Open Journal of Pathology, 2013, 3, 180-185
Published Online October 2013 (
Copyright © 2013 SciRes. OJPathology
Angiosarcoma Following Radiation Therapy for
Breast Cancer: Case Presentation and
Clinical Management Considerations
Joseph R. Scalea1*, Branko Bojovic2, Robin Legros3, Julia Choi4, Andrea Hebert1, Nader Hanna1
1Division of General & Oncologic Surgery, University of Maryland School of Medicine, Baltimore, USA; 2Division of Plastic Sur-
gery, University of Maryland School of Medicine, Baltimore, USA; 3University of Maryland School of Medicine, Baltimore, USA;
4Department of Pathology, University of Maryland School of Medicine, Baltimore, USA.
Email: *
Received May 11th, 2013; revised June 11th, 2013; accepted June 20th, 2013
Copyright © 2013 Joseph R. Scalea et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A 59-year-old woman presented with erythema and pruritis of the breast 4.5 years after undergoing lumpectomy and
radiation for breast cancer. Biopsy confirmed a diagnosis of angiosarcoma. This tumor stained positive for CD34 as
well as 70% Ki67 prior to therapy initiation. A multidisciplinary ap proach yielded a plan for neoadjuvant chemoradia-
tion and surgical resection including delayed completion transverse rectus abdominis flap for tissue coverage. Neoad-
juvant therapy successfully decreased rates of cellular proliferation, as reflected by a Ki67 of 5%, at the time of resec-
tion. Pathophysiologically, angiosarcomas may be very aggressive and may develop following radiation for breast can-
cer. Such tumors may become more common as breast cancer therapies, which frequently include radiation therapy,
improve with time. Early recognition of angiosarcoma is imperative for successful therapy. These tumors may present
with a wide range of symptoms, but may be asymptomatic. Surgical resection is the preferred therapy, but early recog-
nition is critical.
Keywords: Angiosarcoma; Breast Cancer; Radiation Therapy; Immunohistochemistry; TRAM Flap
1. Case Presentation
Our patient is a very pleasant 59-year-old-female who
underwent left breast lumpectomy and axillary lymph
node dissection followed by adjuvant chemoradiation in
2006 for a lesion identified as part of her work-up for
colon cancer. The patient had appropriate follow-up and
underwent routine annual mammographic screening with
no signs of recurrence. In April 2011, the patient devel-
oped pruritus of the left breast associated with multiple
skin lesions. These les ions were described as small, bright
red papules that slowly increased in size on an erythema-
tous base. A punch biopsy was performed which showed
malignant neoplasm. H&E staining revealed dermal and
subcutaneous tumor with poorly-formed vascular chan-
nels (Figure 1(a)). There were atypical epithelioid cells
with brisk mitotic activity lining these channels. These
findings were consistent with high-grade angiosarcoma.
Immunohistochemical staining was positive for p63, vi-
mentin and CD34 (Figure 1(b)), highlighting the vascu-
larity of the tumor. Stains were negative for AE1/AE3,
S100, SMA, desmin, CD68, EMA, CK903, mammaglo-
bin, GCDFP15, FLI1 and HHV8. Staining with Ki67, a
protein which is absent during the resting phase of the
cell cycle and used as a marker of proliferation, revealed
a proliferative index of approximately 70% (Figure 1(c)).
A PET/CT scan was negative for metastasis.
The patient underwent neoadjuvant external beam ra-
diation therapy (XRT). In order to determine the effect of
the XRT on the angiosarcoma prior to surgery, immuno-
histochemistry was re-performed approximately six
weeks following XRT. These studies revealed a signifi-
cant decrease in tumor-associated vascularity, and both
CD34 and Ki67 were markedly lower (Figures 2(a)-(c)).
Six weeks following XRT, the patient underwent modi-
fied radical mastectomy (Figures 3(a)-(e)). Reconstruc-
tion was planned as a two-stage procedure, to be per-
formed along with the plastic surgery team. Initially, a
split thickness skin-graft (STSG) was used for coverage
*Corresponding a uthor.
Angiosarcoma Following Radiation Therapy for Breast Cancer: Case Presentation and Clinical Management Considerations 181
Figure 1. Pre-radiation biopsy. (a) H&E stain (mag 100×)
revealed high-grade angiosarcoma; (b) Tissue CD34 (mag
200×, dark stain) stains revealed a high-degree of vascular-
ity, consistent with angiosarcoma; (c) Pre-radiation Ki-67
(mag 200×, dark stain) demo nstrati ng a prolife rative index o f
approx imately 70% .
