Angiosarcomas are soft tissue sarcomas that originate from endothelial cells. They are exceedingly rare, accounting for less than 1% of all sarcomas [1]. These tumors can develop anywhere in the body and can occur at any age. However, they most commonly present as cutaneous disease in elderly white men, particularly affecting the head and neck region, especially the scalp. Angiosarcomas can also originate from the breast, soft tissues, bone, and visceral organs [2,3]. Several risk factors for angiosarcomas have been identified, including therapeutic radiation, chronic lymphedema, exposure to various carcinogens, and several genetic syndromes [4,5]. Treatment options include surgical resection for localized disease and systemic chemotherapy for metastatic disease. Achieving negative margins can be challenging due to the infiltrative nature of these tumors. A multidisciplinary approach, which may include surgical resection, chemotherapy, radiotherapy, or potential immune-agents, could yield positive outcomes [4-6]. In this article, we aim to review the fundamental characteristics of angiosarcomas and provide a brief overview of the up-to-date treatment options for this disease.

Angiosarcomas account for up to 2% of all soft tissue sarcomas and 5.4% of cutaneous soft tissue sarcomas [7,8]. These tumors are more prevalent among the elderly, with the average age of patients being 73, and they exhibit a similar incidence rate in both sexes [9]. However, angiosarcomas of the head and scalp are more common in males, while those associated with radiation and lymphedema are more frequently observed in females [10,11]. Despite the endothelial cell origin of these tumors, it is rare for them to arise directly from major blood vessels or the heart. Instead, they can develop in any soft tissue structure or viscera [3,12].

Angiosarcomas can be categorized into five types: cutaneous angiosarcoma, lymphedema-associated angiosarcoma, radiation-induced angiosarcoma, primary-breast angiosarcoma, and soft tissue angiosarcoma [13]. Several risk factors have been well described in the literature (Table 1). Chronic lymphedema is a well-recognized factor in the development of breast angiosarcomas following breast cancer treatment. Similar conditions, such as Milroy disease, chronic infections, and filariasis, have also been associated with the development of angiosarcomas [4,14]. Likewise, radiotherapy is acknowledged as an independent risk factor for angiosarcomas, although the connection between radiotherapy and subsequent angiosarcoma is disputed, with some suggesting that the risk may stem from concurrent lymphedema [10,11,15-17]. Various familial syndromes, including neurofibromatosis, Maffucci syndrome, and Klippel-Trenaunay syndrome, have been linked to angiosarcoma. Additionally, some case reports have identified mutations in BRCA1 and BRCA2 as potential risk factors for angiosarcomas following breast cancer treatment [18]. Carcinogens such as vinyl chloride, thorotrast, androgenic steroids, phenylhydrazine, arsenic, and radium are considered potential etiological agents in visceral angiosarcoma, possibly accounting for up to 25% of cases [19,20]. Other proposed risk factors include ultraviolet radiation, immunocompromised states, arteriovenous fistulas, and xeroderma pigmentosum [21-23].

Histologically, the characteristics of angiosarcomas can vary both within a single case and between different cases. It can be challenging to distinguish the morphological features of a malignant vascular tumor from a benign lesion that exhibits proliferation. However, angiosarcomas typically present with abnormal, pleomorphic, malignant endothelial cells. These cells can take on various shapes, including rounded, polygonal, or fusiform, and often exhibit an epithelioid appearance. In areas where the tumor is well-differentiated, it may mimic hemangiomas or lymphangiomas. Here, atypical epithelial cells or diffuse epithelioid and spindle cell proliferations form functioning vascular sinusoids. As the disease becomes more aggressive, these structures grow more complex, with multilayered endothelial cell lining and the formation of papillary projections. Highgrade tumors often exhibit mitotic activity. Indicators of a poorly differentiated, high-grade tumor include necrosis and hemorrhage, along with continuous sheets of endothelial cells [4,5,23,24].

