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Vascular Lesions of the Breast
Gabrielle M. Baker, Stuart J. Schnitt

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Vascular Lesions of the Breast

Gabrielle M. Baker, M.D. and Stuart J. Schnitt, M.D.
Department of Pathology
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, MA

Corresponding Author:
Stuart J. Schnitt, M.D.
Departmen of Pathology
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Phone: 617-667-4344
Fax: 617-975-5620
E-mail:


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Vascular lesions of the breast comprise a heterogeneous group that includes a variety of
benign, atypical, and malignant lesions. The presentation of these lesions ranges from those that
are microscopic and discovered incidentally, to large tumors that may extensively involve the
breast parenchyma and skin. In addition, some breast lesions have features that may mimic those
of vascular lesions and need to be distinguished from them in order to avoid an erroneous
diagnosis. In this review, we discuss the spectrum of vascular lesions of the breast with particular
emphasis on those lesions of greatest clinical importance, angiosarcoma and atypical vascular
lesions. We also discuss lesions that may be mistaken for vascular lesions.

BENIGN VASCULAR LESIONS
Benign vascular lesions of the breast are relatively uncommon and several categories

have been recognized including perilobular hemangioma, hemangioma (capillary, cavernous,
complex, and venous types), and angiomatosis [1-4]. The major clinical importance of benign
vascular lesions is that they must be distinguished from angiosarcoma. As a general rule, benign
vascular lesions are circumscribed and lack the interanastomosing channels and the endothelial
atypia and proliferation seen in angiosarcomas [5]. However, some angiosarcomas have areas
that are very well-differentiated and feature a deceptively bland appearance simulating benign
blood vessels. Conversely, some benign vascular lesions may show atypical cytologic and/or
architectural features [6]. For these reasons, the distinction between a benign vascular lesion and
angiosarcoma may be difficult or impossible in limited samples, such as core needle biopsy
specimens. In this regard, some authors have suggested that all vascular lesions found in core
needle biopsy specimens require excision due to the possibility of sampling error. Others believe
that excision may not be necessary in cases in which there is radiologic-pathologic concordance


3

supporting a benign diagnosis such as hemangioma. However, this is likely to be an infrequent
occurrence [7].
Perilobular hemangiomas are the most common vascular lesions of the breast. Their
reported frequency ranges from as low as 1.2% to as high as 11% of breast specimens [8, 9].
Perilobular hemangiomas are always incidental microscopic findings, typically measuring
<2mm, and may be easily overlooked [1, 8-12]. They are capillary hemangiomas that consist of a
circumscribed collection of small, thin-walled, variably ectatic vascular spaces lined by
relatively inconspicuous, flattened endothelial cells that lack cytologic atypia (Fig. 1). Despite
their designation as “perilobular” they may involve the intralobular stroma, interlobular stroma,
or both. Rarely, perilobular hemangiomas exhibit endothelial cell atypia (“atypical perilobular
hemangioma”) [1]. These lesions have no known clinical significance and surgical excision is
generally not necessary when they are detected in core needle biopsy specimens.
Hemangiomas are benign vascular lesions that are large enough to be detected clinically
or mammographically [1]. In general, they are microscopically well-circumscribed and lack

endothelial cell atypia. However, in some cases vessels extend into the surrounding breast
parenchyma or adipose tissue, which produces an appearance worrisome for low-grade
angiosarcoma. Mammary hemangiomas have been subcategorized as capillary (composed of
compact, sometimes lobular, collections of small blood vessels that resemble a pyogenic
granuloma), cavernous (characterized by dilated blood vessels filled with erythrocytes), complex
(consisting of a mixture of small vessels as seen in the capillary type and dilated vessels as seen
in the cavernous type), and venous (featuring vascular structures that contain muscular walls of
varying thickness) [3, 4] (Fig. 2). In addition, some lesions with features otherwise characteristic


