Late recurrent cutaneous breast angiosarcoma in an elderly woman: A case report

Abstract

Breast angiosarcomas are malignant tumours of the vascular endothelium that arise frequently following radiation therapy. Their clinical and radiological aspects are highly heterogeneous. The current study reports an unusual case, never previously reported, of a late recurrent breast angiosarcoma occurring in an 83-year old female patient 11 years after a breast-conserving surgery followed by radiation therapy for an invasive ductal carcinoma, and 5 years after her initial angiosarcoma excision. The first physician to examine the patient noted a palpable mass near the scar and, following ultrasonography, described the breast lesion as suggestive of an abscess, despite the previous history of neoplasia. Typically, recurrences of breast angiosarcoma occur within the first postsurgical year. The present patient remains alive at 25 months after her last surgical treatment, and no evidence of any local or distant disease is observable.

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ONCOLOGY LETTERS
Abstract. Breast angiosarcomas are malignant tumours of the
vascular endothelium that arise frequently following radiation
therapy. Their clinical and radiological aspects are highly
heterogeneous. The current study reports an unusual case,
never previously reported, of a late recurrent breast angiosar‑
coma occurring in an 83‑year old female patient 11 years after
a breast‑conserving surgery followed by radiation therapy
for an invasive ductal carcinoma, and 5 years after her initial
angiosarcoma excision. The rst physician to examine the
patient noted a palpable mass near the scar and, following
ultrasonography, described the breast lesion as suggestive of
an abscess, despite the previous history of neoplasia. Typically,
recurrences of breast angiosarcoma occur withi n the rst post‑
surgical year. The present patient remains alive at 25 months
after her last surgical treatment, and no evidence of any local
or distant disease is observable.
Introduction
Breast angiosarcoma (BA) is a rare malignant endothelial
tumour (1,2). This tumour may be distinguished into primary
and secondary forms; the overall yearly incidences are
reported in the literature as 0.002‑0.05% and 0.01‑0.02%,
respectively (1). The aetiology of primary BA, typically occur‑
ring in women <40 years of age, remains unknown (2). These
neoplasms present as a growing, palpable mass that arises in
the non‑irradiated breast parenchyma, with rare skin involve‑
ment (3). Secondary BA may occur more frequently after the
fourth decade of life, particularly in patients who have already
been treated with radiation therapy following breast‑conserving
surgery (2‑5). It presents as painless, multifocal skin changes
that may be neglected or misdiagnosed, or as a breast lump (3).
Postoperative chronic lymphoedema is also indicated as a
potential causal factor for the development of angiosarcoma in
the breast and in the upper extremities, where it is known as
Stewart‑Treves syndrome (2). BA generally arises 3‑12 years
after the initial surgical and radiation therapies (6). Recurrences
are rare >2 years after surgery, and their predominant character‑
istics are clinical and imaging heterogeneity (1,5).
The current study presents an unusual ca se of non‑metastatic
late recurrent BA in an elderly woman with atypical clinical
features, including a long time interval between the first
and second occurrences of angiosarcoma, and a 25‑month
disease‑free survival period.
Case report
An 83‑year‑old female, exhibiting a supercial, palpable pain‑
less lump in the left breast that had appeared ~1 month prior,
was admitted to the General Surgery Unit of the University
Hospital of Messina (Messina, Italy) in January 2013. Her
history included hypertension, gastritis and osteoarthritis.
In 2002, the patient had undergone a left superoexternal
quadrantectomy with synchronous ipsilateral axillary lymph
node dissection for an invasive ductal carcinoma. The lymph
nodes did not appear to be involved despite the presence of
palpable nodes in the axilla, and the patient also developed
slight postoperative lymphoedema. She was then assigned
to receive adjuvant radiotherapy in association with a
5‑year hormone‑therapy schedule, consisting of tamoxifen
(20 mg/day). Whole breast irradiation was performed at a dose
of 50 Gy in 25 fractions (200 cGy/fraction), plus a boost of
10 Gy (200 cGy/fraction) on the breast bed, between May and
June of 2002.
In 2008, the patient underwent a Madden mastectomy for a
secondary angiosarcoma (7). The anatomopathological exami‑
nation of the latter indicated a cutaneous, well‑differentiated
angiosarcoma of 15 mm in its largest diameter, with moder‑
ately atypical spindle cells delimiting thin vascular spaces;
the tissue also exhibited frequent mitoses, a moderate (30%)
MIB‑1 labelling index (LI), and an intense immunoreaction to
endothelial markers, including cluster of differentiation (CD)31
and CD34. No adjuvant treatment was performed following the
last surgical procedure, in accordance with the recommenda‑
tion of the International Society of Geriatric Oncology (8).
When assessed in January 2013, the patient presented
a cutaneous mass in the upper‑inner quadrant of the breast,
Late recurrent cutaneous breast angiosarcoma
in an elderly woman: A case report
FAUSTO FAMA', LUANA LICATA, ALESSANDRA VILLARI,
JESSICA PALELLA, GIUSEPPE SPECIALE and MARIA GIOFFRE'‑FLORIO
Department of Human Pathology, University Hospital of Messina, Messina 98125, Italy
Received March 9, 2015; Accepted January 12, 2016
DOI: 10.3892/ol.2016.4389
Correspondence to: Professor Fausto Fama', Department of Human
Pathology, University Hospital of Messina, 1 Via Consolare Valeria,
Messina 98125, Italy
E‑mail: famafausto@yahoo.it
Key wo rds: breast, angiosarcoma, radiotherapy, recurrence

