Angiosarcoma, radiation-associated angiosarcoma, and atypical vascular lesion.
In 1994, Fineberg and Rosen3 reported 4 cases of an unusual vascular lesion occurring in mammary skin after radiation, which they named atypical vascular lesion (AVL). Most AVLs resemble lymphangiomas and pursue a benign course. However, they have a tendency to develop further lesions, usually more AVLs. There are also rare reports of AVL progressing to angiosarcoma, usually after multiple recurrences, (4,5) a fact suggesting that AVL may be a precursor to or incipient angiosarcoma. Distinguishing AVL from well-differentiated angiosarcoma in a biopsy specimen can be very challenging. Recently, a vascular-type AVL resembling capillary hemangioma has been reported. (4,6) This article reviews the clinical, morphologic, and immunohistochemical findings in angiosarcoma in general, with special emphasis on radiation-associated angiosarcoma. It also reviews the clinical and morphologic features of AVL, including recent developments and concepts.
The most common clinical presentation of angiosarcoma is a sporadic cutaneous tumor, typically in the scalp or face of an elderly patient. However, angiosarcoma occurs in virtually any anatomic site, including deep soft tissue, breast, visceral organs, and bone. Although most cases are sporadic, important predisposing conditions include radiation (Figure 1), chronic lymphedema (Figure 2), exposure to toxins (eg, vinyl chloride), and foreign bodies (eg, arteriovenous fistulas).
Cutaneous angiosarcoma usually appears as a bruiselike area that often ulcerates or becomes nodular. Cutaneous tumors frequently have small satellite lesions adjacent to the main tumor. Deep-seated tumors have a hemorrhagic spongelike or microcystic appearance (Figure 3), often with necrosis. Angiosarcoma of bone is peculiar in that it frequently presents as multifocal, polyostotic disease (Figure 4).
The histologic spectrum ranges from well-differentiated tumors that mimic benign vascular lesions to poorly differentiated tumors that present as undifferentiated malignant neoplasms. Well-differentiated angiosarcoma consists of irregular interanastomosing channels that infiltrate surrounding tissue (Figure 5, A). Cytologic features can be deceptively bland in some cases. However, hyperchromasia, mild pleomorphism, prominent nucleoli, mitotic figures, or multilayering are usually present (Figure 5, B). Within dermis, well-differentiated angiosarcoma entraps and surrounds collagenous stroma to form intraluminal papillary structures (Figure 5, C). Atypical lymphatic and/or capillary proliferations are frequently present at the periphery of an angiosarcoma, at times making assessment of surgical margins difficult.
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Moderate and poorly differentiated angiosarcomas have very heterogeneous cytoarchitectural features. The cytologic appearance can be epithelioid, spindled, or pleomorphic (Figure 6, A through C), while the architecture can be vasoformative, sievelike, kaposiform, or solid (Figure 7, A through D). Various combinations of patterns and degrees of differentiation can be present within a single tumor. Often, well-differentiated angiosarcoma is found adjacent to poorly differentiated angiosarcoma, suggesting tumor progression.
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Poorly differentiated angiosarcoma often presents as an undifferentiated malignant neoplasm and immunohistochemistry is often necessary to confirm the diagnosis. CD31 is the single best marker with high sensitivity and specificity. CD31, however, is not always the cleanest marker and can show low-level staining in other tumors as well as frequent background blush. It also stains macrophages. (7) By contrast, angiosarcoma usually has a diffuse, intense staining reaction for CD31, often with accentuation of the cytoplasmic membrane (Figure 8). CD34 and factor VIII are also expressed in most angiosarcomas, but less frequently in poorly differentiated tumors. Aberrant cytokeratin staining is an important pitfall in angiosarcoma, especially in epithelioid angiosarcoma, found in 35% of cases in 1 study. (8) However, it is usually focal. Most carcinomas, by contrast, are CD312. Thus, poorly differentiated angiosarcoma can be misdiagnosed as carcinoma with an overly limited panel of antibodies.
