—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 1 - Epithelioid Angiosarcoma of the Breast (s/p radiation therapy

Laura C. Collins, Beth Israel Deaconess MC, Boston, MA





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Introduction:
The patient is an 80 year old female with a prior history of breast cancer on whom we received a breast core needle biopsy with the differential of "tumor vs. fat necrosis".

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The core needle biopsy shows a cellular proliferation of highly malignant appearing epithelioid cells with large pleomorphic nuclei and prominent nucleoli. The cells are arranged in broad sheets with absent gland formation. Mitoses are abundant and there are large zones of necrosis. The tumor was "triple negative" for estrogen, progesterone and HER2 receptor studies. The architectural and cytologic features could be consistent with a poorly differentiated carcinoma of the breast. However, the morphology of the cells is a little unusual for a typical high grade breast carcinoma. In addition, the lack of any precursor lesion (ductal carcinoma in situ) and the absence of ER, PR and HER2 staining prompted further workup. Given the prior history of breast cancer, attempt was made to review the prior slides. The prior carcinoma was a grade 1 infiltrating ductal carcinoma (slides not available for review). Additional clinical history elicited, revealed that on imaging almost the entire breast was involved by a diffuse infiltrative process and that the skin demonstrated purple hemorrhagic plaques and papules. Additional immunostains for vascular markers (CD31 and Factor VIII) were positive and cytokeratin (negative) confirming the diagnosis of angiosarcoma.


Case 1 - Figure 1
This low power image of the core biopsy shows sheets of hyperchromatic cells infiltrating through the collagenous stroma and fat. At this power the differential diagnosis includes carcinoma and perhaps even lymphoma.
Case 1 - Figure 2
At intermediate power, highly malignant/undifferentiated tumor cells are appreciated.
Case 1 - Figure 3
At highest power, the nuclei appear large and pleomorphic with prominent nucleoli. Mitoses and apoptotic debris are readily seen. An area of necrosis is present at the top of the field. Neither gland formation, nesting or a trabecular pattern is apparent.

Differential Diagnoses:
The diagnosis of angiosarcoma can be challenging. Differential diagnostic considerations for low grade angiosarcomas include hemangiomas, angiolipomas and papillary endothelial hyperplasia which have the same morphology as these lesions when found in other locations of the body. Pseudoangiomatous stromal hyperplasia and atypical vascular lesions (see below) also enter into the differential diagnosis. Low grade angiosarcomas may have areas with very well-differentiated vascular spaces and bland endothelial cells that mimic benign vascular proliferations such as hemangiomas. In contrast, some benign vascular lesions may demonstrate cytologic and/or architectural atypia ("atypical perilobular hemangioma" and "atypical hemangioma") [1, 2] or have organizing thrombi with concomitant papillary endothelial hyperplasia; a pattern that may be misinterpreted as angiosarcoma [3]. Clinical history can be key to distinguishing these relatively bland vascular proliferations.

High grade angiosarcomas, particularly those with a more epithelioid appearance, may be difficult to distinguish from poorly differentiated carcinomas of the breast due to the presence of solid sheets of highly malignant appearing epithelioid tumor cells and the apparent absence of vessel formation [4, 5, 6]. Conversely, some carcinomas have pseudovascular spaces that may mimic angiosarcoma [7]. In this particular case, the presence of sheets of tumor cells, with large pleomorphic nuclei, abundant mitoses, zones of necrosis and a triple negative immunophenotype raised the possibility of a basal-like carcinoma. Other diagnostic considerations include metastatic carcinoma as well as melanoma. When necessary, immunostains for endothelial markers (such as factor VIII-related antigen, CD31, CD34, and D2-40) and epithelial markers (such as cytokeratin), may be required to distinguish between angiosarcoma and carcinoma. Be aware that some angiosarcomas express cytokeratin; therefore, a panel of antibodies should always be used to distinguish these two entities. At the molecular level, recent data indicate that post-radiation angiosarcomas of the breast are characterized by myc amplification whereas atypical vascular lesions and non-radiation cutaneous angiosarcomas do not show alterations in myc [8, 9]. Whether this alteration can be used reliably to distinguish these two lesions remains to be determined.

