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Keywords:

  • angiomatosis;
  • angiosarcoma;
  • breast;
  • epithelioid haemangioendothelioma;
  • epithelioid haemangioma;
  • haemangioma;
  • pseudoangiomatous stromal hyperplasia;
  • vascular lesions

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Vascular proliferations of the breast are uncommon but potentially diagnostically challenging lesions. Clinically apparent processes are more likely to be malignant; however, a range of benign entities which must be differentiated from angiosarcoma also exists. This review discusses first, breast lesions of apparent vascular origin, then benign and histologically bland perilobular, cavernous and capillary haemangiomas. Subsequently, more diagnostically challenging, atypical haemangiomas, papillary endothelial hyperplasia, angiomatosis and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma) are considered. In addition, lesions with low-grade malignant potential such as haemangiopericytomas and epithelioid haemangioendotheliomas may rarely present in the breast. However, primary angiosarcomas and radiation-associated vascular lesions are reviewed in depth, as these entities are of greatest clinical and pathological significance.


Abbreviations:
AS

angiosarcoma

AVL

atypical vascular lesion

CK

cytokeratin

DCIS

ductal carcinoma in situ

DFS

disease-free survival

HPF

high-power field

MRI

magnetic resonance imaging

OS

overall survival

PASH

pseudoangiomatous stromal hyperplasia

RR

relative risk

VEGF

vascular endothelial growth factor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

The normal vascular supply of the breast, as of other subcutaneous structures, comprises arteries, capillaries, veins and lymphatics admixed with adipose tissue, fibrocollagenous stroma and dispersed neural structures. The microvascular pattern of the mammary gland has been characterized by computer-assisted image analysis and it has been shown that the lobules bear larger sinusoidal-type S-shaped capillaries compared with smaller microvessels seen in the periductal stroma.1 No correlation was found between epithelial oestrogen or progesterone expression and vascularization in a series of nine women.

Clinically evident vascular proliferations of the breast are uncommon entities. Although the statement that ‘a benign angioma has never to date constituted a palpable or symptom-producing breast tumour’2 may no longer be considered valid, angiosarcomas (AS) are the most frequently encountered symptomatic intraparenchymal vascular lesions.3

Breast lesions apparently derived from, or including, vascular structures include pseudoangiomatous hyperplasia (PASH), which is a lesion of myofibroblastic origin,4 and angiolipomas, as well as true, pure vascular proliferations. Pure vascular lesions show a wide spectrum of appearances and clinical behaviour and will be considered in five categories: (i) benign and histologically bland perilobular, cavernous and capillary haemangiomas; (ii) lesions which behave in a benign manner, but which are more challenging diagnostically due to potentially suspicious morphology. This group includes atypical haemangiomas, papillary endothelial hyperplasia, angiomatosis and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma); (iii) lesions with low-grade malignant potential, namely haemangiopericytomas and epithelioid haemangioendotheliomas; (iv) AS; and (v) radiation-associated breast lesions.

Lesions of apparent vascular origin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

PASH is frequently a microscopic incidental finding, but may also present as a mass lesion. Such tumours present at a mean age of 37 years (range: 14–67) and have usually been interpreted clinically as a fibroadenoma.4 Histologically, PASH is characterized by anastomosing slit-like empty spaces outlined by spindle cells, which may be flat or plump. The spindle cells are vimentin- and CD34-positive, but factor VIII−. Although this is regarded as a benign lesion, it should be noted that it may ‘recur’; five of 40 patients described in one series4 had ipsilateral recurrence and two developed contralateral PASH.

Angiolipomas comprise capillary-sized vessels bearing hyaline thrombi within a fibroadipose stroma; these may occasionally be seen in the subcutaneous tissue of the breast.5 Two cases with apparently solid spindle cell proliferation with rare mitoses [1 per 10 high-power fields (HPF)] have been described; the solid appearance is interpreted as due to collapse of vascular spaces6,7 and should not be mistaken for a more suspicious lesion.

