Angiosarcomas are aggressive endothelial cell tumors of vascular origin that account for 1% to 2% of all soft tissue sarcomas in the United States.1,2 They can affect any organ in the body but most commonly affect the skin and soft tissue. Cutaneous angiosarcoma (CAS) is a rare type of skin cancer that can present in 2 forms: primary and secondary. The primary form lacks a known underlying cause, but secondary CAS commonly is linked to prior radiation therapy of the breast as well as lymphedema of the breast and arm. Secondary CAS may require different treatment than primary CAS, as radiation therapy poses risks to patients with radiation-induced CAS.3 The prognosis of CAS is poor due to delayed diagnosis. Current treatment modalities have a high rate of local recurrence and/or distant metastasis, but recent advances in surgery and other therapies such as radiation and immunotherapy provide hope for more successful disease control.
Dermatologists may be responsible for the initial diagnosis and management of CAS. They must be familiar with its presentation, as this condition can be difficult to diagnose and mimics other diseases. Additionally, dermatologists must understand the role of varying treatment modalities including Mohs micrographic surgery (MMS) in the management of CAS. This review will provide an overview of the epidemiology, presentation, and pathologic features of CAS and will discuss both emerging and existing treatments.
Epidemiology
Cutaneous angiosarcoma may present in various locations in the body, predominantly on the head and neck.4,5 Approximately 85% of cases arise in patients older than 60 years, and most of these patients are White men.1,4,5 The risk factors for the development of CAS include prior radiation exposure; chronic lymphedema (ie, Stewart-Treves syndrome); and familial syndromes including neurofibromatosis 1, BRCA1 or BRCA2 mutations, Maffucci syndrome, and Klippel-Trenaunay syndrome. Exogenous exposure to toxins such as vinyl chloride, thorium dioxide, or anabolic steroids also is associated with angiosarcoma, primarily in the form of visceral disease such as hepatic angiosarcoma.6
The average tumor size is approximately 4 to 5 cm; however, some tumors may grow larger than 10 cm.7,8 Metastasis through hematogenous or lymphatic spread is fairly common, occurring in approximately 16% to 35% of patients. The lungs and liver are the most common sites of metastasis.9,10 The age-adjusted incidence rate of CAS is decreasing for patients younger than 50 years, from 1.30 in 1995 to 2004 to 1.10 in 2005 to 2014, but increasing for individuals older than 70 years, from 2.53 in 1995 to 2004 to 2.87 in 2005 to 2014.4 The incidence of angiosarcoma also has grown in the female population, likely due to the increasing use of radiotherapy for the treatment of breast cancer.11
The high rates of CAS on the head and neck may be explained by the increased vascularity and UV exposure in these locations.12 In a Surveillance, Epidemiology, and End Results population-based study (N=811), 43% of patients with CAS had a history of other malignancies such as breast, prostate, genitourinary, gastrointestinal tract, and respiratory tract cancers.4 Cutaneous angiosarcoma can develop secondary to the primary cancer treatment, as seen in patients who develop CAS following radiation therapy.11
The underlying mechanism of CAS is believed to involve dysregulation of angiogenesis due to the vascular origin of these tumors. Studies have identified overexpression of vascular endothelial growth factor (VEGF), TP53 mutations, and RAS pathway mutations as potential contributing factors to the pathogenesis of angiosarcoma.6 Molecular differences between primary and secondary angiosarcomas are not well documented; however, radiation-associated CAS has been found to have higher expression of LYN and PRKCΘ, while non–radiation-induced lesions express FTL1 and AKT3.2 Chromosomal abnormalities have been identified in a small set of primary CAS patients, but the specific role of these abnormalities in the pathogenesis of CAS remains unclear.7
Prognosis
Cutaneous angiosarcoma has a poor prognosis, with 3-year disease-specific survival rates as low as 40% and 5-year rates as low as 17%.4,5,13,14 Survival rates increased from 1985 to 2014, likely due to earlier diagnoses and more effective treatments.4 Several factors are associated with worse prognosis, including metastatic disease, increasing age, scalp and neck tumor location, tumor size greater than 5 cm, necrosis, multiple skin lesions, and nodular and epithelioid morphology.4,5,10,13-16 Factors including sex, race, and presence of another malignancy do not affect survival.4,5 Prognosis in CAS may be evaluated by TNM tumor staging. The American Joint Committee on Cancer Staging Manual (8th edition) for soft tissue sarcoma (STS) commonly is used; however, CAS is not included in this staging system because it does not share the same behavior and natural history as other types of STS. This staging system provides separate guidelines for STS of the head and neck and STS of the extremities and trunk because of the smaller size but paradoxically higher risk for head and neck tumors.17 Given that there is no agreed-upon staging system for CAS, prognosis and communication among providers may be complicated.