Rendering a definitive diagnosis on a core needle biopsy sample of a vascular lesion can prove to be particularly challenging and is probably unwise except in the appropriate clinical setting, with classical histologic features and supporting ancillary studies. It may be more prudent to provide a differential diagnosis for the lesion in question and defer definitive characterization of the lesion to the excision specimen.

Atypical Vascular Lesions
Atypical vascular lesions of the skin of the breast have been described in women treated with breast-conserving surgery and radiation therapy for breast cancer [10, 11, 12]. Patients typically present with small papules or plaques with pink, red or brown discoloration. Microscopically, atypical vascular lesions are characterized by a diffuse dermal proliferation of well-formed vascular spaces without invasion into the subcutaneous tissue. The vascular spaces often have branching contours and areas of anastomosis which dissect between bundles of dermal collagen. Overall, the lesion is circumscribed, but unencapsulated, and may have a wedge-shaped appearance on low-power examination. The vascular spaces are lined by a single layer of plump endothelial cells with prominent, hyperchromatic nuclei and some hobnailing present. However, cytologic atypia, endothelial cell multilayering and mitotic figures are absent. The vascular spaces are usually devoid of red blood cells and erythrocyte extravasation into the surrounding stroma is not seen. In addition, a patchy chronic inflammatory cell infiltrate is usually present in atypical vascular lesions [12, 13]. Features useful in distinguishing atypical vascular lesions from angioscarcomas include the wedge-shaped appearance, the lesion being confined to the dermis and the presence of an inflammatory cell infiltrate; the absence of endothelial cell atypia, "blood lakes", mitoses and necrosis all favor the diagnosis of atypical vascular lesion. However, it should be noted that some lesions do exhibit a degree of morphologic overlap making definitive categorization impossible in some cases [12]. Atypical vascular lesions are generally considered to have a benign clinical course, however, there are reports of patients with atypical vascular lesion which have progressed to angiosarcoma [10, 12]. In current clinical practice, there are no ancillary tests that can aid in the distinction of atypical vascular lesion from angiosarcoma (see above for discussion of myc amplification in radiation-induced angiosarcoma vs. atypical vascular lesion). Treatment for atypical vascular lesions is by complete excision with careful clinical follow-up.

Final Diagnosis:
Epithelioid Angiosarcoma of the Breast (s/p radiation therapy.

Case Discussion:
Angiosarcomas are the most frequent primary sarcomas of the breast but are still very uncommon, accounting for less than 0.05% of breast malignancies [14, 15, 16, 17]. Angiosarcomas may be primary or they may arise secondary to radiation therapy for breast cancer or other chest irradiation [18, 19]. In the post-radiation setting, cutaneous angiosarcoma is more common, though involvement of the mammary parenchyma may occur [20]. Angiosarcomas may also arise in the arm following radical mastectomy as a result of chronic lymphedema (Stewart-Treves syndrome); however this is rarely seen now with the marked decline in the number of the radical mastectomies performed [21]. In contrast, the number of post-radiation angiosarcomas is on the rise given the routine use of breast-conserving surgery and radiation therapy in the management of breast cancer today [22, 23, 24].

Clinical features:
Angiosarcomas of the mammary parenchyma typically present as a painless mass. Secondary angiosarcomas more frequently present with violaceous discoloration of the skin, due to cutaneous involvement [24]. These tumors occur across a wide age range with a median age at presentation around 40 years for spontaneously-occurring lesions and 60-70 years for post-radiation angiosarcomas [23, 24, 25].

Pathology:
On gross examination, the tumors have a wide size range, from under 1 cm to more than 20 cm. The median size reported is of the order of 7 cm for primary angiosarcomas and 5cm for secondary tumors [23]. Angiosarcomas usually appear as hemorrhagic masses, often with areas of necrosis or cystic degeneration.

On microscopic examination, angiosarcomas are characterized by inter-anastomosing vascular spaces that disrupt the normal lobular architecture and dissect through the mammary stroma and adipose tissue. The vascular spaces are lined by endothelial cells with hyperchromatic nuclei. Extravasation of erythrocytes may be present. In many angiosarcomas, the endothelial cells lining the vascular spaces at the periphery of the tumor appear extremely bland making distinction from benign blood vessels difficult [26].