Perilobular, cavernous and capillary haemangioma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Perilobular haemangiomas comprise a microscopic meshwork of capillary-sized vessels, often intimately intermingled with lobular and terminal duct epithelial structures (Figure 1A). They have been identified in 7/555 (1.2%) of mastectomies performed for breast carcinoma8 and in 11% of 210 consecutive forensic autopsies.9 There is an isolated case report of a perilobular haemangioma detected by colour Doppler imaging;10 however, these lesions are much more frequently incidental and indeed are not uncommon.

image

Figure 1. A, Perilobular haemangioma. Note that the vessels are intimately intermingled with epithelial structures without disrupting them. B, Primary angiosarcoma. Low-power view shows neoplastic vessels infiltrating between acini in a terminal duct lobular unit. The lobule shows secondary atrophy. C, Primary angiosarcoma. An adjacent area showing back-to-back anastomotic vessels infiltrating fat. There is red cell extravasation with formation of blood lakes. Case courtesy by Dr A. Girling, Norfolk and Norwich University Hospital NHS Trust.

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Haemangiomas of cavernous, venous or juvenile types may be located either admixed with glandular breast parenchyma or in the subcutaneous fat superficial to the anterior pectoral fascia, which may be distinguished by ultrasonography with use of high-frequency transducers.11 Rosen has described 15 haemangiomas sufficiently large to permit macroscopic identification5,12,13 measuring 7–50 mm in diameter in patients ranging in age from 10 to 67 years. They were histologically highly heterogeneous, composed of venous or capillary-sized structures, several with more peripheral non-neoplastic vessels which were interpreted as ‘feeding’ vessels. The lesions were predominantly well-circumscribed or lobulated; only one had an irregular margin, with extension of smaller vessels into a lobule. Areas with endothelial cellular hyperchromasia were present, but no tufting, papillary formations or anastomoses were seen.

Infantile haemangiomas of the breast have been described.14,15 Their development has been associated with reduction in expression of the Hox A5 gene16 and with immunopositivity for Glut-1.17,18 These are not usually excised and submitted to the histopathologist, as they regress spontaneously. However, there is a risk of breast atrophy if the breast bud is included in, or very close to, the haemangioma,19 or if treatment with irradiation is attempted.20

Other reports of benign haemangiomas have emphasized cases with unusual clinical and/or radiological features. Thus, the literature includes reports of lesions measuring up to 60 mm in male patients.21–24 Phlebolith formation with calcification leading to mammographic suspicion of ductal carcinoma in situ (DCIS)25 has been recorded. An enlarging mass on mammography has been diagnosed as a cavernous haemangioma on needle core biopsy.26 There is also a single description of a haemangioma forming a mass with spiculate margins interpreted as highly suggestive of malignancy on mammography (breast imaging reporting and data system category 5);27 histologically, vessels encased by fibrous stroma extended from the margins of the lesion accounting for the radiological appearance. A breast haemangioma clinically simulating an inflammatory carcinoma has also been reported.28

Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

In addition to the clinical and/or radiological appearances occasionally giving cause for concern, the histological features may, rarely, be unusual and cause diagnostic difficulties. Hoda and colleagues have described a series of 18 haemangiomas with atypical features, which they subcategorized into cavernous, compact capillary, capillary budding and mixed forms.29 Eleven lesions were found by mammography. All measured <20 mm.

Eight lesions were of cavernous type. These were lobulated, bearing thin fibrous septae separating the vascular channels with evident, occasionally conspicuous, anastomoses, together with pseudopapillary areas. A proportion showed focal endothelial hyperplasia, usually associated with organizing thrombi, and invasive margins. These resemble a series of sinusoidal haemangiomas described by Calonje and Fletcher,30 of which two were located in the breast. Pseudonecrotic central infarction was seen in two of these 12 cases of sinusoidal haemangioma and should not be mistaken for true necrosis and thus suspicious of overt sarcoma. The compact capillary subtype of atypical haemangioma comprised ill-defined lobules formed by small capillary-type vessels with prominent anastomosing channels and a cellular endothelial component. Capillary budding haemangiomas were small (all <10 mm) and poorly circumscribed, with central foci of papillary endothelial hyperplasia with atypia. However, despite these unusual histological features, follow-up from 1 to 140 months (mean 44 months) revealed no systemic or local recurrences in any of the 18 patients.

Immunohistochemistry for Ki67 has been reported as useful in differentiating atypical haemangiomas from low-grade AS, with a candidate threshold for probable malignancy of 175 positive endothelial cell nuclei per 1000.31 However, increased Ki67 immunoreactivity may be seen in a benign angioma at the site of thrombi or previous core biopsy, and results must be interpreted with caution in such situations.