Figure 2. Response to irradiation. (a) On H&E (mag 100×)
tissue obtained from the mastectomy sample, revealed rare
residual microscopic foci of angiosarcoma within the hy-
alinized and necrotic dermis; (b) Decrease in CD34 (mag
200×, dark stain) concentration following radiation therapy;
(c) Post-radiation Ki-67 (mag 200×, dark stain) stain re-
vealing a proliferative index of approximately 5% at the
ime of mastectomy. t
Copyright © 2013 SciRes. OJPathology
Angiosarcoma Following Radiation Therapy for Breast Cancer: Case Presentation and Clinical Management Considerations
Copyright © 2013 SciRes. OJPathology
(a) (b)
(c) (d)
Figure 3. Surgical management of breast angiosarcoma. (a) Intraoperative photo of post-resection chest wall; (b) Resected
breast tissue; (c) STSG coverage of chest wall defect; (d) Pre-resection image; (e) 3 week post-skin graft image.
cancer in women [1-3]. AS is rare and accounts for less
than one percent of soft tissue sarcomas with an esti-
mated annual age-adjusted incidence in the US of 0.21
cases per 100,000 person-years [4]. Primary tumors are
broadly categorized as cutaneous and non-cutaneous,
with the incidence of each type being roughly equal [4,5].
Caucasians are affected more frequently than African-
Americans, Asians or Native Americans [2,4,5]. The in-
cidence in men and women increases exponentially after
the age of 40 years [4], and according to a publication in
the Lancet, the disease presents most commonly in the
head and neck (27%); However, angiosarcoma of the
breast, as presented here is the second most common
form of angiosarcoma and accounts for 19.7% of cases.
over the open chest wall wound (Figure 3(b)). This was
to be followed by a pedicled transverse rectus abdominis
myocutaneous (TRAM) flap for definitive breast recon-
struction once pathology confirmed local absence of ma-
lignnancy. Post-operative adjuvant chemotherapy had
been initiated shortly after her first-stage STSG, as men-
tioned above.
2. Disease Process and Epidemiology
Angiosarcoma (AS) is a heterogenous, aggressive ma-
lignancy that arises from vascular endothelium that typi-
cally effects elderly white males, however it is a recog-
nized disease process following irradiation for breast
Angiosarcoma Following Radiation Therapy for Breast Cancer: Case Presentation and Clinical Management Considerations 183
In general, the prognosis for angiosarcoma is poor and
rigorous pathological investigation should be undertaken
to assist in the early diagnosis, treatment, and surveil-
lance of this malignancy [1].
3. Diagnosis and Treatment
For therapeutic and epidemiologic purposes, AS can be
categorized according to its anatomical site, the natural
history of the disease, and its predisposing factors [6].
Cutaneous AS occurs most frequently on the head and
neck while lesions on the extremities and trunk are less
common [5,6]. The association of cutaneous AS with
chronic lymphedema and inflammation, particularly lym-
phedema following radical mastectomy, is well docu-
mented [3,7]. These tumors, which appear most com-
monly on the scalp, typically present as painless, ecchy-
motic or nodular lesions with occasional bleeding or ul-
ceration [3,6,7]. Their nondescript clinical features often
lead to misdiagnosis of these tumors as benign disease
[3,7]. AS associated with lymphedematous extremities
(Stewart-Treves syndrome) presents with similar features
and typically presents years after the development of
lymphedema [6,8]. Regular follow-up of these patients
with gadolinium-enhanced MRI may be indicated to in-
crease detection of AS [7].
Critical to the diagnosis of angiosarcoma are the im-
munohistochemical stains. Pathologically, these tumors
typically express endothelial markers such as von Wille-
brand factor, CD34, CD31, and vascular endothelial
growth factor (VEGF) [1]. As was shown for the patient
in this study, markers, such as CD34 can be helpful in
monitoring the success of cancer therapies. However, it
should be noted, that with de-differentiation, tu mors may
lead to loss of cellular markers [1]. Here, the tumor was
positive for p63, which may alter VEGF expression that
may be seen in vascular neoplasia. Vimentin was also
positive on initial staining and is helpful in confirming
the diagnosis of an epithelioid angiosarcoma, in the set-
ting of CD31 and/or CD34 positivity [9]. It is now ap-
preciated that atypical vascular lesions (AVLs) are a pre-
cursors to AS. These two diseases (AVLs and AS) likely
exist on a spectrum [10,11]. AVLs typically begin as
benign-appearing, well-circumscribed collections of cu-
taneous vessels [12]. There also appears to be a clear link
between radiation exposure and the development to
AVLs [10]. Retrospective data has shown that, women
who develop AS are typically older and experience a
shorter duration between radiation exposure and the di-
agnosis of dermatologic pathology [10]. In a recent re-
port of 11 patients with radiation associated AVLs, some
whom subsequently developed AS, authors observed that
AVLs occurred at a mean of 4.3 years following radia-
tion, and that AS occurred slightly later (mean = 5.0
years). In addition, whereas staining for CD34 was simi-
lar among patients with AVL and AS (as was observed
with our patient), investigators found that VEGFR-3 ex-
pression was greater in those patients with AVLs that
went on to develop AS [10].