4

of benign hemangiomas exhibit atypical changes, such as endothelial cell atypia or focally
anastomosing vascular channels (“atypical hemangiomas”) [6].
As with vascular lesions in other sites, thrombosis may occur in the vessels comprising
mammary hemangiomas (as well as in normal or ectactic blood vessels/varices in the breast or
mammary subcutaneous tissue). Organizing thrombi in these vessels may exhibit papillary
endothelial hyperplasia, a lesion which in its fully developed form is characterized by numerous,
often delicate papillary structures covered by endothelial cells. Further, the papillae may fuse and
produce complex patterns that resemble the interanastomosing channels seen in angioarcomas
[13, 14] (Fig. 3). In such cases, the underlying benign vascular lesion or blood vessel(s) and the
intravascular location of this process may be difficult to recognize. However, unlike
angiosarcomas, papillary endothelial hyperplasia involving benign vascular lesions (or normal or
ectatic blood vessels) is typically well-circumscribed with a pushing border which displaces
rather than invades surrounding tissue, and lacks endothelial atypia [14].
Angiomatosis is a rare lesion composed of dilated, anastomosing vascular spaces that are similar
to angiomatoses in other sites. The walls of these spaces may contain sparse, smooth muscle
fibers and lymphocytes. Endothelial cell atypia is not present. Although these are benign lesions,
they extend around mammary ducts and lobules and often involve large areas of the breast. In
addition, angiomatosis lacks the circumscription that characterizes most other benign vascular

lesions, making the distinction from a low-grade angiosarcoma problematic in some cases [2].
Two histologic patterns of angiomatosis have been described. Most commonly, the lesion is
characterized by a diffuse and extensive proliferation of vascular structures of varying caliber
and type [2, 10, 13, 15, 16]. Although the lesion demonstrates an infiltrative pattern, the
mammary epithelial structures are displaced rather than disrupted by the vascular proliferation


5

[2, 15, 17, 18] (Fig. 4). This is in contrast to the destructive nature of the infiltrating vessels of
angiosarcoma. The proliferation is predominantly localized to the interlobular stroma with
relative sparing of the intralobular stroma [10, 18]. A relatively even distribution of the vascular
proliferation is observed throughout the lesion; vascular anastomoses may be observed [2, 10].
The walls of the larger, typically venous, vessels may be irregular with areas of attenuation [13,
16, 19]. The vascular structures comprising angiomatosis are lined by cytologically bland
endothelial cells that lack hyperchromasia, atypia, endothelial tufting, and mitotic activity [2, 10,
15, 17, 20]; neither “blood lakes” nor necrosis are present [2, 10, 15, 17, 20, 21]. Although a
subset of the lesional vessels may exhibit a muscular wall, the bulk of the vascular proliferation
tends to be supported by scant stroma devoid of a significant smooth muscle component [2, 17,
21, 22]. Not infrequently, discrete foci of capillary-sized vessels may be observed within the wall
of or in proximity to larger venous structures [13, 16, 23]. An unusual subtype of angiomatosis,
the capillary variant, is composed of clusters of histologically benign capillaries scattered
throughout fibrous stroma and adipose tissue [16, 22].
Similar to angiomatoses at other anatomic sites, mammary angiomatosis is a benign
lesion that may be locally aggressive and may recur if not adequately excised [2, 10, 13, 15-17,
20, 21, 23].

ANGIOSARCOMA
Angiosarcomas are the most frequent primary sarcomas of the breast, but are still very
uncommon, accounting for <0.05% of breast malignancies. They may arise sporadically (primary

angiosarcoma) or following radiation therapy for breast cancer (secondary angiosarcoma).
Primary angiosarcomas typically involve the mammary parenchyma and may secondarily
involve the skin. In contrast, secondary angiosarcomas that develop after radiation most often