Angiomatosis has been defined by Rao and Weiss as a histologically benign vascular lesion that affects a large segment of the body in a contiguous fashion, either by vertically involving multiple tissue types (e.g. subcutis, muscle, bone) or by involving similar tissue types (e.g. multiple muscles).32 These lesions usually present in the first two decades of life and may occur in a wide variety of sites, most commonly in the lower extremity/buttock. There is a propensity for local recurrence; of 25 cases with follow-up information, 22 recurred locally.32 Angiomatoses do not, however, show histological progression to sarcoma and do not have metastatic potential. Rare cases of angiomatosis of the breast have been described, in patients between birth and 59 years of age.33–36 Histologically, these are characterized by a diffuse network of small and large, predominantly empty, anastomosing vascular channels which proliferate around, but do not dissect into, breast lobules, in contrast to AS. In particular, the vascular channels are distributed uniformly throughout the tumour, again in contrast to AS, which exhibits a heterogeneous population of vessels. Finally, endothelial nuclei in angiomatosis are histologically normal without atypia, tufting or mitotic activity. Nevertheless, two of the six cases cited above recurred, one during pregnancy. Diffuse dermal angiomatosis of the breast has also been described.37 Clinically, this one reported lesion presented as a reticulated, erythematous plaque with superficial ulceration and underlying tender nodules. Histologically, a punch biopsy specimen showed a diffuse proliferation of spindle-shaped endothelial cells with focal small, bland vessel formation, extending through the full thickness of the dermis and into the superficial panniculus. There was complete resolution of symptoms and signs, after a stent was placed in the ipsilateral subclavian artery, which had been almost completely occluded.

Papillary endothelial hyperplasia may cause difficulty in histological interpretation, due to its architectural complexity, particularly if limited material is available for examination. These lesions have presented as a mass or on mammographic screening in patients aged from 13 to 85 years and have ranged in size from 4 to 27 mm.5,38 Histologically, a predominantly circumscribed margin is seen and disruption of adjacent glandular breast parenchyma and epithelial structures is not present. Peripheral papillary areas surround central sclerosis and/or anastomosing vessels. Low mitotic activity, with fewer than one mitosis per 10 HPF, is present. Rarely, areas of necrosis may be identified and should not be misinterpreted as related to malignancy. This entity is considered to represent a variant of an organizing thrombus and may develop either within a large vessel or within another vascular lesion such as a cavernous haemangioma.

Epithelioid haemangiomas, also known as angiolymphoid hyperplasia with eosinophilia, most commonly occur in the subcutaneous tissue of the head and neck,39 but may also rarely be seen in the breast.40 This entity occurs predominantly in patients in the third to fifth decade. The salient histological features are an exuberant proliferation of blood vessels, sometimes in a lobulated pattern, within an inflammatory background (Figure 2). The endothelial cells are cuboidal to dome-shaped and may show papillary tufting. The infiltrate of lymphocytes and eosinophils may range from sparse to abundant. The lesion does not have metastatic potential but, although data regarding outcome of breast lesions are limited, at other sites one-third of such lesions recur locally if incompletely excised.

image

Figure 2.  Epithelioid haemangioma (angiolymphoid hyperplasia with eosinophilia). A proliferation of epithelioid vascular cells with a scattered infiltrate of lymphocytes and plasma cells encircles but does not destroy the native breast epithelium. Slides retrieved by courtesy by Dr Cheryl Gillett, Breast Tumour Tissue Bank, Guy’s Hospital.