Clinically, angiosarcoma is very aggressive, and most patients die because of disseminated disease. Because it is highly infiltrative, beyond its clinically apparent extent and often multifocal, local control is fraught with a high failure rate. Although grading has been shown to have prognostic relevance in breast tumors, (9) most angiosarcomas have a poor outcome, regardless of grade. Recently, Deyrup et al10 showed that prognosis in sporadic cutaneous angiosarcoma correlates with high- and low-risk groups, on the basis of age, epithelioid histology, necrosis, and tumor depth.
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The clinical behavior and morphologic features of radiation-associated angiosarcoma are comparable to those of sporadic angiosarcoma. (11) Compared to the latency of other radiation-associated sarcomas, that for breast angiosarcoma is relatively short (5-7 years), with some patients presenting with the tumor within 3 years, thus challenging the 3-year rule. (11) Compared to sporadic mammary angiosarcoma, which usually arises in the parenchyma, radiation-associated angiosarcoma is usually cutaneous. Clinically, it presents as an erythematous plaque, patch, or nodules, often with edema, and evokes a differential diagnosis that includes inflammatory carcinoma or an infectious etiology. Tumors often present with diffuse, extensive involvement of the breast (Figure 1). Median size is around 7.5 cm, (5) and multifocality is common. (11) Most tumors are high grade. However, low- and intermediate-grade tumors have also been described. (5,11) While overall the prognosis for patients with radiation-associated angiosarcoma is bad, with high rates of local and distant recurrence, some studies have suggested a poorer prognosis, (11) while others a more favorable outcome. (5)
ATYPICAL VASCULAR LESION
Atypical vascular lesion usually presents as 1 or more small, flesh-colored papules or erythematous patches that arise in radiated skin. Microscopically, most resemble lymphangioma, comprising a relatively well-demarcated proliferation of thin-walled, often dilated, interanastomosing channels devoid of erythrocytes and lined by attenuated or hobnail endothelial cells without atypia (Figure 9, A and B). Some resemble benign lymphangioendothelioma (Figure 10, A), others lymphangioma circumscriptum (Figure 10, B), and some have features of both. (12) Most AVLs are limited to superficial and mid dermis. However, examples involving deep dermis and subcutis4 have been described. Although most pursue a benign course, they tend to develop further lesions, usually more AVLs. There are rare reports of progression to angiosarcoma, usually after multiple recurrences, (4,5) a fact suggesting that AVL may be a precursor to or incipient angiosarcoma. Current recommendation is that AVLs should be completely excised and the patient closely followed up for any new lesions. (12)
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In 2005, Di Tommaso and Rosai (6) reported 3 cases of a lobular capillary proliferation in mammary skin after radiation. All 3 patients either had or subsequently developed angiosarcoma. Thus, the spectrum of vascular lesions was expanded to include vascular-type AVL (Figure 11). Recently, Patton et al4 detailed their experience with 8 cases of vascular-type AVL, including several lesions with atypia and 1 that progressed to angiosarcoma. They suggest that vascular-type AVL is more likely to progress than the more common lymphatic-type AVL.
Distinguishing well-differentiated angiosarcoma from AVL can be very challenging in a small sample such as that obtained from a punch biopsy. Because areas within and adjacent to angiosarcoma can be indistinguishable from AVL--both lymphatic and vascular types--it is essential to correlate biopsy results with clinical findings. Size is especially important in this regard since most AVLs are small (median, 0.5 cm), while angiosarcomas are usually much larger (median, 7.5 cm). (5)
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(3.) Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol. 1994;102(6):757-763.
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(10.) Deyrup AT, McKenney JK, Tighiouart M, Folpe AL, Weiss SW. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg Pathol. 2008;32(1):72-77.
(11.) Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol. 2004;28(6):781-788.
(12.) Gengler C, Coindre JM, Leroux A, et al. 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. 2007;109(8):1584-1598.
David R. Lucas, MD
Accepted for publication May 27, 2009.
From the Department of Pathology, University of Michigan, Ann Arbor.
The author has no relevant financial interest in the products or companies described in this article.
Presented at New Frontiers in Pathology: An Update for Practicing Pathologists, University of Michigan, Ann Arbor, September 20, 2008.
Reprints: David R. Lucas, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Room 2G332, Ann Arbor, MI 48109 (e-mail: firstname.lastname@example.org).
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|Author:||Lucas, David R.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2009|
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