6

involve the skin of the breast alone, but may also involve the underlying breast parenchyma.
Less commonly, they involve only the mammary parenchyma [24-27]. Angiosarcomas may also
arise in the arm following radical mastectomy as the result of chronic lymphedema (StewartTreves syndrome); however, this is rarely seen in current practice where radical mastectomies
are uncommonly performed [28].
The age range at presentation of patients with angiosarcomas is broad, but patients with
primary angiosarcomas are usually younger (median age 35-40 years) than those with secondary
angiosarcomas (median age 59-69 years). Angiosarcomas of the mammary parenchyma present
as a painless mass; those that involve the skin may appear as areas of blue or violaceous
discoloration.
On gross examination, the tumors range in size from <1 cm to >20 cm; the majority are
>2 cm. Angiosarcomas most often appear as hemorrhagic masses; larger tumors may have areas
of necrosis or cystic degeneration. On microscopic examination, angiosarcomas are characterized
by interanastomosing vascular spaces that dissect through the mammary stroma and adipose
tissue and surround, invade, and disrupt normal lobules. The vascular spaces are lined by
endothelial cells that show varying degrees of nuclear hyperchromasia and atypia. Erythrocyte
extravasation into the stroma is commonly present. In some angiosarcomas, the vascular spaces
at the invasive edge of the tumor may appear deceptively bland and may be extremely difficult to
distinguish from benign blood vessels.
Angiosarcomas have been subdivided into low-, intermediate-, and high-grades based on
a combination of histologic features [5]. Low-grade angiosarcoma is characterized by bland,
well-formed vascular channels demonstrating a permeative growth pattern that dissects through
the breast parenchyma [5, 10, 15, 21, 30, 32-35]. This infiltrative proliferation of



7

interanastomosing neoplastic vessels is typically lined by a single layer of variably attenuated
endothelium that may exhibit hyperchromasia but lacks significant cytologic atypia or
conspicuous nucleoli [5, 10, 15, 29-31, 34, 36-38] (Fig. 5 A and B). Low-grade angiosarcoma
lacks the variably complex papillary structures observed in higher grade lesions [5, 14]. Minimal
mitotic activity is identified and the proliferation lacks foci of solid growth, hemorrhage, and
necrosis [5, 10, 15, 29, 31, 34]. A rare variant of low-grade angiosarcoma is composed
predominantly of capillary-sized vessels [15].
At the other end of the spectrum, high-grade angiosarcoma may show little to no overt
evidence of vasoformation although foci resembling low-grade angiosarcoma may be scattered
throughout and may be particularly prominent at the periphery of the lesion [5, 31, 32, 37].
Whereas in low-grade angiosarcoma the vascular channels are typically lined by a single layer of
endothelial cells, in high-grade lesions the endothelium is often multilayered, with tufting and
formation of variably complex papillary structures [14, 15, 39]. Additionally, foci of solid
growth are characteristically present [5, 10, 14, 15, 29, 34, 36-38, 40, 41] (Fig. 5 C and D). The
malignant endothelial cells in the solid areas may be spindle shaped or epithelioid in morphology
[5, 10, 14, 15, 29, 34, 36, 38, 41, 42]. When a high-grade angiosarcoma is composed solely of
epithelioid cells, a diagnosis of epithelioid angiosarcoma may be rendered; the endothelial cells
of such lesions typically demonstrate vesicular nuclei and relatively abundant cytoplasm [43]
(Fig. 6). Foci of marked nuclear pleomorphism and frequent mitotic figures, including atypical
forms, are present [10, 14, 15, 29, 34, 40]. Necrosis and hemorrhage may be extensive with the
formation of so-called “blood lakes”, a finding considered pathognomonic for high-grade
angiosarcoma by some authors [5, 10, 14, 15, 29, 34, 37, 38, 40, 41].