An immunochemical analysis reveals that angiosarcoma typically expresses endothelial markers such as CD31, CD34, von Willebrand factor, Ulex europaeus agglutinin 1, and vascular endothelial growth factor (VEGF). Of these markers, von Willebrand factor, Ulex europaeus agglutinin 1, and CD31 are particularly useful in distinguishing poorly differentiated diseases. Additionally, the absence of melanocytic markers, including S100, human melanoma black-45, and melanoma antigen, can aid in differentiating angiosarcoma from melanoma [25].

While no specific chromosomal abnormalities have been identified in the development of angiosarcoma, certain somatic gene mutations have been reported. Behjati et al. [26] examined 39 angiosarcoma cases and discovered somatic mutations in PTLR and PLCG1, as well as in KRAS, NRAS, HRAS, PIK3CA, and FTL4. Other research has identified mutations in TP53 and CDKN2A, which were the most frequently altered genes in the study, with half of the cases exhibiting MAPK pathway derangements [27]. In addition, several studies have shown that the amplification of the proto-oncogene MYC is commonly found in radiation-induced angiosarcoma, but not in sporadic types [15,27,28]. This broad spectrum of genetic abnormalities may account for the clinical variability of tumor subtypes. As such, the use of gene-expression microarray technology is crucial for identifying molecular markers, and a multidisciplinary approach is necessary for treatment.

Despite their aggressive nature, angiosarcomas initially present as a bruise, erythematous patch, plaque, or small papule (Fig. 1) [10,24]. Their innocuous clinical appearance often leads to delayed presentation and diagnosis [29]. As the tumor size increases, symptoms such as ulceration, hemorrhage, tissue infiltration, edema, and tumor fungation may occur. The invasion of surrounding structures can result in unclear resection margins, leading to large soft tissue defects following radical resection surgery (Fig. 2) [12,29,30]. The visceral type of angiosarcoma can occur in the spleen, liver, or even the heart. It often presents as an expanding mass associated with pain and discomfort, and rarely with pericardial effusion. Angiosarcomas may also present as pleural disease, hemorrhagic pleural effusion, or pneumothorax due to hematogenous spreading. Other common sites of metastasis include the liver, bone, skin, and regional lymph nodes [3,29,31-33].

Angiosarcomas have a 5-year survival rate that varies between 30% and 56%. Even the most optimistic study indicates that only 60% of patients with localized disease survive beyond 5 years [3,12,31,34]. While there are studies documenting longterm survivors with metastatic disease, they have not been able to identify significant prognostic factors [12]. Numerous studies have sought to uncover the prognostic factors of angiosarcomas. Similar to other aggressive tumor types, age, size, grade, and margin status have been identified as indicators of recurrence and survival [5]. Although angiosarcomas can develop in young patients and even children, it is predominantly a disease of the elderly [35]. A poor prognosis in elderly patients may be due to a longer interval between initial diagnosis and treatment, a more compromised immune system, and a poorer performance status [29]. From the standpoint of tumor biology, a tumor size exceeding 5 cm is associated with worse outcomes [24,36-41]. Tumor depth is another factor linked to a poorer prognosis, but there is no consensus on whether greater tumor depth predicts worse survival or only affects local recurrence [24,31,42]. Other factors that predict a poor prognosis include the metastatic state at presentation and poor patient performance [12,29,43]. Furthermore, the site of origin also influences the prognosis, with angiosarcomas of the liver or other viscera and retroperitoneal disease associated with a worse prognosis compared to cutaneous disease [12].

While there have been no specific randomized clinical trials for angiosarcomas, treatment has been guided by the published guidelines for other soft tissue sarcomas. There has been no evidence-based management available for patients with this rare disease. However, a multidisciplinary approach to treatment is always recommended to manage the disease and enhance survival outcomes. Currently, more clinical trials are being conducted to broaden treatment options and improve patient outcomes.

Angiosarcoma is an extremely rare soft tissue sarcoma, characterized by its complex biology and aggressive nature. For the treatment of angiosarcoma without clear metastasis, a wide margin resection is necessary, coupled with a staged multimodal approach. The use of both radiotherapy and systemic chemotherapy is advisable to enhance outcomes, while antiangiogenic biological therapies may provide specific treatments for angiosarcoma. Further clinical trials, grounded in translational work, hold the potential to significantly influence and clarify treatment strategies.