Introduction
Cutaneous angiosarcoma (CAS) is a rare neoplasm of mesenchymal origin, accounting for less than 1% of all sarcomas (1). While the pathogenesis of angiosarcoma remains unclear, it has been associated with multiple etiological risk factors, including radiotherapy, chronic lymphedema, various chemicals, and immunodeficiency (2). In a population-based retrospective cohort study, radiotherapy significantly increased the risk of angiosarcoma (3). Angiosarcoma arising in the base of chronic lymphedema is known as Stewart-Treves syndrome. Some investigators have reported a relationship between antecedent traumatic tissue injury and pathogenesis (4). Recently, ultraviolet light exposure has been associated with a common etiological and genomic mutational basis for the pathogenesis of angiosarcoma of the head and neck region (5).
The most commonly affected sites of CAS are the scalp and facial skin (6), which are associated with a poor prognosis compared to other sites (7). The clinical presentation of CAS is single or multiple bluish or violaceous nodules, and occasionally ulceration or bleed (8). No definitive criteria have yet been formulated for the staging of angiosarcoma. According to the 8th edition of the American Joint Committee on Cancer staging manual on the TNM staging system, angiosarcoma is excluded from the soft tissue tumor chapter because of its aggressive infiltrative nature. On immunohistochemistry, vascular endothelial markers, including CD31, CD34, and von Willebrand factor-related antigens, are informative for diagnosis (9). In addition, lymphatic endothelial markers, such as D2-40, Prox-1, and VEGFR-3, might be positively expressed, which indicates lymphatic differentiation of angiosarcoma (10).
Although several treatment procedures have been investigated, as yet, there is no consensus on the treatment of angiosarcoma, due to a lack of statistically significant evidence. Surgical resection with a free tumor margin is the primary treatment of choice for angiosarcoma (11). The microscopic negative surgical margin was significantly correlated with longer overall survival (OS), which is considered an important prognostic factor (12). However, due to the diffuse infiltrative and multifocal nature of CAS, preoperative medical assessment of the lesion and careful selection of the patient are critically important.
Radiotherapy is also considered a curative local therapy for unresectable or incompletely resected tumors. The effectiveness of postoperative radiotherapy for local control (LC) and OS has been reported in several studies (13) however studies on the treatment of angiosarcoma by radical radiotherapy without surgery are very limited. The aim of the present study was to investigate the clinical outcomes of radiotherapy without surgery for patients with scalp CAS.
Discussion
The results of our study did not deviate significantly from those of other studies. The clinical outcomes of patients in our study were comparable to those of previous reports. Hata et al (16) reported that 17 patients with angiosarcoma of the scalp underwent total scalp irradiation therapy with curative intent and found that the 3-year OS and disease-free survival rates for all patients were 22 and 6%, respectively. They adopted a two-step cone-down technique, with an initial phase CTV including the entire scalp for a median dose of 50 Gy in 25 fractions, followed by a tumor site with an additional margin for a dose of 20 Gy in 10 fractions. However, five patients experienced disease progression in the scalp distant from the primary site, which had received prophylactic irradiation at doses of 46-50 Gy. They, therefore, concluded that a dose of less than 50 Gy in conventional fractions might be insufficient to control microscopic tumors. Clear evidence to determine the effective radiation dose and coverage field is debated, and the optimal treatment strategy for radiotherapy remains controversial.
Multimodal treatments, including surgery and radiotherapy, were more effective than single-modality treatment in improving clinical outcomes for patients with CAS. Ogawa et al (17) revealed that patients treated with combined therapy had a significantly more favorable OS than patients treated with either surgery or radiotherapy alone (2-year OS: 45.8% vs. 11.1%, P<0.001). Guadagnolo et al (18) also reported that combined modality local therapy was associated with improvement in LC, OS, and disease-specific survival in 70 patients with angiosarcoma of the face or scalp.
The role of adjuvant systemic therapy after initial treatment has been investigated in previous retrospective studies. Ihara et al (19) reported that the administration of adjuvant chemotherapy consisting of a taxane regimen after concurrent chemoradiotherapy was a significant prognostic factor for PFS (P=0.036). Fujisawa et al (20) showed that patients who received taxane-based concurrent chemoradiotherapy (CCRT) with maintenance chemotherapy showed a significant improvement in OS compared to those receiving CCRT alone (P<0.01). In the present study, while the OS and PFS were superior in the maintenance chemotherapy group, the difference was not statistically significant.
The most frequent metastatic site of angiosarcoma is the lungs (21), as shown in our report. Treatment options for the management of recurrent or advanced CAS are limited. However, in recent years, immunotherapeutic approaches have emerged as promising anti-cancer systemic therapies. In particular, immune checkpoint inhibitors have proven efficacious in various cancer entities. Florou et al (22) treated seven angiosarcoma patients with immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte antigen 4 or programmed cell death protein 1 monoclonal antibody, five (71%) of whom had a partial response, without severe toxicity.
In the present study, no statistically significant prognostic factors were identified. However, local recurrence and distant metastasis, especially in the lungs, were observed at a considerable frequency. These pulmonary metastases could cause fatal hemopneumothorax, and careful follow-up for distant metastasis, including lung metastasis, after treatment is considered crucial.
This study had several limitations. As the study was conducted at a single institution, the sample size was small, making it difficult to identify significant prognostic factors from the data. Because of the retrospective nature of data collection, our data had numerous risks of bias. Moreover, the retrospective analysis of medical records makes it impossible to describe the complete condition of patients at the time of treatment.
This retrospective study reported the clinical outcomes of radiotherapy for CAS in our institution. Radiotherapy combined with adjuvant chemotherapy showed a more favorable outcome than radiotherapy alone; however, there were no statistically significant differences between these groups. Further comprehensive research is needed to clarify the optimal treatment strategy for CAS.