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Intermediate-grade angiosarcoma is typically composed predominantly of well-formed

interanastomosing vascular channels lined by hyperchromatic endothelial cells characteristic of
low-grade angiosarcoma; however, a greater degree of nuclear pleomorphism, mitotic activity,
and endothelial proliferation is present [10, 29, 31, 34, 36, 40, 41]. The endothelial proliferation
may manifest as multilayering of cells lining the vascular spaces, endothelial tufting, and the
formation of papillary structures protruding into the vascular spaces [5, 10, 29, 34, 37, 40, 41].
Additionally, foci of more cellular or solid growth may be present [5, 29, 31]. Focal necrosis or
focal hemorrhage may be identified, but these are not as extensive as is seen in high-grade
lesions [34, 40, 41].
Although many angiosarcomas may be readily classified according to this grading
system, a subset of lesions demonstrates overlapping features making assignment of grade
problematic. In the past, grading of angiosarcomas was thought to have prognostic importance.
In the most widely cited study to address the relationship between grade and outcome, the 5-year
survival was 76%, 70%, and 15% for low-, intermediate-, and high-grade angiosarcomas,
respectively [31]. However, a subsequent study failed to demonstrate a relationship between
grade of angiosarcoma and outcome; this is more in keeping with the lack of a relationship
between grade and outcome for angiosarcomas in non-mammary sites [34].
Angiosarcomas require complete excision and are most often treated by mastectomy.
Axillary lymph node involvement is rare. Local recurrences are common even when margins of
the initial surgical specimen are negative [27, 44, 45]. The most common sites of metastatic
spread are the lungs, liver, contralateral breast, other skin and soft tissue locations, and bone [27,
43]. The prognosis is generally poor with a median recurrence-free survival rate less than 3 years
and a median overall survival less than 6 years [10, 27]. Some authors have reported that the


9

prognosis of secondary angiosarcomas is worse than that of primary angiosarcomas, but all series
are limited by small numbers of patients [27, 46].
About 10% of mammary angiosarcomas demonstrate activating mutations in KDR, the
gene that encodes vascular endothelial growth factor receptor 2 [30, 47]. Mutations in the

angiogenesis-related genes PTPRB and PLCG1 have also been described in some cases [48].
These findings, as well as the observation of FLT4 amplification in some angiosarcomas as noted
below, provide a rationale for therapeutic targeting of angiogenic pathways in these tumors [26,
49].
Several features of secondary angiosarcomas of the breast merit particular comment. The
interval between radiation and the development of angiosarcoma is substantially shorter (median
5-6 years) than that noted for other radiation-related malignancies in which the time between
irradiation and malignancy is often 10 years or more [10]. In fact, some secondary
angiosarcomas have developed within as little as 2 years after radiation. In addition, although all
grades of angiosarcoma have been recognized in this setting, most have intermediate- or highgrade areas. A striking observation in secondary angiosarcoma is the discordance between the
degree of nuclear atypia and the degree of architectural complexity such that significant
cytologic atypia is often present even in tumors with very well-formed neoplastic vessels (Fig.
7). In contrast, discordance between nuclear grade and architectural atypia is not a common
observation in primary angiosarcoma [24]. Finally, recent studies have shown that secondary
angiosarcomas commonly show MYC amplification [26, 30, 50-53]. This feature appears to
distinguish these lesions from primary angiosarcomas and from atypical vascular lesions, both of
which lack amplification of this oncogene [30, 51-55]. Amplification of FLT4 (which encodes
vascular endothelial growth factor receptor 3) has also been identified in secondary


10

angiosarcomas but not in primary angiosarcomas or atypical vascular lesions, and FLT4 is
typically co-amplified with MYC [30, 51, 53]. While these findings are of great interest, it
remains to be determined whether amplification of MYC and/or FLT4, or the demonstration of
their corresponding proteins by immunohistochemistry, will be of value diagnostically for
distinguishing secondary angiosarcomas from atypical vascular lesions in histologically
ambiguous cases (Fig. 8).
Although the diagnosis of angiosarcoma is straightforward in most cases, diagnostic
problems may arise. Differential diagnostic considerations for low-grade angiosarcomas include

