ANGIOSARCOMA OF THE BREAST



“A 35 year-old Woman with a Lump in the Breast”

California Tumor Tissue Registry’s

Case of the Month

CTTR COTM Vol 7(3), 2004

December, 2004

During a routine physical examination, a 35 year-old woman was found to have a lump in her right breast. Following a needle biopsy, a modified radical mastectomy was performed.

The 550 gram, 17.0 x 17.0 x 10.0 cm breast resection contained a 4.5 x 3.5 x 3.5 cm poorly circumscribed indurated red-tan mass.

The tumor was microscopically composed of anastomosing vascular channels lined by mildly atypical endothelial cells (Fig. 1). Focal areas showed more proliferative activity, and increased cellularity (Fig. 2). Scattered regions demonstrated ‘tufting’ and focal papillary growth (Fig 3). Mitotic figures were present, but rare (Fig. 4). Some lobularity was retained, but these areas were scattered, and had an infiltrative perimeter. The tumor periphery was infiltrative into the surrounding fat (Fig. 5).

Diagnosis: “Angiosarcoma of the breast, Intermediate-grade / type 2”

Sajjad P Syed, MD, and Donald R Chase, MD

Loma Linda University Medical Center

Loma Linda, California

Angiosarcoma (AS, aka hemangiosarcoma, hemangioendothelioma, hemangioblastoma, angioblastoma and benign metastasizing hemangioma) is a rare, highly lethal neoplasm accounting for < 0.05% of primary mammary cancers. It is exceptionally rare in males, with only five reported cases, but in females, it has been described as occurring between the ages of 14 and 82 years, at a rate of one for every 2000 – 3500 “traditional” breast cancers 1. Patients diagnosed during pregnancy tend to have high-grade tumors, and ultimately, an exceptionally bad prognosis3.

AS has an insidious clinical onset and usually presents as a painless, discrete mass that grows rapidly and may, in rare incidences, acquire large proportions. Twelve percent of patients present with diffuse enlargement of the breast. Although the breast surface usually is unremarkable, a bluish red discoloration has been described. Nipple retraction, discharge, or axillary node enlargement are generally absent. Bilateral tumors have been reported 5 particularly in association to pregnancy and in postmenopausal women 6,7. On mammography, the lesion is ill-defined and displays a ‘soap bubble’ appearance 8, with a mean size of around 4 cm 9. False negative results however have been reported, and in a series of 29 cases, 33% were missed on mammography (9). Sonography usually can confirm a solid, well defined, lobulated mass with both hyperechoic and hypoechoic signals, which generally show no acoustic shadowing 10. MRI shows the presence of vascular channels containing slow-flowing blood 9. Because patients with angiosarcoma in one breast may develop asynchronous contralateral lesions, MRI of the opposite breast should is suggested at the time of diagnosis, and periodically during follow-up 3.

Postmastectomy angiosarcoma of the chest wall has been described in patients who received postoperative radiotherapy in this anatomic region 3, furthermore, virtually all sarcomas that have occurred in the mammary gland after breast-conservative surgery and irradiation for carcinoma have been angiosarcomas 11-17, and most occur within 6 years after radiotherapy. Postradiation angiosarcoma of the breast has a variety of presentations; thus diagnosis is often delayed 18. The estimated risk of cutaneous or parenchymal angiosarcoma of the breast after breast conservation and radiation for carcinoma is 0.3% to 0.4% 17,19 . The prognosis of postradiation angiosarcoma of the breast parenchyma or skin of the breast is influenced by the tumor grade and is most favorable in women with low-grade tumors 20. The 3 and 5 year overall survival rates have been reported as 72% and 55% respectively 20. The Kasabach-Merritt syndrome, characterized by consumptive thrombocytopenia, has occasionally been attributed to angiosarcoma of the breast 21. Angiosarcoma of a chronically lymphedematous limb as a complication of the treatment of mammary carcinoma has been referred to as the Stewart-Treves syndrome 22