FA M A' et al: LATE RECURRENT BREAST ANGIOSARCOMA
2
~25 mm in diameter, surrounded by a hyperaemic area, with
no other systemic symptoms or abnormal clinical ndings
(Fig. 1). An ultrasound scan (Esaote MyLab™ 25; Esaote
SpA, Genoa, Italy) of the breast conrmed a circumscribed
hypo‑anechoic oval nodule (~22 mm in diameter) located in
the left upper‑inner breast quadrant, with an irregular vascular
pattern observed on colour Doppler, and a posterior acoustic
increase (Fig. 2). A previous practitioner had considered this
finding to be suggestive of an abscess, despite the history
Figure 6. Intense and homogeneous cytoplasmic immunoreactivity for CD34
antibody (immunoperoxidase + Mayer's haemalum counterstain; magnica‑
ti on, x16 0).
Figure 1. Cutaneous painless lump in the superomedial quadrant of the left
breast surrounded by a hyperaemic area.
Figure 2. Hypo‑anechoic oval nodule (22 mm in largest diameter) with pos‑
terior acoustic enhancement.
Figure 3. Rich network of thin reddish vessels (arrow) lined with atypical
endothelial cells, in the context of breast glandular stroma (hematoxylin
eosin staining; magnication, x200).
Figure 4. Tumour cell proliferation was high. MI B‑1 labelling index, >80%
(immunoperoxidase + Mayer's haemalum counterstain; magnication, x160).
Figure 5. Intense and homogeneous cytoplasmic immunoreactivity for CD31
antibody (immunoperoxidase + Mayer's haemalum counterstain; magnica‑
ti on, x16 0).