Angiosarcomas have been divided into low, intermediate and high grades, though the grade can vary within a single lesion [27]. Low grade angiosarcomas are characterized by well-formed, anastomosing vascular channels that contain a variable number of erythrocytes. The endothelial cell nuclei are hyperchromatic, but mitoses are absent or scant, as are areas of papillary endothelial cell tufting or solid growth pattern. Intermediate-grade lesions show increased cellularity, with endothelial cell tufting and papillary formations with or without solid areas of growth. Mitotic figures may be present in the more cellular areas. High- grade angiosarcomas are composed of vascular spaces lined by cytologically malignant endothelial cells arranged in prominent tufts and papillations with abundant mitoses. Solid spindle cell areas which lack vascular lumen formation are often present. Areas of stromal hemorrhage ("blood lakes") and necrosis can be seen. The endothelial cells of high grade angiosarcomas can have an epithelioid appearance, as in this case, making these lesions particularly difficult to distinguish from carcinomas [4, 5, 6].

Review of the Literature/Treatment Options:
It had long been held that outcome for patients with angiosarcoma varied with grade, with the 5-year survival being reported as 76%, 70% and 15% for low, intermediate and high grade angiosarcomas, respectively [28]. However, a recent study failed to demonstrate a relationship between grade of angiosarcoma and outcome, in keeping with angiosarcomas at other sites [29]. More recent studies have stratified outcome according to whether the angiosarcoma is primary or secondary to radiation therapy with poorer outcome reported for secondary angiosarcomas or no difference being seen [23, 24]. However, it should be noted that all these reports are hampered by small numbers and variable treatment strategies.

Angiosarcomas require complete excision and are most often treated by mastectomy. Axillary lymph node involvement is rare, though a recent publication found 25% of patients to have lymph node involvement at the time of recurrence [24]. The most common sites of metastatic spread are the lungs, liver, contralateral breast, other skin and soft tissue locations and bone [14]. Recent therapeutic efforts have shown promising results with hyperfractionated radiation therapy and radiation therapy with hyperthermia [30, 31] as well as encouraging results with taxane therapy [32] in a tumor for which the diagnosis portends a grave prognosis.

Conclusion(s):
Angiosarcomas, both low and high grade, can present a diagnostic challenge. Epithelioid morphology, in particular, can be a pitfall. Communication of all clinical information available is critical to accurate interpretation. In problematic cases, use of ancillary studies may be helpful.

References:
  1. Jozefczyk MA, Rosen PP. Vascular tumors of the breast. II. Perilobular hemangiomas and hemangiomas. Am J Surg Pathol 1985;9(7):491-503.

  2. Hoda SA, Cranor ML, Rosen PP. Hemangiomas of the breast with atypical histological features. Further analysis of histological subtypes confirming their benign character. Am J Surg Pathol 1992;16(6):553-60.

  3. Branton PA, Lininger R, Tavassoli FA. Papillary endothelial hyperplasia of the breast: the great impostor for angiosarcoma: a clinicopathologic review of 17 cases. Int J Surg Pathol 2003;11(2):83-7.

  4. Farina MC, Casado V, Renedo G, Estevez L, Martin L, Requena L. Epithelioid angiosarcoma of the breast involving the skin: a highly aggressive neoplasm readily mistaken for mammary carcinoma. J Cutan Pathol 2003;30(2):152-6.

  5. Muzumder S, Das P, Kumar M, et al. Primary epithelioid angiosarcoma of the breast masquerading as carcinoma. Curr Oncol 2010;17(1):64-9.

  6. Macias-Martinez V, Murrieta-Tiburcio L, Molina- Cardenas H, Dominguez-Malagon H. Epithelioid angiosarcoma of the breast. Clinicopathological, immunohistochemical, and ultrastructural study of a case. Am J Surg Pathol 1997;21(5):599-604.

  7. Nappi O, Wick MR, Pettinato G, Ghiselli RW, Swanson PE. Pseudovascular adenoid squamous cell carcinoma of the skin. A neoplasm that may be mistaken for angiosarcoma. Am J Surg Pathol 1992;16(5):429-38.