In general, mammary AS ranges from 1 - 12 cm, has poorly defined margins, and a spongy, friable consistency. Extension to the pectoral fascia is rare. Histologically, the tumor proliferates around and into lobular stroma, and usually advances into surrounding tissue with ill-defined margins and significant infiltration of adipose tissue, separating the lobules and terminal-duct units. The tumor is composed of irregular, anastomosing vascular channels lined by one or more layers of endothelial cells (in tufts, papillae, and/or solid nests). Solid areas are composed of spindle cells, blood lakes, and necrosis; features usually indicative of poor differentiation (high-grade angiosarcoma). To avoid undercalling angiosarcomas, generous sampling of large lesions is crucial. Epithelioid transformation has been reported to occur where the tumor cells show cytoplasmic microlumina which can be easily be misinterpreted as infiltrating ductal carcinoma 23. Coincidentally, however, angiosarcoma and infiltrating ductal carcinoma can occur in the same breast 24.

Three histologic patterns of growth in the primary tumor have been described. These reflect the degree of differentiation and have been proven to correlate with prognosis 25,26 (Table 1):

|Table 1 Grades of Angiosarcoma |

| |Low-gr./Type 1 |Intermediate gr./Type 2 |High gr./Type 3 |

|Key features |Distinct, open, anastomosing |Type1 + Scattered focal areas of |Type 1 & 2 areas + |

| |vascular channels, proliferate |more cellular proliferation +/- |conspicuous solid and |

| |diffusely in the glandular tissue |hemorrhage |spindled areas with sparse |

| |and fat | |vascular elements |

|Lobular glandular units |Separated and atrophic |Atrophic |Infiltrated |

|Endothelial cells |Hyperchromatic, flat single-cell |Hyperchromatic, small buds or |Hyperchromatic, cytologically|

| |layer around vascular spaces |papillary fronds of endothelial |malignant, prominent |

| | |cells project into vascular lumens|endothelial tufting |

|Papillary formations |Absent |Focally present |Prominent |

|Mitotic figures |Rare to absent |Seen in papillary areas |Easily identified |

|Solid and spindle cells |Absent |Minimal |>50% |

|‘Blood lakes’ |Absent |Absent |Present |

|Necrosis |Absent |Absent |Present |

|Variants |Capillary type; resembling |May show numerous nodules of |Epithelioid angiosarcoma |

| |pseudoangiomatous hyperplasia; |spindled cells with a swirling | |

| |resembling angiolipoma |pattern | |

|Adapted from Rosen’s Breast Pathology. 2nd Ed. Pg. 831 |

With few exceptions, angiosarcomas have infiltrative borders that feature well-formed or low-grade vascular channels. The peripheral vascular component may be so orderly that the neoplastic vascular channels may be structurally indistinguishable from existing capillaries in the normal parenchyma. It is the infiltrativeness, however, that separates AS from benign mammary vascular tumors (i.e. hemangioma).

In the setting of conservative breast surgery and postoperative radiation, benign atypical vascular lesions (AVL) must be distinguished from cutaneous postradiation angiosarcoma of the breast. AVLs typically develop 2 to 5 years after radiotherapy as single or multiple pink papules in the skin, usually < 5 mm in diameter (Table 2).

|Table 2 Atypical Vascular Lesion (AVL) vs Angiosarcoma (AS) |

|Characteristic |AVL |AS |

|Infiltration of subcutis |- |+++ |

|‘Blood lakes’ |- |+++ |

|Papillary endothelial hyperplasia |- |+++ |

|Prominent nucleoli |- |+++ |

|Mitotic figures |- |+++ |

|Marked cytologic atypia |- |+++ |

|Anastomotic vessels |++ |+++ |

|Chronic inflammation |+++ |+ |

|Hyperchromatic endothelial cells |+++ |++ |

|Dissection of dermal collagen |+/- |+++ |

|Relative circumscription |+++ |- |

|Projection of stroma into lumen |+++ |- |

|Rosen’s Breast Pathology. 2nd Ed. Pg. 844 |

Immunohistochemical staining for CD31, CD34, factor VIII, Ulex europaeus agglutinin-I (UEA-I), in angiosarcomas is usually positive 23,27,28. These stains are especially useful for distinguishing epithelioid forms of AS from carcinoma and other neoplasms. Ultrastructurally, Weibel-Palade bodies have been described in neoplastic endothelial cells, which may also contain pinocytotic vesicles at the luminal and basal surface 23,29.

