Angiosarcoma

Definition

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 493
• Sabiston Textbook of Surgery, 14e

Epidemiology

• Peak incidence in the 7th and 8th decades; older adults predominate
• Male:female ratio ~2:1 for cutaneous head-and-neck form
• Most common sites (decreasing order): skin > soft tissue > breast > liver > spleen
• ~20% of patients present with distant metastasis at diagnosis
• ~40% of all angiosarcomas are radiation-associated

Pathogenesis and Risk Factors

Molecular Biology

• MYC amplification is the molecular hallmark of secondary (post-radiation and post-lymphedema) angiosarcoma - it is absent in primary cutaneous angiosarcoma and in atypical vascular lesions (AVL), making it a key discriminator
• KDR (VEGFR2) activating mutations have been identified in human angiosarcomas
• High Ki-67 proliferation index is characteristic

Pathology

Gross

• Ill-defined, dark-brown/hemorrhagic mass; often multifocal
• In the heart/right ventricle: appears as a large, dark, infiltrating mass (see image A below)

Histology

• Well-differentiated: irregular vascular channels in dermis lined by atypical endothelial cells with enlarged, pleomorphic nuclei
• Poorly differentiated: solid sheets of epithelioid cells, increased cellularity, nuclear atypia, high mitotic activity; subtle infiltration between collagen bundles producing "crack-like" spaces with hyperchromatic nuclei

Immunohistochemistry (IHC)

• CD31 - most consistent and specific
• CD34
• FLI-1 (transcription factor)
• ERG (endothelial transcription factor)
• Podoplanin (D2-40) - positive in most malignant vascular tumors
• Ulex europaeus lectin
• c-MYC nuclear staining - helps distinguish radiation-induced angiosarcoma from AVL

Clinical Presentation

Cutaneous (Head/Neck - most common)

• Poorly defined bluish macule on the scalp/face of elderly men - easily mistaken for a bruise
• Distinguishing features: peripheral erythematous ring, satellite nodules, spontaneous bleeding, intratumoral hemorrhage
• Progressive asymmetric enlargement with indurated bluish nodules/plaques
• Sudden thrombocytopenia may herald metastasis or rapid tumor expansion
• Multicentricity and early metastasis are hallmarks; most patients die within 2 years
• Prognosis worse in men >70

Stewart-Treves Syndrome

• Angiosarcoma in chronic lymphedematous upper arm after mastectomy
• Mean survival 19-31 months; 5-year survival ~6-14%
• Lung metastases are the most frequent cause of death
• Early amputation offers the best prognosis

Spread and Prognosis

• Locally invasive with early hematogenous metastasis
• Lung is the most common metastatic site; breast angiosarcoma may spread to liver
• Overall 5-year survival: 10-30% (Robbins)
• 5-year disease-specific survival for resectable disease: ~53% (Sabiston)
• Stage IV median survival: 8-12 months

Management

Surgery

• Wide resection with negative margins (at least 2 cm of normal tissue) is the mainstay
• Tumors microscopically extend well beyond gross margins
• Radiation-associated breast angiosarcoma: mastectomy including all irradiated skin (vs. simple mastectomy - dramatically reduces local recurrence from 76% to 23% and improves 5-year DSS from 46% to 86%)
• Stewart-Treves: amputation

Radiation Therapy

• Adjuvant radiotherapy for head/neck and scalp angiosarcomas (high locoregional recurrence)
• Cannot use for radiation-induced tumors

Systemic Therapy (Palliative/Metastatic)

Key Points to Remember

1. Malignant endothelial neoplasm - arises from blood/lymphatic vessel endothelium
2. Four clinical settings: sporadic head/neck, Stewart-Treves (lymphedema), post-irradiation, chemical (hepatic)
3. MYC amplification = molecular hallmark of secondary (radiation/lymphedema-associated) angiosarcoma
4. IHC: CD31 + CD34 + FLI-1 + ERG (confirm endothelial origin); c-MYC distinguishes radiation-induced from AVL
5. Paclitaxel is first-line systemic therapy; doxorubicin and pazopanib are alternatives
6. Overall poor prognosis: 5-year survival 10-30%; stage IV median survival 8-12 months
7. Wide surgical margins critical - tumors extend microscopically well beyond gross disease

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease | Sabiston Textbook of Surgery, 14e | Andrews' Diseases of the Skin, 12e | Fitzpatrick's Dermatology, 9e