Cutaneous angiosarcoma is an uncommon malignant tumor of vascular endothelial cells that most often affects the elderly and has a very poor prognosis. Although it may affect any area of the body, the most common areas of involvement are the face and scalp. Surgical excision, often followed by high-dose radiotherapy, represents the current standard of care, but recurrence remains frequent, and many patients develop the systemic disease. The cytotoxic chemotherapy effects partial response in metastatic disease, but is far from optimal. Targeted therapy with inhibitors of vascular epithelial growth factor (VEGF) and its receptor (VEGFR), or with tyrosine kinase inhibitors, has shown some efficacy and agents of this type may represent some promise for the future in treating this condition.
The etiology of cutaneous angiosarcoma remains unknown, but the vast majority of cases arise in sun-exposed skin, mainly the scalp and face, in elderly patients. Chronic or congenital lymphedema, chronic radiodermatitis, and immunosuppression can predispose patients to the development of angiosarcoma in other locations. Most radiation-induced angiosarcoma occurs in the breast. Angiosarcoma may also arise in areas of chronic lymphedema, and in this setting is called Stewart-Treves syndrome. The association between angiosarcoma and chronic lymphedema is clear, but the mechanism of this association remains uncertain. Radiation therapy is an independent risk factor for the development of angiosarcoma and pathogenesis has been linked to amplification of MYC and FLT4 genes.
Angiosarcomas account for less than one percent of all sarcomas and have a predilection for the skin and superficial soft tissue, whereas most sarcomas are found in deeper tissues. Adults, especially elderly patients, are most often affected by cutaneous angiosarcoma with a male to female ratio of 3 to 1, and Caucasians are affected more frequently than individuals of African or Asian descent.
The pathogenesis of angiosarcomas is largely unknown. Tumor histology varies widely and ranges from well-differentiated variants, appearing very similar to benign vascular neoplasms, to poorly differentiated neoplasms that are difficult to discern from other malignant neoplasms. More banal tumors are comprised of clonal proliferations of endothelial cells that line blood vessels and lymphatics. Angiosarcomas typically do not have a capsule or well-defined histologic margins, in contrast to benign vascular growths. Less-differentiated lesions may require immunohistochemical studies for diagnosis. Most tumors stain with endothelial markers such as CD31, CD34, von Willebrand factor, agglutinin 1 and vascular epithelial growth factor. The best marker with high sensitivity and specificity is CD31.
The typical presentation is an ill-defined, expanding erythematous to a violaceous plaque on the scalp and face of an elderly patient. Lesions can resemble a bruise and are often subtle and asymptomatic, which can lead to a delay in medical treatment. As these lesions progress, they may assume a more thickened, nodular surface and ulceration or bleeding. Left untreated, angiosarcomas may assume significant diameter. Satellite lesions are also common. Less commonly, angiosarcoma can occur in areas of chronic lymphedema or areas treated with radiation therapy.
Angiosarcoma has a very aggressive course, with the lymphatic or vascular spread. Metastases most commonly occur in the lungs, followed in incidence by the liver, bone, soft tissue, and lymph nodes. Metastases may occur years after initial treatment, and most patients succumb to the effects of the systemic disease.
Skin biopsy should be performed for diagnosis. Well-differentiated cutaneous angiosarcoma will demonstrate numerous irregular vascular channels lined by endothelial cells. Poorly differentiated cutaneous angiosarcoma will demonstrate sheets of spindle cells or epithelioid shaped cells with increased mitotic activity and poorly formed vascular spaces. Immunohistochemistry is positive for CD31 especially, and CD34 in the majority of cases. MRI can greatly aid particularly in angiosarcoma of the scalp in delineating the extent of the primary neoplasm. Involvement often extends significantly beyond clinical margins. CT with contrast is helpful in identifying nodal involvement and lung metastases.
Patients diagnosed with cutaneous angiosarcoma benefit from a multidisciplinary approach to treatment. These tumors are difficult to treat, and recurrences are common. Historically, wide surgical excision is the treatment of choice, yet local recurrence rates of 72% to 84% have been reported. Wide excision is often difficult due to the size of many of these lesions and their common occurrence in areas where the extensive surgery will result in substantial functional impairment and wounds that are extremely difficult to reconstruct. Mohs micrographic surgery has been considered as the treatment for cutaneous angiosarcoma as it is a tissue-sparing procedure that provides complete margin evaluation; however, its efficacy depends on the contiguous growth of tumors. Unfortunately, angiosarcomas are believed to demonstrate a noncontiguous growth pattern commonly, and for this reason, most dermatologic surgeons do not attempt to treat angiosarcomas with the Mohs technique.
Adjuvant radiotherapy is often employed primarily in an attempt to decrease chances of recurrence, and it has been shown to moderately improve prognosis. High doses of radiation are administered over a large field, often irradiating the entire scalp for cases of angiosarcoma in that location.
Continuous chemotherapy with docetaxel and/or paclitaxel has shown to improved disease-specific survival and event-free survival, but that improvement is limited, and side effects of these drugs in usual elderly patients often is not tolerable for long periods. Monotherapy with propranolol has been reported to reduce the proliferative index of cutaneous angiosarcoma. Combined treatment with propranolol, paclitaxel, and radiotherapy led to substantial regression of a facial angiosarcoma in one patient. Targeted biologic therapy with bevacizumab and imatinib have been reported to treat cutaneous angiosarcoma with variable success. In one study of the vascular epithelial growth factor-A monoclonal antibody, bevacizumab, eleven of 23 patients (57%) showed either partial response or stabilization of disease.
Cutaneous angiosarcomas are difficult to treat given their aggressive behavior and high recurrence rate, with almost half of cases having local or distant metastases at the time of diagnosis. Metastasis often occurs in the lung, liver, lymph nodes, soft tissues, brain, and bone. The majority of patients present with local disease, but 20% to 40% have distance disease when first seen. Five-year survival for angiosarcoma is approximately 30%. For patients presenting with systemic disease, median survival is seven months.
Surgical excision, followed by high-dose, wide-field radiotherapy, represents the current standard of care, but many patients progress to widespread disease. Cytotoxic chemotherapy with anthracyclines, taxanes, and ifosfamide are employed in disseminated disease, with partial effect. Ongoing studies with agents that target the vascular epithelial growth factor receptor hold promise for more effective treatment in the future.