Total mastectomy is the recommended surgical therapy. Because the tumor metastasizes usually via hematogenous routes, regional lymph node dissection is generally not indicated. Recurrences have been reported to be less frequent with adjuvant chemotherapy and postoperative radiotherapy 26. Survival rates in mammary AS are quite poor, with 14% - 41% of the patients have been reported to be disease free at 3 years and with only 7% - 33% survival (disease free) after 5 years 25,30,31. Tumor grade is the most important prognostic factor. Virtually all women with high-grade tumors die of recurrent disease within 5 years. In a series of 87 patients, disease free survival 5 and 10 years after treatment has been reported as: low-grade: 76%; intermediate-grade: 70%; and high-grade: 15%. Hence, the prognosis of angiosarcoma of the breast after radiotherapy is determined by the degree of differentiation of the tumor, which does not appear to differ substantially from that of spontaneous parenchymal angiosarcoma unassociated with radiotherapy. The most frequent sites of metastases are bone, lungs, liver, contralateral breast, and the skin 26. Rare metastasis has also been described in the ovary and placenta 32.

References:

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4. Yadav RVS, Sahariah S, Mittal VK, et al. Angiosarcoma of male breast. Int Surg 1976;61:463-464.

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15. Givens SS, Ellerbroek NA, Butler JJ, et al. Angiosarcoma arising in an irradiated breast: a case report and review of the literature. Cancer 1989;64:2214-2216.

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18. Rao j, Dekoven JG, Beatty JD, Jones G. Cutaneous angiosarcoma as a delayed complication of radiation therapy for carcinoma of the breast. J Am Acad Dermatol. 2003 Sep;49(3):532-538.

19. Slotman BJ, van Hattum AH, Meyers S, et al. Angiosarcoma of the breast following conservative treatment for breast cancer. Eur J Cancer 1994;30A:416-417.

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21. Mazzocchi A, Foschini MP, Marconi F, et al. Syndrome associated to angiosarcoma of the breast: a case report and review of the literature. Tumori 1993;79:137-140.

22. Antman KH, Corson J, Greenberger J, et al. Multimodality therapy in the management of angiosarcoma of the breast. Cancer 1982;20:2000-2003.

23. Marcias-Martinez V, Murrieta-Tiburcio L, Molina-Cardenas H, et al. Epithelioid angiosarcoma of the breast. Clinicopathological, immunohistochemical, and ultrastructural study of a case. Am J Surg Pathol 1997;21:599-604.

24. Britt LD, Lambert P, Sharma R, et al. Angiosarcoma of the breast. Initial misdiagnosis is still common. Arch Surg 1995;130:221-223.

25. Donnell RM, Rosen PP, Lieberman PH, et al. Angiosarcoma and other vascular tumors of the breast: Pathologic analysis as a guide to prognosis. Am J Surg pathol 1981;5:629-642.

26. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma: the prognostic significance of tumor differentiation. Cancer 1988;62:2145-2151.

27. Guarda LA, Ordonez NG, Smith JL, et al. Immunoperoxidase localization of Factor VIII in angiosarcoma. Arch Pathol Lab Med 1982;106:515-516.

28. Sirgi KE, Wick MR, Swanson PE. B72.3 and CD34 immunoreactivity in malignant epithelioid soft tissue tumors: adjuncts in the recognition of endothelial neoplasms. Am J Surg Pathol 1993;17:179-185.

29. Alvarez-Fernandez E, Salinero-Paniagua E. Vascular tumors of the mammary gland: a histochemical and ultrastructural study. Virchows Arch 1981;394:31-47.

30. Masser SR, Mongeau CJ, Rioux A. Angiosarcoma of the breast. Can J Surg 1977;20:341-343.

31. Myerowitz RL, Pietruszka M, Barnes EL. Primary angiosarcoma of the breast. JAMA 1978;239:403.

32. Sedgely MG, Oster AG, Fortune DW. Angiosarcoma of breast metastatic to the ovary and placenta. Aust N Z J Obstet Gynecol 1985;25:229-230.

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