hemangiomas of various types, angiolipomas, papillary endothelial hyperplasia, atypical vascular
lesions, and PASH. It has been proposed that the Ki67 proliferation rate may be used to
distinguish between low-grade angiosarcoma and hemangioma in diagnostically problematic
cases [56]. While the Ki67 proliferation rate is significantly higher for low-grade angiosarcomas
as group than for hemangiomas as a group, the utility of Ki67 staining in making this distinction
in an individual case is less certain. As noted above, high-grade angiosarcomas, particularly
those in which the endothelial cells have a more epithelioid appearance, may be difficult to
distinguish from carcinomas. In addition, some spindle cell carcinomas demonstrate
pseudovascular spaces that may mimic angiosarcoma. In problematic cases, immunostains for
endothelial markers (such as factor VIII-related antigen, CD31, CD34, D2-40, ERG, and FLI1)
and epithelial markers (such as cytokeratin, EMA) may be necessary to distinguish between
angiosarcoma and carcinoma [30] (Fig. 9). It should be noted, however, that some
angiosarcomas may exhibit cytokeratin expression, particularly those with an epithelioid pattern;
therefore, cytokeratin antibodies should never be used in isolation to attempt to distinguish an


11

epithelioid angiosarcoma from a carcinoma. Finally, some high-grade angiosarcomas may be
difficult to distinguish from other types of spindle cell sarcoma.

ATYPICAL VASCULAR LESIONS
In 1994 Fineberg and Rosen described a group of localized vascular proliferations of the
mammary skin in women who had undergone previous breast conserving surgery and radiation
therapy for breast cancer [57]. The lesions they described were composed of ectatic vessels with
cytologically bland endothelial cells which were restricted to the dermis; they regarded these
cutaneous lesions as an uncommon manifestation of radiation injury and termed them “atypical
vascular lesions” (AVL) [57]. Similar or identical lesions have been described under a variety of
other terms including benign lymphangiomatous papule or plaque, benign
lymphangioendothelioma, acquired progressive lymphangioma, acquired lymphangiectasis, and

lymphangioma circumscriptum [26, 58-60]. Although Fineberg and Rosen concluded that these
were benign lesions unrelated to angiosarcoma, others have suggested AVL may represent part
of a spectrum of post-radiation vascular proliferations and a precursor to angiosarcoma.
AVL typically present as discrete, small, colorless, flesh-colored or erythematous
papules, vesicles, or plaques arising within the radiation field in the breast skin; telangiectasia
may be noted [24, 26, 57-61]. Up to half of affected patients develop multiple lesions, either
synchronously or metachronously [24, 57, 59, 61]. A wide age range has been reported, although
the majority of patients are in their 6th-7th decades, with a mean reported age of 61 years (range,
29-95 years) [58-62]. The median latency period between radiation and development of AVL is
typically 3-6 years, an interval somewhat shorter than that observed for secondary
angiosarcomas [27, 57, 59, 61, 63].


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The histologic appearance of AVL presents a significant diagnostic dilemma for the
pathologist as there may be great overlap with angiosarcoma. Low-power examination
characteristically demonstrates a relatively circumscribed, symmetric, wedge-shaped dermal
lesion with its base oriented toward the dermal-epidermal junction [57-61, 64]. Although the
vessels are predominantly located in the superficial dermis, involvement of the deeper reticular
dermis may be observed; involvement of the underlying subcutaneous tissue may uncommonly
occur [27, 57-59, 61, 63].
Closer evaluation of the constituent vessels typically demonstrates variably dilated, thinwalled vessels lined by a single layer of cytologically bland endothelial cells; the endothelial cell
nuclei may protrude in a hobnail manner and exhibit hyperchromasia but conspicuous nucleoli,
significant cytologic atypia, mitotic activity, and necrosis are not evident [57, 59, 61, 64] (Fig.
10). Rarely, focal multilayering of endothelium has been described [63]. The vessels are variably
ectatic and irregular; vascular anastomoses may be observed and focal dissection of the dermal
collagen may be present [57, 58, 61]. Thin papillary stromal projections covered by endothelium
are frequently observed to project into the vascular lumina, an observation that has been likened
to the lymphatic counterpart of papillary endothelial hyperplasia [57, 58, 63, 65]. The lumina are

typically devoid of erythrocytes; a lymphocyte-predominant chronic inflammatory cell infiltrate
is frequently present in the vicinity and may be remarkable for germinal center formation [57,
58, 61, 63].
Two types of AVL have been described: lymphatic-type and vascular-type, with mixed
features often noted [59]. The lymphatic type is composed of empty, variably ectatic vessels
reminiscent of lymphangioma and is most similar to the lesion originally described by Fineberg
and Rosen [57]. The vascular type resembles a capillary hemangioma and is composed of