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Haemangiopericytomas and epithelioid haemangioendotheliomas

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Arias-Stella and Rosen have described a series of five female patients with haemangiopericytoma of the breast and reviewed the literature, which includes a further eight patients.41 Tumours varied from 10 to 290 mm in maximum dimension. The lesions may be partially encapsulated. As in other sites, they comprise vascular channels (stag-horn, irregular or slit-like) within a highly cellular stroma composed of mildly pleomorphic round, oval or elongated spindle cells with infrequent mitoses. All patients remained disease free after follow-up of 3–276 months. Presentation in the breast of a male patient has also been described.42

Epithelioid haemangioendothelioma is an uncommon vascular tumour with a predilection for pulmonary or hepatic involvement, but which may develop at almost any soft tissue site. This is most commonly in the lower extremities, but rare cases in the breast have been reported.43,44 As with several other rare vascular mammary lesions, single case reports predominate; for example, one case with a potential association with polyurethane/silicone breast implants has been described.44 In a more substantial series of 30 patients with skin or soft tissue involvement, age at presentation ranged from 16 to 74 years (mean 48, median 50).45 Local recurrence and systemic metastasis may occur; in this series four (17%) patients died of disease. Histologically, the lesions most commonly have infiltrative margins and comprise nests, cords and short strands of epithelioid tumour cells within a myxohyaline stroma which may show varying degrees of degeneration (Figure 3). The epithelioid cells, at least focally, show prominent intracytoplasmic vacuolization, occasionally containing erythrocytes. The immunohistochemical profile of this entity may initially suggest the diagnosis of metaplastic carcinoma, as epithelioid haemangioendotheliomas express cytokeratin (CK) 7 as well as CK18 in the majority of cases.46 However, these tumours also express a wide range of vascular antigens (CD31, CD34 and factor VIII), not seen in breast carcinomas. In addition, they are negative for high-molecular-weight cytokeratins, such as CK14, whose presence is a characteristic feature of metaplastic breast carcinoma.47

image

Figure 3.  Epithelioid haemangioendothelioma. This lesion comprises pleomorphic cells in cords and singly within a myxohyaline matrix. Intracytoplasmic lumena are present; one bears an erythrocyte. Slides photographed by courtesy by Dr Peter Atkinson, Southend Hospital.

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Angiosarcoma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

AS of the breast is a rare lesion, accounting for 0.04% of breast tumours and between 3% and 9% of breast sarcomas.48–50 However, conversely, up to 44% of all AS occurs within the breast.48 Breast AS can be divided into two broad categories, primary and secondary (radiation-associated). Although these share similar histological features and typically poor prognostic outcomes, there are differences in patient demographics, tumour behaviour and differential diagnosis. Secondary AS will be discussed below with post-radiation vascular lesions.

Primary AS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Primary AS typically occurs in premenopausal women, mean age of 35 years (range: 14–82), i.e. a younger age, in general, than primary breast carcinoma.51,52 Cases of primary AS arising in pregnancy are well documented. For example, a review by Chen et al. included 87 cases of AS, of which 11 were pregnancy related.51 It is noteworthy that pregnancy-related AS tends to be of high histological grade and is reported to have an especially poor prognosis.53 However, despite the association with young age of onset and pregnancy, there is no evidence that breast AS is female hormone dependent.54 Indeed, there have been four documented cases of primary breast AS arising in men.53

Clinically, the majority of primary AS present as a painless mass.51,55 This can be associated with skin discolouration (in up to 34% of cases),51 although this tends to occur in larger and more superficial lesions.53 Synchronous bilateral AS has been reported,54 although the contralateral breast is a common site of metastasis and such cases may potentially represent metastatic spread. Primary AS has also been described in conjunction with synchronous primary breast carcinoma56 (East Anglia Cancer Registry Data).

Mammography of palpable AS lesions often shows a poorly defined, lobulated mass without spiculations or calcification.57–59 However, the imaging features are often non-specific and between 19% and 33% of lesions are undetectable by mammography.59,60 On ultrasound examination, there is often heterogeneous echogenicity with hyperechoic areas without acoustic shadowing.57,59–62 Colour Doppler shows hypervascularity.60 Magnetic resonance imaging (MRI) shows hypervascular, heterogeneous masses that are hypointense on T1-weighted images and hyperintense on T2-weighted images,59–62 with rapid uptake of gadolinium with prolonged enhancement.62 MRI is particularly useful in defining disease extent pre-operatively, as for malignant epithelial lesions. In addition, as there is a high risk of contralateral metastasis, MRI may be the best form of imaging for patient follow-up.53,60

Macroscopically, primary AS in the breast ranges from 10 to 200 mm in diameter, with an average size of 40–55 mm.3,52,55,63,64 The cut surface is often friable to firm and haemorrhagic. In high-grade lesions areas of necrosis may be visible to the naked eye. Areas of haemorrhage or discolouration may extend beyond the main tumour mass, and microscopically malignant vessels frequently extend beyond the macroscopically defined tumour.3 Alternatively, an AS may appear as an ill-defined area of thickening and induration with a vascular nature not apparent macroscopically.53

