Post-radiation angiosarcoma (AS) of the breast, also known as radiation-associated angiosarcoma (RAAS) or radiation-induced angiosarcoma (RIAS), is a rare malignancy of vascular origin that occurs secondary to breast irradiation for the treatment of breast cancer. 12 Unlike primary breast angiosarcoma which develops spontaneously in young women between 20-40 years, secondary angiosarcoma develops mainly from the dermis of the irradiated breast tissue. 23 Breast angiosarcoma accounts for less than 1% of breast malignancies and post-radiation AS accounts for an even smaller percentage (<0.1%). 3 The diagnosis and management of post-radiation AS is challenging because patients usually present asymptomatically with non-specific skin changes that mimics benign skin lesions, delaying diagnosis. By the time a diagnosis is made, the disease has often metastasized to become incurable. 45 Mastectomy to achieve negative margins is currently the mainstay of treatment and sentinel lymph node biopsies are not performed because of its hematogenous spread. 6 Postradiation AS is becoming increasingly relevant to clinicians due to the rise in rates of breast conserving surgery and radiotherapy. 2 The purpose of this study is to maintain clinical awareness of post-radiation AS by reviewing the clinico-pathological characteristics, management and outcomes of patients diagnosed in the Western Sydney Local Health District (WSLHD), Sydney, Australia. Histopathology reports were reviewed individually to confirm that a diagnosis of breast angiosarcoma was made. Post-radiation AS is defined by histological-proven angiosarcoma with a history of previous breast irradiation. 7 Exclusion criteria included patients with primary angiosarcoma which arises de novo, or patients with inconclusive histopathology. Patient demographics (age, sex and risk factors), oncological history (surgery, chemotherapy, and radiotherapy records), and followup data were collected by reviewing individual patient medical records. The time of diagnosis of post-radiation AS was defined as the date of first histological diagnosis. Latency period refers to the time when the last radiotherapy was given to the time of diagnosis of post-radiation AS. Duration of followup was calculated from the time of diagnosis of postradiation AS to the time of death, or until the study end date was reached, whichever was later. Diseasefree survival was defined as the length of time after surgery, to the time of the last follow up or until disease recurrence.

Basic descriptive statistics were performed using IBM SPSS v26. 8 This study was approved by the Western Sydney Local Health District Human Research Ethics Committee.

Using the ICPMR database, twelve patients were diagnosed with breast angiosarcoma between 2000 and 2021. One patient had primary angiosarcoma and 11 patients had post-radiation AS. Five patients were excluded from descriptive analysis because they were not treated in WSLHD resulting in a total of six postradiation AS patients for further analysis in our study. These 11 patients were diagnosed with breast postradiation AS out of 10,060 patients who have had breast radiotherapy in WSLHD from 2000 to 2021. The annual incidence of post-radiation AS in our study population is 1 in 18,000 patients.

Patient demographics and clinicopathological features are presented in Table 1. All patients were female and had a history of ipsilateral radiotherapy for primary breast cancer. The median age was 67 years (range: 55 to 86 years). Patients and their risk factors for secondary angiosarcoma are listed in Table 1. The median latency period was 5.5 years.

All patients presented with skin changes that were noticed during routine follow-up, such as a rash or ulceration. Two patients had a history of a nonhealing skin ulcer that they thought were secondary to trauma. Patient 1 presented with an ulcer presumed to be due to a cat scratch and did not seek immediate medical attention. Patient 3 presented with a 10-month history of skin lesions over her left breast first appearing as a solitary, itchy lesion ( Figure 1). She had a mammogram and breast ultrasound earlier that year which did not detect any new breast lesions or abnormalities (Figure 2 and 3). She was one of the four patients who had a core needle biopsy and was diagnosed with post-radiation AS. The other three patients, however, had an inconclusive result on core biopsy and required a surgical excisional biopsy to diagnose post-radiation AS. Two patients (33.3%) had a punch biopsy as their initial form of investigation and one of them had an inconclusive result requiring surgical excision to confirm the diagnosis. Treatment Computed tomography (CT) was performed in all patients for staging and all but one patient had no evidence of metastasis. Table 2 summarizes the treatment and management of patients in our cohort. Four out of six patients (66.7%) were treated with simple mastectomy. Sentinel lymph node biopsy was not performed in this cohort. One patient (16.7%), who initially declined a mastectomy, had a wide local excision but subsequently had a mastectomy for positive margins. One patient had a wide local excision because she already had a mastectomy previously for primary breast cancer. Only one patient with evidence of bone metastasis on CT received adjuvant chemotherapy. No patients received adjuvant radiotherapy.