13

variably attenuated and irregularly dispersed capillary-sized vessels lined by hobnailed
endothelial cells and often containing erythrocytes [58, 59]. The vascular type may demonstrate
mild endothelial atypia [59]. The entity classified as the capillary lobule pattern of angiosarcoma
has been grouped with the vascular type of AVL by some [59]. The endothelial cells in both
lymphatic and vascular type AVL show staining for CD31 and variably express CD34; the
endothelial cells of the lymphatic type are D2-40 positive whereas those of the vascular type are
D2-40 negative [58, 59]. Although the lymphatic type lacks circumferential pericytes as
demonstrated on smooth muscle actin immunostains, the vessels of the vascular type are invested
by pericytes [58, 59].
AVL may recur and patients not infrequently develop new lesions. Therefore, lesions
clinically suggestive of AVL should be excised to negative margins to ensure that unsampled
areas with sufficient combined cytologic and architectural atypia for a diagnosis of angiosarcoma
are not overlooked [24, 57-59, 61, 63]. Close clinical follow-up is critical to ensure that no new
or recurrent skin lesions are left undiscovered. Similarly, any subsequent lesion arising within
the radiation field should be evaluated histologically. Furthermore, it is recommended that a
diagnosis of AVL not be rendered on limited biopsy material; on a biopsy, it is prudent to
categorize the lesion non-specifically as ‘atypical vascular proliferation’ with final categorization
deferred to the evaluation of the surgical excision specimen. Although AVLs may mimic other
benign vascular proliferations including capillary hemangioma and lymphangioma

circumscriptum, the entity most critical to distinguish AVL from is low-grade angiosarcoma. As
noted above, AVLs were historically regarded as benign post-radiation vascular proliferations
with no risk of progression to malignancy, a stance which is maintained by some investigators;
others regard AVL as a potential precursor to angiosarcoma [24, 26, 57-59, 61-63]. Even in their


14

seminal article, Fineberg and Rosen acknowledged that significant clinical and histologic overlap
exist between AVL and secondary angiosarcoma; however, they distinguished AVL on the basis
of their benign clinical course [57]. To date, no reports of metastasis or death due to a vascular
neoplasm have occurred in patients with a diagnosis of AVL only. The natural history and
malignant potential of AVL remains uncertain as does the relationship between AVL and
secondary angiosarcoma. Whereas some authors favor that AVL and secondary angiosarcoma
represent discrete entities others suggest that they constitute points along a clinicopathologic
spectrum of post-radiation vascular proliferations [24, 66].
The histologic distinction of AVL from secondary angiosarcoma currently lacks strict
histologic parameters; significant histologic overlap exists and some lesions defy classification.
Both lesions are composed of an anastomosing vascular proliferation originating in the dermis.
Having observed that secondary angiosarcoma frequently infiltrates the subcutis it was
previously thought that involvement of subcutaneous tissues constituted a means of
differentiating the two entities; however, AVL may occasionally extend into the subcutis [59]. In
contrast to the overtly infiltrative growth characteristic of angiosarcomas, AVL tends to be welldemarcated often with a wedge-like shape [58]. AVLs have a wide histologic spectrum ranging
from bland superficial proliferations of dilated lymphatic channels to more complex combined
lymphatic and capillary proliferations but AVL lack the complex architecture typically present in
angiosarcoma. However, multilayering of endothelial cells which is characteristic of
angiosarcoma may be focally present in AVL [63]. Some authors have suggested that vascular
type AVL are more likely to display cytologic atypia and have a greater likelihood of
progression to angiosarcoma, including high-grade or epithelioid angiosarcoma [59]. In contrast,
others have reported an increased risk of angiosarcoma with lymphatic AVLs [24, 27, 60, 61].



