cases of radiation associated SAS diagnosed in European countries [7]. With lack of prospective studies and limited retrospective data optimal management is based on expert opinion, mostly based from experience with other soft tissue sarcomas. Currently, PAS and SAS are managed similarly, with surgical excision being the most common frontline management. Complete resection with optimal margins (R0 resection) is the goal of surgical intervention. The best surgical method of resection remains unclear, with lack of long-term outcome data comparing breast conservative surgery (BCS) versus mastectomy. Role of radiotherapy and chemotherapy remains unclear [12].

In this report, we are describing a single institution experience with both types of breast angiosarcoma, detailing tumor characteristics, treatment, and survival outcomes. We also performed a meta-analysis to update prognostic factors and treatment modalities in this rare population of patients, evaluating treatment modalities including surgery, radiation, and chemotherapy.

Breast angiosarcoma is a rare and heterogeneous malignancy; therefore, most of the available literature about this disease is in the form of single institutional experiences with limited outcome data. To our knowledge, this is the largest sample size meta-analysis that is comprehensive in nature, including outcome data from both primary and secondary breast angiosarcoma, in addition to our single institutional experience.

Despite the limited literature available about breast angiosarcomas, the clinical and pathological data seem to be quite consistent across all studies. In general, SAS patients tend to be older than PAS patients, with a smaller tumor size, and generally poorer OS. Median time from radiotherapy to development of SAS varied in different reports, ranging from 51 to 180 months. Our retrospective report had a median time of 93 months, compared to the pooled literature review presented by Depla et al which reported 72 months [7].

Prognostic factors differed in impact across cohorts. Tumor size and grade seemed to be the most consistent prognostic factors for both PAS and SAS tumors in regards to both OS and RFS. Age appears to be a prognostic factor only in PAS tumors, where age > 60 was associated with worse OS. We did not find previously reported association with worse outcomes with age and interval from radiation history for SAS patients [7]. Definitive surgical resection with negative margins remains the mainstay of treatment, although the best surgical approach remains unclear. Currently, it is believed that more aggressive surgery with mastectomy concurs clinical advantage with more regional control, despite questionable survival benefit. Our retrospective data, in addition to the meta-analysis results showed no survival advantage with mastectomy. A SEER database review by Pandey et al reported that patients with PAS Grade 3 disease who were treated with surgical intervention showed no OS advantage to mastectomy vs BCS, (5-year OS 36% vs. 44%; p = 0.445) [11]. Yin et al’s updated SEER analysis demonstrated similar results in both PAS and SAS cohorts [10]. Furthermore, Toesca et al. also demonstrated that patients who underwent BCS did not show worse prognosis compared with those who underwent mastectomy [17]. Therefore, the question of best surgical modality for patients with breast angiosarcoma remains unsettled with R0 resection being the goal of any surgical intervention. The need for axillary lymph node dissection is unclear given nodal metastasis is not common in angiosarcoma [18].

While adjuvant chemotherapy had no survival impact in both PAS and SAS groups, adjuvant radiation therapy seemed to have a significantly positive impact on RFS when both PAS and SAS groups were analyzed together. Similar to other small studies, our retrospective study did not show any significant associations between survival and adjuvant chemotherapy or radiation therapy. However, higher grade tumors did demonstrate a trend towards improved RFS when adjuvant chemotherapy was used.

In the analysis done by Depla et al, adding adjuvant radiation therapy to definitive surgery for SAS demonstrated significant reduction in local recurrence (Local relapse free interval 57% vs. 34%, HR 0.46, p = 0.01) but not in OS (HR 0.87, p = 0.65), which is similar to the results reported in our meta-analysis. Prior studies show statistically significant benefit of adding adjuvant chemotherapy in the treatment of angiosarcomas [19], however neither our analysis nor the analysis done by Depla et al. [7] showed statistically significant benefit in breast angiosarcomas. Although, we do show that for poorer prognosis patients with high grade tumors, there was a trend toward increased benefit of RFS after administration of adjuvant chemotherapy.

Based on these results, we cannot help but speculate that mastectomy does not seem to have an additional benefit over BCS, despite seeing a more popular trend for mastectomy in these patients. Also, adjuvant radiation therapy does seem to have additional benefit in these types of tumor; however, the role of adjuvant chemotherapy remains questionable, except in high grade tumors where it seems more beneficial.

This study is limited by the rarity of breast angiosarcoma and the retrospective nature of this analysis that prevents us from drawing any definite conclusions. Some findings that failed to reach statistical significance may be due to lack of power. Furthermore, we have to take into account selection and search biases, which we tried to minimize by using two independent researchers with the final list of included studies finalized by consensus. Another limitation was the heterogeneity of the sample sizes and the reported results, with several missing data making the studies not 100% comparable, making multivariate analysis difficult.

In conclusion, breast angiosarcoma is a rare aggressive tumor characterized by high grade and high rate of local recurrence. Tumor size and grade seem to be reliable predictors of survival. At this point there are no standard guidelines for treatment, with optimal R0 surgical resection and wide margins remaining to be the most agreed upon approach. Role of mastectomy verses BCS remains questionable, although mastectomy does not seem to be adding any additional benefit to BCS. Adjuvant chemotherapy does not seem to play a significant role in improving survival although taxane-based therapy can be considered in high grade and high-risk tumors. Adjuvant radiation showed statistically significant improvement in RFS and should be considered especially in cases of positive or close margins. Further studies are needed to define best treatment options for this rare tumor subtype and to define clinical differences in PAS versus SAS.