ONCOLOGY LETTERS 3
of neoplasia in the patient. Following ne‑needle aspiration
cytology, performed by means of a 25‑gauge needle, a mesen‑
chymal neoplasm was suspected; however, these ndings were
inconclusive and did not allow the conrmation of a diagnosis.
Routine laboratory investigations yielded normal results,
with the exception of an elevated C‑reactive protein level
of 1.9 mg/dl (normal range, 0‑0.5 mg/dl). Standard thorax
radiography did not reveal any parenchymal lesions or pleural
effusions. Values for the tumour markers carcinoembryonic
antigen, carbohydrate antigen (CA)15‑3 and CA125 were in
the normal ranges.
Based on these ndings, the patient was subjected to a
superomedial second‑look excision. The tumour was highly
vascularised, and the estimated blood loss was ~50 ml. An
aspirative drain was placed locally. Grossly, the surgical spec‑
imen measured 55x28x25 mm and appeared as a cutaneous,
greyish, nodular lesion (25 mm in its greatest diameter).
Histological examination of the specimen was conducted
as follows. Formalin‑xed and parafn‑embedded specimens
were cut into 4 µm‑thick serial sections and mounted on
silane‑coated glass slides. Following de‑waxing in xylene
and re‑hydration in graded ethanol, antigen retrieval was
performed by heating slides in 0.01 M citrate buffer (pH 6.0)
in a microwave oven for 3 x 5 min. For the immunohisto‑
chemical study, sections were incubated in a moist chamber
with 0.1% H2O2 in methanol to block intrinsic peroxidase
activity, and then with normal sheep serum to prevent
nonspecic adherence of serum proteins. Subsequently, the
slides were incubated with the following primary antibodies:
Mouse monoclonal anti‑human vimentin (#GA630; Clone V9;
Dako, Glostrup, Denmark; dilution, 1:100), CD34 (#GA632;
Clone QBEnd 10; Dako; 1:50), CD31 (#GA610; Clone JC70A;
Dako; 1:50) and Ki‑67 (#GA626; Clone MIB‑1; Dako; 1:75).
The slides were then incubated with sheep anti‑mouse IgG
antiserum (#ab6808; Abcam, Cambridge, UK; 1:25) and
mouse anti‑horseradish peroxidase‑antiperoxidase complexes
(LSAB 2 System‑HRP; #K0672; Dako; 1:25) for 30 min each
at room temperature. For the demonstration of peroxidase
activity the sections were incubated in dark ness for 10 min with
3‑3'‑diaminobenzidine tetra hydrochloride (Sigma‑Aldrich,
St. Louis, MO, USA). Nuclear counterstaining was conducted
with Mayer's haemalum. Negative controls included omission
of the primary antiserum and replacement of the primary
antiserum with phosphate‑buffered saline solution (pH 7.4) or
normal horse serum; in each of these conditions, no staining
was evident. Histological sections of capillary haemangi‑
omas/haemangioblastomas were utilized as positive controls
for CD34 and CD31.
The microscopic appearance following hematoxylin‑eosin
routine staining was consistent with recurrent BA. The tumour
exhibited a pseudo‑papillary architecture constituted by a
vascular core surrounded by spindle‑ or oval‑shaped cells,
with frequent mitoses, and signica nt inlt ration of the super‑
cial and deep dermis (Fig. 3). An increa sed rat e of neoplastic
cell proliferation was revealed by the high MIB‑1 LI (>80%;
Fig. 4). On immunostaining, the evident cytoplasmic immu‑
noreactivity for CD31 and CD34 conrmed the endothelial
nature of the proliferating cells (Figs. 5 and 6), and the immu‑
nopositivity for vimentin further supported the mesenchymal
origin. Surgical margins were unaffected and clear.
The patient's in‑hospital stay was uneventful, the drainage
was removed, and she was discharged on the third postoperative
day. No complementary t reatment was prescribed. At 25 months
post‑surgery, the patient was well and free of any clinical local
recurrence or distant metastases. In the follow‑up period,
locoregional ultrasound examination ndings were normal,
and whole‑body scintigraphy and brain‑thoracoabdominal
computed tomography scans (LightSpeed VCT; GE Health‑
care, Fairfield, CT, USA) did not reveal any recurrence or
metastatic lesions.
Informed consent for the current report was obtained from
the patient.
Discussion
Angiosarcomas represent <2% of all soft tissue sarcomas (1,5).
BAs are rare neoplasms that develop from the endothelial lining
of the blood vessels (1‑3). These tumours are considered as
primary in the absence of known risk factors and, with an uncer‑
tain aetiology, they affect typically women aged <40 years (1,2).
Secondary BAs generally occur in elderly patients
subsequent to adjuvant external‑beam radiation therapy
performed with a breast‑conserving surgery, with or without
lymphoedema (5). The rst case of BA following conserva‑
tive surgery in association with radiation was reported in
1987 (9). A number of reports indicate that, following the
initial surgical and radiation therapies, the interval of latency
for the onset of an angiosarcoma is 3‑12 years (1,5,6).
These tumours are inltrative, non‑capsulated, cutaneous,
soft‑tissue sarcomas (2). Their incidence has been rising over
the past 30 years (3). Histologically, they are characterised
by high cellularity, consisting of pleomorphic endothelial
cells, spindle‑shaped, rounded or oval‑shaped, arranged in
loose or cohesive clusters or sheets, or sometimes as single
cel ls with a sca nty pale blue cytoplasm (6). BAs are cla ssied
according to Donnel's Classication (10). Well‑differentiated
tumours include open anastomosing vascular sinusoids,
with a single layer of abnormal endothelial cells that exhibit
hyperchromatic nuclei and few mitoses (2). In increasingly
aggressive disease, classied as a moderately differentiated
angiosarcoma, the vascular channels are less clearly dened,
and are associated with small foci of spindle‑shaped cells,
which are multilayered or arranged in pseudopapillary
structures with several mitoses (6). The poorly differentiated
variety exhibits malignant endothelial cells organised in
continuous sheets, generally with epithelioid features, blood
lakes and necrosis (2).
Immunohistochemistry is useful to conrm the diagnosis
of BA (2,6,10). Typically, the tumors are positive for endothelial
markers, including CD31, CD34, von Willebrand factor and
vascular endothelial growth factor (2). The pathological differ‑
ential diagnosis of this tumour includes phyllodes sarcoma,
stromal sarcoma, benign hemangioma, myoepithelioma
bromatosis, brosarcoma, liposarcoma, metaplastic carci‑
noma, squamous cell carcinoma with sarcomatoid features
and high‑grade mammary carcinoma (3). The diagnosis of
secondary BA is predominantly clinical at rst observation,
yet its appearance is highly variable in form (5,6). In the litera‑
ture, these tumours have been described as a palpable masses,
which may be painful or painless, or as an erythematous area

FA M A' et al: LATE RECURRENT BREAST ANGIOSARCOMA
4
or even as a lipoma (1,3,11). A ne‑needle aspiration biopsy is
highly recommended (2,6).
A wide‑margin surgical excision represents the treatment of
choice (2,5,12); supplementary radiotherapy boost is typically
avoided in cases of radiation‑associated BA (2). Generally, BAs
are localised and the tumour recurrences are most frequent
within 1 year from surgical treatment (5,12). Affected or
unclear surgical margins and large tumour size are considered
poor prognostic factors (2,5). Due to the increase in comple‑
mentary radiotherapy following breast conservative treatment,
great attention to skin alterations is recommended during
the follow‑up period in order to allow the early detection of
secondary lesions (1,5). Biopsies must be encouraged, and radio‑
logical results should be analysed by breast surgery specialists.
In conclusion, the current study reports a case of BA in
an elderly woman which recurred twice, 11 years after a
breast‑conserving surgery with adjuvant radiotherapy, and
5 years after the patient's rst angiosarcoma excision. To the
best of our knowledge, this has not previously been reported
in the literature. Clinicians should be aware of this unusual
occurrence and of any possible misdiagnosis.
Acknowledgements
The authors wish to thank Dr Giuseppe Campisi, a member of
the surgical team at the University Hospital of Messina.
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