The pathogenesis of angiosarcoma is poorly understood. The tumor may originate from vascular or lymphatic endothelium or both.⁹ In most cases, it develops de novo without predisposing conditions, although its predilection for sundamaged skin of the head and neck suggests a role for solar damage.⁵ It has been reported to develop 5 to 10 years following radiation therapy for preexisting lesions,¹⁰,¹¹,¹² at sites of chronic lymphedema in Stewart-Treves syndrome,⁸,¹³ and after exposure to some imaging contrast agents and insecticides.⁴,⁸,¹⁴ Four cases of angiosarcoma arising from malignant transformation of benign/vascular malformations have been described.¹⁵ Angiosarcoma has also been associated with xeroderma pigmentosum in six reported cases, possibly related to the nucleotide excision repair defect resulting in defective repair of DNA damaged by ultraviolet and ionizing radiations.¹⁶,¹⁷,¹⁸,¹⁹ Since angiosarcomas are endothelial-cell tumors, it has been suggested that angiogenic factors might be associated with their pathogenesis, which could allow for novel targeted treatment. VEGF and its receptors are overexpressed in angiosarcomas at higher concentrations than in benign vascular or normal tissue controls.²⁰

The cytogenetics of angiosarcomas shows a wide range of nonspecific chromosomal abnormalities including trisomy 5; deletions on chromosome 7p; abnormalities on chromosomes 8, 20, and 22; and loss of chromosome Y.²⁰ No consistent genetic abnormalities are found in cutaneous angiosarcoma, but some cases have mutations in TP53, PTPRB, PLCG1, CDKN2A, or MYC. NUP160-SLC43A3 gene fusion occurs in 36% of cases.²¹

Angiosarcomas usually present as single or multiple benign-appearing bruise-like macules or nodules, often associated with erythema, chronic edema, cellulitis, or even as a hematoma.²²,²³,²⁴,²⁵,²⁶ Occasionally, they may appear as rosacea-like lesions and can simulate localized bacterial or fungal infections.²⁷ When on the eyelid, they may be violaceous, yellow, or flesh colored; may bleed intermittently; and occasionally are associated with pain (Figure 127.1). Demirci and Christanson²⁸ reviewed 22 published cases of eyelid angiosarcoma and noted that 38% presented as an erythematous nodule, 25% as a violaceous maculopapular lesion, 13% as a yellow plaque or infiltrative lesion, and 13% as a yellow nodule. Tumors may be more extensive into deeper tissues, beneath a relatively less conspicuous surface lesion.²⁹

When more advanced, angiosarcomas can become very large, elevated, and even ulcerated (Figure 127.2).³⁰ Because of their variable appearance, definitive diagnosis is often delayed up to 18 months.²⁹ They are often misdiagnosed as more common lesions such as basal cell carcinoma or pyogenic granuloma.⁴ They characteristically spread widely through the skin and soft tissue of the head and neck region, and eyelid tumors may extend into the orbit in about 4% of cases.²⁹,³¹

The differential diagnosis includes ecchymosis, hemangioma, Kaposi sarcoma, xanthelasma, contact dermatitis, lupus-related lesions, intravascular papillary endothelial hyperplasia, angiolymphoid hyperplasia with eosinophilia, and focal infections.