Case 2 -

Sporadic Cutaneous Angiosarcoma, High Risk for Aggressive Behavior Andrea T. Deyrup Emory University Atlanta, GA

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Diagnosis Sporadic Cutaneous Angiosarcoma, High Risk for Aggressive Behavior. Clinical History: The patient is a 45 male who presented with a 1.8 x 1.7cm bump on his forehead. Clinically this was thought to be a cyst. Past medical history and clinical examination were noncontributory. The lesion was biopsied and then excised. The images are from the resection specimen. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 The tumor extends from the deep reticular dermis to subcutaneous tissue and displays a vaguely nodular architecture. Case 2 - Figure 2 Higher magnification view of the tumor. Case 2 - Figure 3 The nodules are composed of sheets of spindled cells aranged in short fascicles. Intratumoral and peripheral collections of lymphocytes can be appreciated. Case 2 - Figure 4 The tumor cells have indistinct cell borders, lightly eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. Case 2 - Figure 5 Focally, tumor cells dissect through dermal collagen forming anastamosing channels. Case 2 - Figure 6 Tumor cells are negative for S100 protein. Case 2 - Figure 7 Tumor cells are negative for cytokeratin AE1/AE3 Histologic Findings: The tumor extends from the deep reticular dermis to the subcutaneous tissue and displays a vaguely nodular architecture, most evident at the periphery. The nodules are composed of sheets of spindled cells arranged in short fascicles with indistinct cell borders, lightly eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. Focally, a vasoformative pattern consisting of anastomosing vessels dissecting through collagen can be appreciated. Mitotic activity is brisk and there are foci of necrosis. A peripheral lymphocytic response is evident. Immunohistochemical Studies The tumor cells are positive for CD31 and Fli-1 and negative for CD34, cytokeratins AE1/AE3 and S100 protein. Discussion Angiosarcomas occur in diverse clinical settings that are best conceptualized as several different diseases, united by certain common histologic features, rather than as a single disease entity. Well recognized forms of angiosarcoma include 1) cutaneous angiosarcoma occurring in sun-exposed skin ("sporadic" cutaneous angiosarcoma), [8] 2) cutaneous angiosarcoma arising in lymphedema (e.g. Stewart Treves syndrome), [10] 3) angiosarcoma of deep soft tissue, [7] 4) radiation-induced angiosarcoma [1, 2] and 5) angiosarcoma associated with foreign material. [5] Clinical presentation, patient demographics, prognostic factors and treatment considerations show some overlap; however, subclassification according to type is necessary for clearest interpretation of data. Sporadic cutaneous angiosarcomas (SCA) primarily affect older male patients (1.5M:1F; mean 69 years) and typically arise in the head and neck (~70%) and trunk (~20%). [3] Patients present with a several month history of enlarging red to violaceous plaques or papules that may be multifocal. [8] The lesions may be mistaken for "bruises" and delay in diagnosis is not uncommon. Grossly, cutaneous angiosarcomas are ill-defined, hemorrhagic lesions. Microscopically, several different histologic patterns can be seen in SCA. The most easily recognized appearance consists of anastomosing thin-walled blood vessels lined by enlarged, hyperchromatic endothelial cells that dissect through the dermal collagen and around adnexal structures. The endothelial cells may display stratification and tufting into the vascular lumen. At the other extreme, cutaneous angiosarcomas may be composed almost entirely of solid sheets of epithelioid to spindled cells. "Epithelioid", in this context, implies a polygonal cell shape, abundant eosinophilic cytoplasm, and oval to round nucleus with prominent nucleoli and irregular nuclear membranes. As such, epithelioid angiosarcomas are cytologically high grade. The third histologic pattern consists of a mixture of the vasoformative and solid appearances. The incidence of these 3 patterns depends somewhat on referral patterns: in our experience, the solid pattern was most common as opposed to Morgan and colleagues who reported a larger percentage of vasoformative tumors. [8] In all three histologic variants, mitotic activity is usually brisk and foci of necrosis may be seen. Depending on the particular morphology of each case, the differential diagnosis for SCA includes benign vascular lesions, Kaposi sarcoma, carcinoma, atypical fibroxanthoma/superficial malignant fibrous histiocytoma (MFH), and melanoma. Distinguishing a well-differentiated angiosarcoma from a benign vascular lesion can be quite difficult. Clues to a diagnosis of malignancy include diffuse permeation of the surrounding tissue, infiltration of tumor cells through dermal collagen, endothelial stratification and hyperchromatic, atypical cells. Sporadic cutaneous angiosarcomas that are primarily spindled may mimic a sarcomatoid squamous cell carcinoma; fortunately, unlike epithelioid angiosarcomas which may express cytokeratins, this antigen is rarely seen in spindled SCA. Kaposi sarcoma also enters the differential diagnosis in spindled SCA and can be excluded by the minimal cytologic atypia seen in that entity, as well as a positive immunohistochemical stain for HHV-8. Poorly differentiated angiosarcomas may be interpreted as atypical fibroxanthoma/superficial malignant fibrous histiocytoma. However, that is a diagnosis of exclusion and should only be made once the appropriate immunohistochemical panel has been evaluated. In addition, the frequent association of hemorrhage with angiosarcoma and focal vasoformation aid in diagnosis. Predominantly epithelioid and/or solid angiosarcomas raise a differential diagnosis of poorly differentiated carcinoma or melanoma. Carcinoma being much more common than angiosarcoma, it is easy to interpret a positive cytokeratin stain as evidence of epithelial differentiation. A negative panel of melanocytic markers generally excludes melanoma. However, a reasonable degree of suspicion and willingness to perform endothelial immunostains are important when epithelial or melanocytic stains are equivocal. Cutaneous angiosarcoma expresses the usual endothelial markers including CD31, CD34, and Fli-1. It is important to recognize, however, that histiocytes are also positive for CD31 and intralesional histiocytes can lead to misdiagnosis of a vascular neoplasm. [6] Grading in Cutaneous Angiosarcomas Histologic grade, as determined by established grading criteria, does not appear to correlate with clinical behavior in cutaneous angiosarcomas. [4, 8] . By multivariate analysis, Morgan and colleagues determined that tumor diameter, depth of invasion, and positive margins correlated with survival. Recently, we have shown that the presence of epithelioid morphology and/or necrosis is associated with a worse prognosis: patients without these two features ("low risk for aggressive behavior) had a 3-year survival of 77% compared to 24% for patients with either of these histologic findings ("high risk of aggressive behavior"). [3] Clinical Considerations Complete surgical excision is the recommended primary therapy for cutaneous angiosarcomas. [9] However, due to the infiltrative, ramifying nature of these tumors and frequent multifocality, it may be nearly impossible to achieve negative surgical margins, particularly in anatomically constrained sites such as the head and neck. Adjuvant radiation therapy has been shown to reduce mortality in cutaneous angiosarcomas in these tumors. Cutaneous angiosarcomas most commonly metastasize to lymph node and lung. Cause of death may be metastatic disease or disease progression. Follow-Up Due to the presence of necrosis in the current case, this patient would be considered high risk. In fact, 2 years after diagnosis, the patient presented with lung metastases. He received 6 cycles of d oxorubicin and paclitaxel and is currently disease-free (2 years after final chemotherapy treatment). Think outside the box: use a broad range of immunohistochemical stains if the diagnosis eludes you. Criteria for prognosis continue to evolve: keep up to date on the literature. 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