Primary breast AS are a heterogeneous group of lesions histologically, composed of interanastomosing vascular channels lined by hyperchromatic endothelial cells, occurring within the breast parenchyma.3 A classification system has been described by Donnell et al. that subdivides AS of the breast into three main growth patterns (Table 1).3 These show a significant correlation with patient age and clinical outcome, with higher-grade lesions occurring in younger patients and showing a worse prognosis (Table 1). However, variations in growth pattern are commonly found within a single lesion; in particular, high-grade lesions can have lower-grade areas at their peripheral and superficial aspects (Figure 4).52 This means one needs to be cautious about grading a lesion on the basis of an incisional biopsy specimen alone, and extensive sampling of the excisional specimen is required to identify higher-grade foci.

Table 1.   Grade of primary angiosarcoma – clinical and histological characteristics
Clinical and histological characteristicsLow grade (type I)Intermediate grade (type II)High grade (type III)
  1. Adapted from Donnell et al.3

Median age at diagnosis (years)433429
Median survival (years)>15>12 1.5
5-year overall survival (%)916814
5-year recurrence-free survival (%)767015
Endothelial tuftingMinimalPresentProminent
Papillary formationsAbsentFocally presentPresent
Solid and spindle cell areasAbsentAbsent/minimalPresent
MitosesAbsent/rarePresent in more papillary areasFrequent
Blood lakesAbsentAbsentPresent
NecrosisAbsentAbsentPresent
image

Figure 4.  Primary angiosarcoma (AS) showing intralesional heterogeneity. Initial core biopsy shows type III AS with solid areas. High-power view shows marked nuclear pleomorphism with high mitotic activity. Immunohistochemistry shows diffuse reactivity for CD34 and occasional cells immunopositive for CD31. The resection specimen shows high-grade AS centrally with solid areas and foci of haemorrhage, whereas the periphery is composed of anastomosing dilated channels lined by a single layer of atypical cells in keeping with type I AS. Case courtesy by Dr A. Girling, Norfolk and Norwich University Hospital NHS Trust.

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Low-grade lesions are characterized by proliferation of well-formed, anastomosing vascular channels that diffusely infiltrate both glandular parenchyma of the breast and fat. Neoplastic channels may permeate between the acini of individual lobular units. The vessels are lined by a single layer of endothelial cells with hyperchromatic nuclei and inconspicuous nucleoli. Papillary formations and solid areas are absent. Mitotic figures are rare; readily identifiable mitoses should prompt an especially thorough search for higher-grade regions elsewhere in the tumour.53 Red blood cells can usually be identified within vascular lumena. The vascular spaces are usually closely packed with minimal intervening stroma, although occasional cases may have a collagenous stroma. Unusual low-grade variants include lesions composed predominantly of small, capillary sized vessels that can resemble a haemangioma, or PASH-like stromal infiltration, narrow vascular channels without an obvious anastomosing architecture or a predominantly spindle cell infiltration within fat that may mimic an angiolipoma on limited sampling.53

Intermediate-grade AS resembles low-grade lesions, but with scattered cellular foci showing a papillary and/or solid growth pattern, although such areas should comprise <25% of the entire lesion.53 The endothelial proliferation is in the form of tufts or papillary projections, and occasional mitoses may be found. Less commonly, the cellular areas may contain spindled cells surrounding vascular spaces suggestive of Kaposi’s sarcoma.

