Bone & Soft Tissue Pathology
Case 1 -
Multifocal Angiosarcoma Arising in Atypical Vascular Lesions of the Breast
Sharon W. Weiss, Emory University Hospital, Atlanta, GA
Click on slide thumbnail images for an enlarged view.
If you have any difficulties viewing these slides, email the webmaster.
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.
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
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
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.
Multifocal angiosarcoma arising in atypical vascular lesions of the breast
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)
. Others noted the
similarity of these proliferations to lymphangiomas and employed other terms such as "benign
lymphangiomatous papules," benign lymphangioendothelioma" and acquired progressive lymphangioma"
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,  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.
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  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.  These data suggest that LT AVLs and VT AVLs have different biologic implications.
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.
- 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