The median follow-up was 55 months (Range: 4.5 to 177.0 months). Three out of six patients (3/6, 50.0%) had evidence of disease recurrence. The median disease-free survival was 98 months. One patient had locoregional recurrence to the ipsilateral chest wall and lung that was treated with aggressive surgical resections. Two patients had distant metastasis. Figure 6 shows a PET-CT of patient 3 demonstrating extensive metastases eight months post-surgery. She later received taxol-based chemotherapy and radiotherapy but died from her disease progression. The other patient unfortunately died before any treatment could commence. The 5-year survival rate was 66.7% (4/6). Both patients who died within 5 years had distant metastatic disease.

Post-radiation AS is a rare complication after breast radiotherapy. The rarity of post-radiation AS is reflected in our study, with an annual incidence of approximately 1 in 18,000 of the breast radiotherapytreated population. Post-radiation AS commonly affects older women with a median age of 67.5 years in our study, and this is comparable to what was reported in the literature of 70 years. 9 The median latency period observed in our study was 5.5 years, also comparable to literature of 6 years. 9 Postradiation AS often presents asymptomatically; skin changes may be difficult to differentiate from irradiated skin changes and skin lesions can appear benign, which can contribute to a delayed diagnosis. 10 Post-radiation AS is diagnostically challenging because radiological findings are often normal or non-specific. 11 Mammogram may reveal skin thickening, calcifications, or an ill-defined mass; and the ultrasound appearance can appear hypo or hyperechoic. 912 One study reported that approximately 33% of mammograms appear normal, resulting in a delayed diagnosis. 13 Punch or core biopsies can also give a false negative or an inconclusive result, as seen in our study. One study reported a false negative rate of 37% 14 .

Post-radiation AS is an aggressive malignancy with a poor prognosis. In our study, we report a recurrence rate of 50% and a 5-year survival of 66.7%. Surgery is the standard of care and usually involves a mastectomy and excision of all irradiated tissue with wide clear margins. 10 There have been variable data published about the effectiveness of adjuvant treatment. Lahat et al. showed that taxolbased chemotherapy was a positive predictor of disease-specific survival, although this was not statistically significant (HR 0.67, p 0.06). 15 In a retrospective study of ten patients, Johnstone et al. showed that all patients treated with adjuvant radiotherapy had a 5-year disease-free survival of 68% and an overall survival of 66%. 16 In addition, seven out of ten patients were alive and free of disease at 11.8 years, suggesting that adjuvant radiotherapy can potentially achieve excellent local control. Another meta-analysis showed that patients treated with surgery and adjuvant radiotherapy had significantly better recurrence-free survival compared to surgery alone (HR 0.48, 95%CI 0.27-0.86, p<0.05). 17 In our retrospective study, no patients received adjuvant radiotherapy, possibly due to the lack of data on its efficacy. If radiotherapy is shown to have good outcomes, perhaps clinicians should consider using it as adjuvant therapy. More research is warranted in this area to provide robust evidencebased recommendations for patients.

Breast conserving surgery followed by radiotherapy has been shown to be equivalent to mastectomy in terms of oncologic outcomes in early breast cancer and as a result, most patients receive breast conserving therapy with local surgery and radiotherapy. 18 Clinicians should be aware of the subtle presentation of post-radiation AS, its tendency for multifocality and have a high index of suspicion. Prompt diagnosis with excisional or generous incisional biopsy and subsequent treatment with radical surgical excision should improve outcomes. Due to the rarity of this disease, it is difficult to make treatment recommendations from this study. Our study does reinforce published literature and serves as a reminder to clinicians about the subtle presentation, diagnostic pitfalls, aggressive clinical behavior, and treatment patterns for this rare disease.

Post-radiation AS of the breast is a rare disease associated with a poor prognosis due to its aggressive nature and high recurrence rate. Diagnosis is challenging with high false-negative rates associated with breast imaging and skin punch or core needle biopsy. Prompt diagnosis is required to improve patient outcomes, including careful physical examination, appropriate investigations and maintaining a high index of suspicion in patients treated with past breast radiotherapy.

The authors declare that they have no conflict of interest.

None.

DATA AVAILABILITY Not Applicable.

All patients whose medical records were used in this study singed an informed consent to present the detail of her pathology and medical findings in this medical journal.