High-grade AS has overtly sarcomatous areas showing solid growth with spindled or epithelioid cell morphology. Endothelial tufting and papillary formations are prominent and the endothelial cells show marked cytological atypia with prominent nucleoli and frequent mitotic figures. ‘Blood-lakes’ and areas of necrosis may be present. A case of epithelioid AS of the breast composed of sheets and cords of cells with abundant eosinophilic cytoplasm and occasional microlumina containing red blood cells has been described.49

Differential diagnosis of primary AS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Given the bland appearance, a high index of suspicion is required to make an accurate diagnosis of low-grade AS. In one review, 32 of 87 cases were misdiagnosed as benign on the initial biopsy, the correct diagnosis being made after one or more local recurrences and sometimes with a delay of up to 2 years.51 The previous, incorrect, benign diagnoses included haemangioma, lymphangioma and haematoma. As noted above, haemangiomas are well-circumscribed lesions, sometimes with a thick-walled feeding vessel evident, that are typically <20 mm in size,52 which grow around ducts and lobules. AS, conversely, tends to invade into pre-existing breast epithelial structures. Necrosis, blood lakes and mitotic activity are distinguishing features of AS, but are of limited use in diagnosis of the difficult low-grade lesions as they are seen only in high-grade tumours. The Ki67 labelling index has been reported as being of diagnostic utility in challenging cases.31Figure 1 contrasts a perilobular haemangioma with lobular invasion by an angiosarcoma.

The main differential diagnoses of high-grade AS are metaplastic carcinoma with angiosarcomatous differentiation and other poorly differentiated sarcomas. Histologically, the presence of characteristic low-grade AS at the periphery of the lesion can be helpful in diagnosis. Similarly, metaplastic carcinomas may be associated with DCIS or areas of typical invasive carcinoma of ductal/no special type. In more difficult cases, immunohistochemistry for vascular markers and cytokeratins may be invaluable. More than 90% of cases of AS are immunopositive for CD31 and CD34.65 CD31 is the most specific marker for endothelial differentiation, whereas CD34 is more sensitive, but also stains other lesions, such as phyllodes tumour and PASH.66,67 Factor VIII-related antigen is highly specific, but is positive in only 50–75% of AS.65Ulex europaeus agglutinin-1 has lower specificity and also stains many epithelial tumours65 and is thus of limited value. Of particular note, whereas the majority of AS are negative for cytokeratins immunohistochemically,68 epithelioid areas may stain positively in up to 35% of cases.49,69 Conversely, breast carcinomas are generally CK+, but <2% are immunopositive for CD31 and CD34.65,66 AS of the breast is oestrogen and progesterone receptor negative in the majority of cases.54,64

Prognosis of primary AS and management

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Primary AS is an aggressive neoplasm with a tendency to local recurrence and distant metastasis. The commonest sites of metastasis are bone, lung, liver, brain, ovary and skin.51,52 As noted above, the contralateral breast is also a common site of metastasis, occurring in approximately 21% of cases.51 Lymph node involvement is present in only 6–8% of cases.51,64 Histological progression in recurrences from low- to high-grade lesions is well described.3,51 The prognosis of primary AS of the breast is thus generally poor, with 70% of patients dying (mean survival 22 months51). Nevertheless, cases of long-term survival are well documented.50,54,55,63,70 Rosen et al. have demonstrated that tumour grade is the most important predictor of recurrence (Table 1).52 Merino et al., with follow-up of 2–20 years, have found a similar association between grade and prognosis: none of five well-differentiated cases, three of four moderately and three of six poorly differentiated cases died of disease (mean survival 3.7 and 1 year, respectively).63 There was no association between outcome and lesion size found in this series, although other studies have identified both high mitotic index and large lesion size as predictive of worse outcome.55,64,71 Vorburger et al. have reported that although lesion size <50 mm was associated with increased disease-free survival (DFS), tumour recurrence was the only significant predictor of overall survival (OS); median OS was 1.2 years in patients with local recurrence and 0.8 years in patients with metastatic disease (median OS for primary AS 6.7 years).71

Complete local excision with histologically clear margins is the basis of management and, given the propensity for microscopic extension beyond the macroscopically defined lesion, mastectomy is often required.52 Wide local excision may be considered for the rare small lesions identified. Radical mastectomy is indicated only when there is invasion beyond the deep fascia. Axillary dissection is not indicated routinely, as lymph node metastasis is uncommon.52

