Case 1 -

Multifocal Angiosarcoma Arising in Atypical Vascular Lesions of the Breast Sharon W. Weiss, Emory University Hospital, Atlanta, GA

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Cliincal History: The patient was a 68 year old woman who underwent lumpectomy and radiation for breast carcinoma in 1998. In 2001, she developed multiple, small (<1 cm) flesh-pink colored papules within the area of radiation several of which were biopsied. One lesion is depicted in images 1 and 2. Another lesion is depicted in images 3 and 4. The lesions persisted and increased in number necessitating a second set of biopsies in 2003. These lesions more closely resembled those depicted in images 3 and 4. Over the next 4 years she developed approximately 60 new lesions. A third set of biopsies was performed in 2007. At this time some of the lesions appeared red and raised. Following biopsy, a wide excision of the chest wall was performed. Images 5-7 are taken from the chest wall excision. Case 1 - Figure 1 Low power view of one of the initial lesions removed in 2002 showing the classic features of AVL. Case 1 - Figure 2 High power view of image 1 showing lymphatic type spaces lined by attenuated endothelium. Case 1 - Figure 3 Low power view of another lesion removed from 2002 showing a solid appearing endothelial proliferation within the AVL. Case 1 - Figure 4 High power view of image 3 showing a solid proliferation of endothelium involving the AVL. Case 1 - Figure 5 Low power view of resection specimen from 2007 showing an angiosarcoma composed of "hobnail" endothelium. Case 1 - Figure 6 High power view of resection specimen from 2007 illustrating the features of the hobnail endothelial cells Case 1 - Figure 7 Interface of AVL and angiosarcoma. Note one of the lymphatic spaces of the AVL is colonized by cells identical to those in the angiosarcoma. Introduction: Vascular lesions of the breast developing in women who have been treated with lumpectomy and radiation for breast carcinoma are becoming an increasingly frequent problem for the pathologist. Most are benign [i.e. atypical vascular lesion (AVL)]and require little more than clinical follow up. A small number, however, are bone fide angiosarcomas. Although in the past these two lesions have been considered distinct, and perhaps even unrelated, there is growing evidence that they may represent a morphologic spectrum. The current case is presented not only to discuss the spectrum of changes but also because it provides morphologic evidence that in some cases AVLs may actually give rise to angiosarcomas. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The features of an atypical vascular lesion (AVL) following radiation are well illustrated in the first biopsy from 2002. There is a demarcated proliferation of thin-walled, back to back lymphatic vessels limited to the superficial dermis. (Image 1 and 2) The endothelial cells lie flat or protrude slightly into the lumen and contain small, dark nuclei without atypia. A slight lymphocytic infiltrate accompanies the vessels. A curious change was observed in one of the lesions. In a small microscopic area the lymphatic vessels were lined by endothelial cells which were distinctly larger with a rounded to cuboidal shape, so called "hobnail endothelium." (Image 3 and 4) This form of endothelial cell characterizes several lymphatic- derived lesions such as the retiform and Dabska hemangioendotheliomas. In the second set of biopsies, which you were not given, the lymphatic proliferation was more extensive; the vessels interconnected in a more elaborate fashion and extended more deeply into dermis; and more of the endothelium had a hobnail appearance. These lesions neither resembled classic AVL nor a full fledged angiosarcoma. The third set of biopsies showed further progression, and a diagnosis of angiosarcoma was made. This diagnosis was borne out by the wide excision. Grossly the specimen showed a myriad of small erythematous macules and papules which in areas coalesced and corresponded histologically to a multifocal vascular proliferation which extended deeply into dermis, abutted the subcutaneous tissue and consisted of vessels which anastomosed with one another in a fashion destructive of normal structures. These features are portrayed in images 5. The cuboidal endothelial cells were uniformly enlarged with perceptible nucleoli similar to the cells within a retiform hemangioendothelioma (image 6). Lymphoid aggregates were intimately associated with the proliferation. Interestingly, there were still areas that were recognizable as AVL associated with the angiosarcoma. Your image 7 nicely illustrates the interface of the two lesion. You will note that one of the lymphatic spaces is lined by cuboidal endothelium identical to that in the adjacent angiosarcoma. Differential Diagnoses: The diagnosis of the original lesions is relatively straight forward (images 1,2). The superficial location, sharp margination and lymphatic channels lined by bland endothelium are not especially suggestive of angiosarcoma. However, out of context one could reasonably suggest the diagnosis of lymphangioma. By convention, when such lesion follow radiation they are designated "atypical vascular lesion," rather than "lymphangioma." One of the original lesion is hard to categorize(images 3-4). Whereas it mostly has features of AVL, it is not classic. This is the type of lesion that is perhaps best described, rather than labeled. The lesions depicted in the resection specimen are clearly angiosarcomas for the reasons described above, although the cells do not appear to be of high nuclear grade. Because the cells resemble those in a retiform hemangioendothelioma , one might suggest this diagnosis. However, the vascular channels in retiform hemangioendotheliomas are elongated, do not intercommunicate very much, and are surrounded by a dense hyaline sclerosis. Retiform hemangioendotheliomas have not thus far been reported in this clinical setting and, therefore, do not comprise part of the spectrum of post- irradiation vascular lesions of the breast. Final Diagnosis: Multifocal angiosarcoma arising in atypical vascular lesions of the breast Case Discussion: Atypical vascular lesion is the name employed for post- irradiation vascular proliferations that do not fulfill all the criteria for angiosarcoma. The term was first used in 1994 by Fineberg and Rosen who called attention to an unusual group of cutaneous vascular