October 2008: A 70 y.o. man with multiple scalp nodules

History: A 70 year old man presented with an approximately 12 cm region of red-orange discoloration of the skin over the left scalp. He underwent a left radical excision with parotidectomy and neck dissection. The excised specimen showed an ill-defined and hemorrhagic mass measuring 9 cm in greatest dimension.

Microscopically, the tumor was poorly circumscribed and composed of complex, irregularly anastamosing vascular channels dissecting between dermal collagen fibers (Fig. 1,2,3). The vascular channels were lined by pleomorphic endothelial cells showing irregular, enlarged nuclei with prominent nucleoli and increased mitotic activity. Some areas showed multilayering and tufting of the endothelial cells lining the vascular channels. Metastatic tumor was identified in 3 regional lymph nodes.

Diagnosis: “Cutaneous angiosarcoma, metastatic to lymph nodes”

Yvonne Noronha MD, Donald R Chase, MD
Department of Pathology and Human Anatomy, Loma Linda University and Medical Center, Loma Linda, CA
California Tumor Tissue Registry, Loma Linda, CA.

Discussion: Angiosarcomas, also known as hemangiosarcoma, lymphangiosarcoma and malignant hemangioendothelioma are malignant tumors of lymphatic or vascular endothelium characterized by an atypical, multilayered or solid endothelial proliferation and a vasoformative architecture. They are one of the rarest forms of cutaneous and soft tissue neoplasms comprising less than 1% of all sarcomas.

Classically, skin and soft tissue angiosarcomas occur in 3 main forms:
• in the head and neck region of elderly males
• less often, in a lymphedematous limb, usually following radiation for breast cancer (Stewart-Treves syndrome)
• Post radiation angiosarcoma which is recognized by its shorter latency period and lack of association with lymphedema

Clinically the lesions vary from small reddish-brown papules or bruise-like lesions to large echymotic plaque-like lesions.

Histologically, the appearance varies depending on the degree of differentiation even within the same lesion. Well differentiated lesions, as in our case, are characterized by complex, irregularly anastamosing, dissecting vascular channels lined by pleomorphic endothelial cells showing nuclear atypia, increased mitotic activity and multilayering often with tufts or papillae. With increasing anaplasia tumor cells become more atypical, more closely-packed and often have spindled cells with loss of vascular channels, resembling a spindle cell sarcoma (nos). Some cases of angiosarcoma show a prominent lymphocytic infiltrate, a finding which has been suggested as a favorable prognostic indicator.

A rare variant of cutaneous angiosarcoma is the epithelioid angiosarcoma composed of sheets of rounded epitheloid cells with abundant pink cytoplasm, vesicular nuclei and prominent nucleoli. Irregular vascular channels are not usually seen but the epithelioid cells may exhibit intra-cytoplasmic vacuoles as an expression of early luminal differentiation and the tumor may be keratin positive.

Most angiosarcomas are positive for CD31, the preferred endothelial marker, as well as for less specific markers such as CD34 and Factor VIII. The differential diagnosis includes:

• Benign hemangiomas which are usually well circumscribed and do not show a complex anastamosing pattern. Endothelial multi-layering as well as atypia are absent, and they maintain an arborizing “tree-like” pattern of vascularity with central “feeders” and peripheral lobular capillaries.

• Atypical vascular lesions which may be seen following radiation usually present as smaller circumscribed papules. Histologically, there is an anastamotic growth pattern of vascular channels within the dermis with focal dissection of dermal collagen. In contrast to angiosarcoma, they appear circumscribed and relatively wedge shaped and do not extend to the subcutaneous tissue. While the endothelial cell nuclei may be prominent and hyperchromatic, no significant cytologic atypia, multilayering, mitotic activity or necrosis is seen. The lesions behave in a benign fashion.

• Malignant spindle cell neoplasms including metastatic carcinoma, melanoma and other sarcomas can be distinguished from poorly differentiated angiosarcomas by immunohistochemistry, especially CD31 which is the most sensitive endothelial marker.

• Epithelioid hemangioendothelioma may be a difficult diagnosis but can be distinguished from epithelioid angiosarcomas by its well-formed canalized vessels, its often lobular architecture, and by its characteristic intracytoplasmic vacuoles. Epithelioid angiosarcomas also tend to grow in diffuse sheets, the tumor cells being larger with more prominent amphophilic nucleoli.

Course and prognosis: Angiosarcomas, as a group, are very aggressive tumors with a high metastatic rate. The most consistent factor favoring a somewhat better prognosis is tumor size less than 5 cm. Histologic appearance or grade are not reliable prognostic indicators, except in mammary angiosarcomas. Evaluation in rapid frozen sections is particularly difficult as determination of infiltrative patterns may not be possible.

Suggested Reading:

1. Tumors of the soft tissues, Third series, fascicle 30

2. Enzinger and Weiss, Soft Tissue Tumors, 5th edition.

3. Billings, Steven D; McKenney, Jesse K; Folpe, Andrew L; Hardacre, Michael C; Weiss, Sharon W. Cutaneous Angiosarcoma Following Breast-conserving Surgery and Radiation: An Analysis of 27 Cases. Am J Surg Pathol 28(6):781-788, 2004.

4. Brenn, Thomas; Fletcher, Christopher D. M. Radiation-Associated Cutaneous Atypical Vascular Lesions and Angiosarcoma: Clinicopathologic Analysis of 42 Cases. Am J Surg Pathol 29(8):983-996, 2005.

5. Requena L, Santonja C, Stutz N, Kaddu S, Weenig RH, Kutzner H, Menzel T, Cerroni L. Pseudolymphomatous cutaneous angiosarcoma: a rare variant of cutaneous angiosarcoma readily mistaken for cutaneous lymphoma. Am J Dermatopathol. 29(4):342-50, 2007.

6. Gengler C, Coindre JM, Leroux A, Trassard M, Ranchère-Vince D, Valo I, Michels JJ, Guillou L. Vascular proliferations of the skin after radiation therapy for breast cancer: clinicopathologic analysis of a series in favor of a benign process: a study from the French Sarcoma Group. Cancer 109(8):1584-98, 2007.

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