The role of adjuvant radiotherapy and chemotherapy remains controversial, and much of the information in the literature comes from single case reports or small series. In Rosen’s series, 20% of low, 29% of intermediate and 71% of high-grade lesions recurred following chemotherapy. In contrast 27%, 40% and 100%, respectively, of low, intermediate and high-grade lesions recurred in patients who did not receive adjuvant chemotherapy.52 These differences were not statistically significant, but the numbers were small. As the few long-term survivors with type III lesions in this series had received adjuvant chemotherapy, the authors recommended that this be offered to patients in this group, given their otherwise poor prognosis. However, long-term survivors, with high-grade AS who did not receive any adjuvant therapy, have also been reported.63,70 In a more recent study, 29 of 69 patients received adjuvant combination chemotherapy with anthracycline-ifosfamide or gemcitabine-taxane.64 Four had a complete response and 10 a partial response (48% overall response rate), but there was no difference in DFS or OS between patients who had adjuvant chemo- or radiotherapy and patients who received no adjuvant treatment. Thus the role of adjuvant chemotherapy for AS of the breast remains unclear.

There have been no published series reporting the role of newer molecular drugs such as bevacizumab, a human monoclonal antibody against the vascular endothelial growth factor (VEGF) receptor. Mouse models have shown up-regulation of VEGF receptors in low-grade AS derived from endothelial cell lines.72 It is therefore possible that VEGF inhibition may represent a future therapeutic option for this group of tumours.

Secondary AS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Secondary AS in breast cancer patients occurs in two clinical settings. The first, described by Stewart and Treves in 1948, is AS of the upper limb following long-standing lymphoedema after mastectomy, with or without radiotherapy.73 AS in this setting is related to the chronic lymphoedema itself, as it involves non-irradiated skin, and has also been described in chronic lymphoedema due to other causes.74 The incidence of post-mastectomy AS is between 0.07% and 0.45%,75 but with the shift towards breast-conserving surgery and sentinel lymph node biopsy this is likely to decrease. Instead, the problem of secondary AS following chest wall irradiation is emerging, with >100 cases in the literature.76

Several population-based studies have examined the incidence of sarcoma of the breast following radiotherapy for breast cancer. In series of patients who have received radiotherapy for breast cancer, between 37% and 57% of sarcomas are AS, with 54–55% occurring on the chest wall (compared with 6–9% and 14%, respectively, in non-irradiated patients).77,78 Postradiotherapy, the relative risk (RR) of AS is reported to be 15.9 and for non-vascular sarcoma 2.2.77 The incidence of AS ranges from 5.8 to 9.0 times that of patients who have not received radiotherapy.78,79 Another study has found a RR of AS of 11.6 in all breast cancer patients (treatment data not available), compared with a RR of 3.29 for non-vascular sarcomas.48 A French series has found nine cases of AS and three atypical vascular lesions (AVL) in 18 115 patients treated over 17 years.80 However, the RR ranges are wide, as these lesions remain rare, and in one series from the Netherlands the incidence of secondary AS was estimated at 1.27/1000, giving an increased risk of 3200 (1.59% versus 0.0005% for primary AS).81

Interestingly, the risk of AS does not appear to be related to the dose of radiation given,79 but the increase in risk is reported to be maximal 5–10 years postradiation77,81 Overall, AS is a rare complication of radiotherapy following breast-conserving surgery for the treatment of breast cancer, and the benefits of radiation outweigh the risk.77,82

The latency period, postbreast cancer therapy, ranges from 6 to 204 months, median 63–74 months.80–83 This is much shorter than the latency seen in radiation-associated AS at other sites (median 174 months; range: 84–480).84 This indicates that other factors, such as co-existent lymphoedema, genetic predisposition or chemotherapy, may play a role, and cases have been reported where these, or other, features have been present.82,85–88 For example, in one study seven of eight patients were reported to have postoperative breast oedema,89 although another found that lymphoedema was absent in the majority of patients and, when present, was only mild.82 In contrast to primary AS, secondary AS is a disease of postmenopausal women, the median age of onset ranging from 59 to 69 years in larger series (range: 36–90).81–83 It is also possible that older age at the time of breast cancer therapy may contribute to risk.76,81