proliferations that developed in women following lumpectomy and radiation for breast carcinoma (AVL) [1]. Others noted the similarity of these proliferations to lymphangiomas and employed other terms such as "benign lymphangiomatous papules," benign lymphangioendothelioma" and acquired progressive lymphangioma" [2, 3, 4]. All terms essentially refer to the same lesion. On the basis of four cases, Fineberg and Rosen concluded the lesions were benign and unrelated to post irradiation angiosarcomas. More recently, this conclusion has been challenged, [5] although opinions are still divided. This case is presented because it illustrates in a sequential fashion progressive changes in an AVL ultimately resulting in angiosarcoma. It is the best documented case to date suggesting a causal link between the two lesions and that AVLs may be a precursor lesion. Clinically, patients, virtually all women, with AVLs develop one or more small (usually <1 cm), colorless to slightly erythematous, maculo-papular lesions within the skin of the radiation field within a period of 3-6 years following lumpectomy and radiation for breast carcinomas. The classic appearance is similar to what was depicted in the first set of biopsies from this patient and similar to what Fineberg and Rosen originally described. Circumscribed collections of back to back lymphatic vessels are restricted to the superficial dermis. The endothelium is either flattened or slightly protuberant. Stains for podoplanin (D240) are positive, as one would expect of lymphatic endothelium. However, AVLs may become architecturally more complex. In such cases the lymphatic channels ramify more extensively within the dermis carving out irregular channels similar to those of a well differentiated angiosarcoma. However, the endothelium retains its innocuous appearance. It forms a single layer of cells which lack atypia, perceptible nucleoli, and mitotic activity. What has not generally been recognized is that some AVLs assume the appearance of a capillary vascular proliferation. These lesions resemble a capillary hemangioma in which the well formed, pericyte- invested (actin-positive) vessels lie dispersed within the dermis. The dermis often has micro-extravasations of erythrocytes and focal hemosiderin deposits. Many, but not all, vascular AVLs (VT AVL) also have an associated component of lymphatic AVL (LT AVL) suggesting, but not proving, that LT AVLs may evolve into VT AVL. Our recently published study of AVLs proposes that AVLs are more heterogeneous than previously appreciated and should be divided into two groups those having lymphatic features (LT AVL) and those having vascular features (VT AVL). The biologic significance of the two groups is discussed below. Review of the Literature/Treatment Options (if applicable): Our understanding of the long term behavior of AVLs is still evolving. Based on two relatively large studies of AVLs, 10-20% of patients may be expected to develop recurrent or additional lesions. [6, 7] the critical question of course is whether they carry an increased risk for angiosarcoma, and, if so, can it be predicted. The majority of AVLs reported in the literature are LT AVLs. With two exceptions, none of the more than 80 reported cases of LT AVLs have developed angiosarcoma. The first exception, described by Brenn and Fletcher, was a patient with an "infiltrating" AVL who developed an angiosarcoma 24 months later [5] The second is this case, having small foci of atypical lymphatic endothelium were in the first biopsy, which ultimately progressed to angiosarcoma over a 9 year period. However, it is important to put these two cases into the proper perspective. The vast majority of LT AVLs are so innocuous that they are probably cured by simple excision, never sent to a referral center or consultant, and never included in a follow up study. Based on preliminary data from our group VT AVLs appear to be different. In our experience with 10 VT AVLs, 4 displayed nuclear atypia and 1 of the 4 developed angioarcoma within 14 months. A second developed numerous additional lesions with varying degree of atypia for which she underwent a mastectomy. [6] These data suggest that LT AVLs and VT AVLs have different biologic implications. Conclusion(s): In summary, AVLs represent a histologically more heterogeneous group of lesions than was formerly appreciated, and there is circumstantial evidence that these lesions represent a histologic continuum. Defining the risk of angiosarcoma in AVL continues to be a challenge as the number of cases remains small and the largest studies rely on referred cases, likely underepresenting the more innocuous forms of AVL. Nevertheless, AVLs seem to carry some,albeit an extremely low,risk for angiosarcoma which seems to be related to histologic differences amongst this group. This places responsibility on the pathologist to make recommendations. This is the way I like to handle these cases: 1. Classic LT-AVLs presenting as superficial lymphangiectasias seem to pose little short term risk for angiosarcoma. Patient can be treated by a conservative excision for diagnostic purposes and follow up care. 2. LT AVLs with atypical features such as extensive infiltration or, as in this case, progressive endothelial atypia, should be viewed with more caution. This case is an example of an LT-AVL with atypical features. Closer clinical surveillance is recommended. The incidence of angiosarcomas still appears to be low, however. 3. VT AVLs are the most worrisome lesions; those with atypia have a significant risk for angiosarcoma. Prophylactic or pre-emptive wide resection should be considered. References: 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; 102:757-763 Requena L, Kutzner H, Mentzel T, et al.: Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002; 26:328-337 Rosso R, Gianelli U, Carnevali L: Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995; 22:164-167 Wagamon K, Ranchoff RE, Rosenberg AS, et al.: Benign lymphangiomatous papules of the skin. J Am Acad Dermatol 2005; 52:912-913 Brenn T, Fletcher CD: Radiation-associated cutaneous atypical vascular and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol 2005; 29:983-996 Patton, KT, and Deyrup, AT, Weiss, SW: Atypical vascular lesions following surgery and radiation of the breast: A clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Amer J Surg Pathol, 2008;32:943-50. 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; 109:1584-1598