  8. Mentzel T, Schildhaus HU, Palmedo G, Buttner R, Kutzner H. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol 2012;25(1):75-85.

  9. Fernandez AP, Sun Y, Tubbs RR, Goldblum JR, Billings SD. FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol 2011.

  10. 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):757-63.

  11. Requena L, Kutzner H, Mentzel T, Duran R, Rodriguez- Peralto JL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002;26(3):328-37.

  12. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol 2005;29(8):983-96.

  13. Mandrell J, Mehta S, McClure S. Atypical vascular lesion of the breast. J Am Acad Dermatol 2010;63(2):337-40.

  14. Drijkoningen M, Tavassoli FA, Magro G, Eusebi V, Devouassoux-Shisheboran M, Belloq JP, Lanzafame S, MacGrogan G, Peterse JL. Mesenchymal tumors. In: Tavassoli FA, Devilee P, ed. Pathology and Genetics: Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003:89- 98.

  15. Wang XY, Jakowski J, Tawfik OW, Thomas PA, Fan F. Angiosarcoma of the breast: a clinicopathologic analysis of cases from the last 10 years. Ann Diagn Pathol 2009;13 (3):147-50.

  16. Biswas T, Tang P, Muhs A, Ling M. Angiosarcoma of the breast: a rare clinicopathological entity. Am J Clin Oncol 2009;32(6):582-6.

  17. Nakamura R, Nagashima T, Sakakibara M, et al. Angiosarcoma arising in the breast following breast- conserving surgery with radiation for breast carcinoma. Breast Cancer 2007;14(2):245-9.

  18. Monroe AT, Feigenberg SJ, Mendenhall NP. Angiosarcoma after breast-conserving therapy. Cancer 2003;97 (8):1832-40.

  19. Vorburger SA, Xing Y, Hunt KK, et al. Angiosarcoma of the breast. Cancer 2005;104(12):2682-8.

  20. Schnitt SJ. Angiosarcoma of the mammary skin following conservative surgery and radiation therapy for breast cancer. Pathol Case Reviews 1999;4:194-8.

  21. Heitmann C, Ingianni G. Stewart-Treves syndrome: lymphangiosarcoma following mastectomy. Ann Plast Surg 2000;44(1):72-5.

  22. Styring E, Fernebro J, Jonsson PE, et al. Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall. Breast Cancer Res Treat 2010;122(3):883-7.

  23. Scow JS, Reynolds CA, Degnim AC, Petersen IA, Jakub JW, Boughey JC. Primary and secondary angiosarcoma of the breast: the Mayo Clinic experience. J Surg Oncol 2010;101 (5):401-7.

  24. Fraga-Guedes C, Gobbi H, Mastropasqua MG, Botteri E, Luini A, Viale G. Primary and secondary angiosarcomas of the breast: a single institution experience. Breast Cancer Res Treat 2011.

  25. Hodgson NC, Bowen-Wells C, Moffat F, Franceschi D, Avisar E. Angiosarcomas of the breast: a review of 70 cases. Am J Clin Oncol 2007;30(6):570-3.

  26. Schnitt SJ, Collins, LC. Biopsy Interpretation of the Breast. Lippincott Williams & Wilkins 2009.

  27. Donnell RM, Rosen PP, Lieberman PH, et al. Angiosarcoma and other vascular tumors of the breast. Am J Surg Pathol 1981;5(7):629-42.

  28. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma. The prognostic significance of tumor differentiation. Cancer 1988;62(10):2145-51.

  29. Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the breast: clinicopathologic analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg Pathol 2008;32(12):1896-904.

  30. Palta M, Morris CG, Grobmyer SR, Copeland EM, 3rd, Mendenhall NP. Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy. Cancer 2010;116(8):1872-8.

  31. de Jong MA, Oldenborg S, Oei SB, et al. Reirradiation and hyperthermia for radiation-associated sarcoma. Cancer 2011.

  32. Hirata T, Yonemori K, Ando M, et al. Efficacy of taxane regimens in patients with metastatic angiosarcoma. Eur J Dermatol 2011;21(4):539-45.