AS of the breast may arise spontaneously or be associ-
ated with prior radiation therapy. In another series of 57
patients with breast AS, 27 patients (47%) had previously
received breast irradiation; only three of these patients
experienced upper extremity lymphedema [6]. The de-
velopment of AS in previously irradiated fields such as
the face, tongue, pleura and GI tract has been reported in
other retrospective publications [2].
Primary AS of deep, soft tissue and of solid organs
may be asymptomatic [6,7]. In symptomatic patients, the
clinical presentation of AS is related to tissue origin. AS
of the spleen and liver may present as a painful mass
whereas cardiac tumors may lead to pericardial effusion
[5]. Both primary and metastatic AS may be found in
virtually any deep soft tissue, organ or bone [2,13]. At
diagnosis, these tumors are frequently high-grade, poorly
differentiated neoplasms, making complete surgical re-
section difficult and both local and distal recurrence
common [2,3,7]. Rare cases of AS associated with for-
eign material have been reported [13,14].
4. Outcomes
Because breast conservation therapy typically involves
lumpectomy and radiation, and because many more
women are electing to have breast conservation therapy,
the incidence of angiosarcoma is expected to increase
[15]. However, some authors have reported lower-than
expected rates of angiosarcoma secondary to radiation
exposure [15]. In 2008, a retrospective review of 32
cases of AVLs in women that had undergone breast con-
servation therapy brought more attention the incidence of
this disease process [12].
Our patient, as the data above describes, underwent
lumpectomy and radiation. After development of her
angiosarcoma, a careful clinico-pathologic analysis was
performed to clarify her tumor type. In doing so, CD34
and Ki67 (Figures 1 and 2) were followed by biopsy, in
order to determine the clinical success of radiation ther-
apy. We demonstrated successful decrease in these mark-
ers (CD34, Ki67, etc.) indicating decreased rate of tumor
growth following XRT, as has been shown for other tu-
mor markers such as VEGF [16].
Five-year survival in AS patients in approximately
45% based on population surveillance data [5]. Surgical
resection is the standard of care fo r AS, and patients with
resectable disease experience increased survival com-
pared to patients with unresectable tumors [13]. In one
large series, overall survival (OS) was 48% in patients
Copyright © 2013 SciRes. OJPathology
Angiosarcoma Following Radiation Therapy for Breast Cancer: Case Presentation and Clinical Management Considerations
with localized disease and 23% in patients with metas-
tatic disease (p < 0.001) [6]. Univariate analysis in a
separate series revealed a statistically significant differ-
ence (p< 0.001) in disease-specific survival (DSS) be-
tween patients with advanced, unresectable AS at cuta-
neous (median DSS = 10.3 mo) an d deep soft tissue sites
(median DSS = 2.8 mo) [7]. For patients with localized
or advanced disease, another series demonstrated im-
proved overall survival for patients with superficial (3.6
± 1.0 yrs) versus deep (2.3 ± 0.5 yrs) tumors [2]. In pa-
tients with localized cutaneous disease, primary tumor
origin in the head/n eck, extremities or breast was associ-
ated with significantly longer survival than tumors aris-
ing in the trunk (median survival: 3.6 ± 0.5 yrs vs. 2.1 ±
0.2 yrs; p = 0.01) [2]. Among patients with primary
breast AS, the presence of preexisting lymphedema and
radiation fields were negative prognostic indicators for
local and distal disease recurrence and overall survival
[2,7]. Several studies have failed to find a significant as-
sociation between microscopically positive surgical mar-
gins and poor disease outcomes [2,13]. Furthermore, the
role of adjuvant and neoadjuvant chemoradiation for pa-
tients with resectable AS is unclear. In our patient, we
observed favorable histologic results using neoadjuvant
irradiation. In two case series, adjuvant radiotherapy pro-
vided no survival benefit in AS patients irrespective of
tumor margin status [2,6]. Trials of adjuvant chemother-
apy using paclitaxel-based regimens have not shown a
survival advantage over more widely used doxorubicin-
based therapies [2,6]. Paclitaxel may, however, may be
of greater benefit than doxorubicin in patients with ad-
vanced, unresectable AS [13].
5. Recommendations
Angiosarcoma is incompletely understood and is gener-
ally very aggressive. Unfortunately, AS is likely to in-
crease in incidence. With the appropriate pathological
analyses it is possible 1) to make an early diagnosis, 2) to
monitor the tumor for treatment efficacy, and 3) to sur-
vey for recurrence. Interestingly our patient’s malign-
nancy was positive for p63, which alters VEGF expres-
sion [17] and is identified in approximately 22% of an-
giosarcomas. However, this marker is somewhat non-
specific and its presence should be carefully interpreted.
In contrast, the identification of establish ed markers such
as CD34 may yield more helpful prognostic and surveil-
lance information [18]. Based on clinical and pathologic
characteristics, we used a staged, multidisciplinary ap-
proach to post-mastectomy reconstruction, which favors
definitive reconstruction only after appropriate time for
adjuvant treatment and follow-up to rule-out disease re-
currence has occurred. Unfortunately, our patient did
have local recurrence following the first-stage of treat-
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