Case 1 -
Epithelioid Angiosarcoma of the Breast (s/p radiation therapy
Laura C. Collins, Beth Israel Deaconess MC, Boston, MA
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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.
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")
or have organizing thrombi with concomitant papillary
endothelial hyperplasia; a pattern that may be misinterpreted as angiosarcoma . 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
Conversely, some carcinomas have pseudovascular spaces that may mimic angiosarcoma . 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
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
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
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 . 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
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.
Epithelioid Angiosarcoma of the Breast (s/p radiation therapy.
Angiosarcomas are the most frequent primary sarcomas of the breast but are still very uncommon,
accounting for less than 0.05% of breast malignancies
Angiosarcomas may be primary or they may
arise secondary to radiation therapy for breast cancer or other chest irradiation
post-radiation setting, cutaneous angiosarcoma is more common, though involvement of the mammary
parenchyma may occur . 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 . 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
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 .
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
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 .
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 .
Angiosarcomas have been divided into low, intermediate and high grades, though the grade can vary
within a single lesion . 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
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 . However, a recent study failed to demonstrate a relationship between grade of
angiosarcoma and outcome, in keeping with angiosarcomas at other sites . 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
it should be noted that all these reports are hampered by small numbers and variable treatment
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 . The most common sites of metastatic spread are the lungs, liver,
contralateral breast, other skin and soft tissue locations and bone . Recent therapeutic efforts
have shown promising results with hyperfractionated radiation therapy and radiation therapy with
as well as encouraging results with taxane therapy
 in a tumor for which the
diagnosis portends a grave prognosis.
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.
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