15

Despite a few reports of progression, even AVLs with cytologic atypia usually have a benign
clinical course [57, 58, 63]. However, despite cytologic atypia in a subset of AVL, the degree of
atypia falls short of that observed in most angiosarcomas. Even in angiosarcomas with a lowgrade architectural appearance, the nuclear features tend to be discordant, with intermediate to
high-grade cytologic atypia observed.
Many unequivocal secondary angiosarcomas have areas that, in isolation, are
histologically indistinguishable from AVL. These areas are most often localized to the
superficial and peripheral portions of the lesion although they may be scattered throughout. In
such cases, a lesion that appears to be an AVL on biopsy may be upgraded on excision due to
sampling bias, an observation that has been referred to as a ‘tip of the iceberg’ phenomenon [60].
Indeed, in one series 5 of 11 cases diagnosed as AVL on initial biopsy were found to be
angiosarcomas on excision [60]; similar upgrade rates have been found in other series [59, 61].
The observation of AVL-like areas in angiosarcoma may account, in part, for cases of purported
progression from AVL to angiosarcoma. The potential for sampling error is particularly evident
in small biopsies and reinforces the importance of complete excision for post-radiation vascular
proliferations. Additionally, lesions consistent with AVL have been identified in grossly
uninvolved skin of patients with angiosarcoma, a finding similar to the lymphangiomatosis
frequently observed in clinically uninvolved tissue of patients with Stewart-Treves syndrome;
this finding further supports the proposal that AVL may represent a pre-malignant condition [57,
64].
It has recently been suggested that the radiation dermatitis-like pattern of secondary
angiosarcoma may represent a transitional form between AVL and secondary angiosarcoma [67].
Additional lesions with sufficient cytologic atypia for a diagnosis of angiosarcoma but with


16


simple architecture and maintained investiture of pericytes have been proposed as AVL evolving
to secondary angiosarcoma [24].

MIMICS OF VASCULAR LESIONS
Pseudoangiomatous stromal hyperplasia (PASH)
PASH is a benign proliferation of stromal fibroblasts and myofibroblasts. Although the original
description of PASH applied to discrete mass-forming lesions (so-called ‘nodular PASH’),
PASH is more commonly identified as an incidental microscopic finding in specimens procured
for a variety of other indications. In a review of 200 consecutive breast specimens, one series
identified incidental foci of PASH in 23% of cases; in 60% of these multiple foci of PASH were
identified [68]. PASH may also be seen in association with other breast lesions, particularly
fibroadenomas and phyllodes tumors, and is commonly present in conjunction with
gynecomastia. Most female patients with PASH are premenopausal. The association of PASH
with gynecomastia and the preferential occurrence in premenopausal women suggests that
hormonal factors may be involved in the development and/or growth of these lesions.
Nodular PASH is a grossly well-circumscribed, non-hemorrhagic nodule that may be
reminiscent of a fibroadenoma; the cut surface is typically homogeneous and tan-white to yellow
[69-73]. Microscopically, PASH is characterized by slit-like spaces mimicking capillaries that
may appear to show anastomoses. These cleft-like spaces are typically empty and are
discontinuously lined by cytologically banal spindle cells with poorly defined cell borders that
mimic endothelial cells [68-71, 74, 75]. The involved stroma may be densely hyalinized/keloidal
in appearance [68-70] (Fig. 11). The stromal proliferation of PASH appears to disrupt and
separate the stromal collagen fibers. PASH may involve interlobular and intralobular stroma;
when present in association with epithelial elements, a concentric or fascicular configuration


17

may be noted [68-70]. When PASH involves the intralobular stroma it does not disrupt or
destroy pre-existing epithelial structures [69]. In a subset of PASH cases the spindle cells

comprising the lesion aggregate and lack the characteristic slit-like spaces, a pattern referred to
as “fascicular PASH” [15, 68, 70]. The cells of fascicular PASH typically have a more myoid
appearance and these foci may closely resemble areas seen in myofibroblastomas [70] (Fig. 12).
Fascicular PASH typically merges with foci of conventional PASH. Epithelial hyperplasia of the
usual type is frequently observed in the vicinity of PASH, particularly when PASH involves the
intralobular stroma; this hyperplasia frequently has a micropapillary appearance similar to that
observed in gynecomastia [69-71, 74, 76].
Rare cases of PASH exhibit modest nuclear pleomorphism and hyperchromasia as well
asoccasional mitotic figures; these findings may be observed in conventional as well as
fascicular PASH [68-71]. Such cases may be termed ‘atypical’ although the clinical significance
of these findings is uncertain. Occasionally, multinucleated stromal giant cells may line the slitlike spaces of PASH [76]. Extremely rarely, the stromal cells of PASH may demonstrate
cytoplasmic inclusions similar to those observed in digital fibromas [22].
The stromal cells of PASH are positive for vimentin and CD34; variable expression of
bcl-2, desmin, and smooth muscle actin is observed [15, 70, 71, 74, 76]. Although the nuclei of
PASH are frequently PR positive, ER is typically negative [70, 71, 73-75, 77, 78]. The stromal
cells of PASH are negative for cytokeratins, EMA, ERG, CD31, D2-40, von Willebrand factor,
Ulex europaeus antigens, Factor VIII antigen, CD68, CD99, and S100 [70-74, 76, 77]. Periodic
acid-Schiff stain does not identify basement membrane in association with the
pseudoangiomatous spaces [69]. The same immunohistochemical profile is observed in PASH
whether occurring in females or males. Although CD34 expression in PASH was initially


18

unexpected, its expression in a population of cells that also express SMA and desmin supports a
myofibroblastic phenotype for these cells [70]. Of note, desmin and SMA expression is typically
more conspicuous in fascicular PASH, corresponding to greater myoid differentiation in this
variant [70].
PASH is a benign lesion that is adequately treated by local excision. Patients with a
diagnosis of PASH on a core needle biopsy do not require surgical excision provided that the

diagnosis of PASH is concordant with the findings on imaging studies [79]. A recent follow-up
study demonstrated that patients with PASH do not have an increase in their risk of subsequent
breast cancer [80]. The major importance of PASH is that it must be distinguished histologically
from a true vascular lesion, specifically angiosarcoma.
Angiolipoma
Angiolipoma is a variant of lipoma rather than a vascular lesion [10, 15, 81]. However, a
vascular lesion involving adipose tissue is often a diagnostic consideration when these lesions
are encountered, particularly in core needle biopsy specimens. Angiolipomas may arise in the
breast parenchyma but are more often seen in the mammary subcutaneous tissue [4, 15, 82].
They may come to clinical attention as a palpable mass or an incidental finding on imaging
studies [83]. Gross examination of a surgically excised angiolipoma demonstrates a wellcircumscribed lesion with a tan-yellow to brown cut surface [81, 84]. Microscopically, capillarysized vessels are admixed with mature adipose tissue. Fibrin thrombi are often present within the
vascular lumina [10, 15, 21, 81, 82] (Fig. 13). The endothelial cells are cytologically banal [10,
81]. The ratio of adipocytic to vascular components is variable and there may be heterogeneity
within a given lesion [81]. Regardless of the relative proportions of vascular and adipocytic
components, the vessels tend to be distributed unevenly throughout the lesion with frequent


19

disposition and aggregation toward the periphery [81, 82]. Rarely, an irregular or infiltrative
border may be seen [83]. The diagnosis of the cellular variant of angiolipoma is appropriate for
lesions in which the vascular component constitutes in excess of 50% of the tumor volume [82].
The cellular variant may, in particular, present a histologic appearance that raises concern for an
angiosarcoma (Fig. 14). Angiolipomas are benign lesions. If a definitive diagnosis can be
confidently rendered on core needle biopsy, surgical excision is not necessary.


20

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