Secondary AS commonly arises within the dermis, in contrast to the parenchymal location of primary AS, and therefore patients most commonly present with skin changes such as erythematous or violaceous plaques or nodules.80–83,90 Lesions are often multiple and range from 3 to 200 mm in size.82,83 Histologically, there is a poorly circumscribed proliferation of vascular spaces within dermis that diffusely dissect dermal collagen and frequently extend into underlying subcutis.82,83,90 The endothelial cells lining these vessels show at least focal nuclear atypia with enlargement, hyperchromasia and the presence of nucleoli. Mitoses and multilayering of endothelial cells may be seen. Solid areas composed of spindled and/or epithelioid cells are frequently found82,83 and contain slit-like vascular spaces with intraluminal or extravasated red blood cells.53 Secondary AS shows a variety of growth patterns and can be divided into low, intermediate and high-grade lesions based on the presence and extent of solid areas, as with primary AS. Other patterns described include sieve-like arrangements of back-to-back vessels.82 Blood lakes and areas of necrosis can be found in the more solid areas of high-grade lesions. As with primary AS, a mixture of low- and high-grade areas is often present within a single lesion,83,90 and progression to higher grades can be seen in recurrences86 (Figure 5). Radiation-associated changes such as homogenization of dermal collagen and atypical fibroblasts may be present in adjacent dermis.82

image

Figure 5.  Secondary angiosarcoma (AS) showing progression with recurrences. Low-power view shows a vascular proliferation within dermis that extends down to subcutis but does not invade subcutaneous fat. Although the central part of the lesion appears circumscribed, there is subtle infiltration of adjacent dermis by atypical vessels. At higher power, there is red cell extravasation, and the vessels are lined by atypical endothelial cells with hyperchromatic nuclei and occasional nucleoli. There have been several recurrences over the course of 3 years, the most recent of which shows progression to high-grade AS with increased cellularity, focal solid growth and more severe nuclear pleomorphism with mitotic activity. Case courtesy by Dr R. C. G. Rowe, The Ipswich Hospital.

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The typical course of secondary AS is of locally aggressive disease with multiple local recurrences.80,81,83,86 Distant metastases are rare at presentation86 and generally occur in the setting of local recurrence.82,86 Although it has been suggested that secondary AS may follow a more indolent course than primary AS,83 this has been disputed.82 In a recent review, 73% of patients suffered a local recurrence, the majority (84%) occurring within 12 months of surgery.86 The most common site was at the mastectomy scar, and in 82% this was the sole site of recurrence. However, 48% of patients suffered further recurrences, despite salvage surgery. The most common site of distant failure was the contralateral breast. On follow-up, 58% had no evidence of disease (2–96 months, mean 30 months) and 41% died of disease (survival 0.5–38 months, mean 13 months). As with primary AS, outcome was related to grade.

In other series the local recurrence rate reported has been lower (42–67%),81–83 with a distant recurrence rate of 33%.82 Some have reported patient outcome to be related to margin status; in one series the 2-year OS was 86% and DFS was 51% in patients with clear margins, compared with 50% and 0%, respectively, in patients with involved margins.81 Other authors have noted that although local recurrence occurred in well-differentiated lesions (five of 11 from a total of 26 patients), all four patients who developed distant metastases had poorly differentiated or epithelioid AS,83 supporting the view that high-grade lesions have a poorer outcome. However, other groups have found no association between survival and histological parameters.82

The primary goal of management is complete surgical excision, although even with histologically clear margins the rate of local recurrence is high.76 Aggressive initial local therapy appears justified, as distant metastases usually occur in the context of locally recurrent disease. However, the role of adjuvant chemotherapy is still not well defined. In secondary AS, radiotherapy is clearly restricted by previous dosage to the region. Nevertheless, in a small series (three patients) good results have been seen with hyperfractionated radiotherapy, with clinical regression and disease-free follow-up at 22–39 months.91

Other radiotherapy-associated lesions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

Benign vascular changes have also been well described following breast irradiation. Late radiation-induced skin changes include hyalinization of dermal collagen fibres, telangiectatic dilation of vessels within the superficial dermis with swelling of endothelial cells, and myointimal proliferation and hyalinization of deeper venules and arterioles.92 Fibrosis and skin changes following radiotherapy should stabilize within 3 years, so any late skin changes should be regarded as suspicious76 and investigated further.

Atypical vascular lesions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References

AVLs are a group of lesions that form a morphological continuum with low-grade AS, but follow a benign clinical course.83,90,93,94 AVLs have been described under a variety of names in the literature, including benign lymphangiomatous papules,95 benign lymphangioendothelioma and lymphangioma circumscriptum.83 AVLs present clinically as solitary or multiple skin-coloured vesicles or papules, 1–20 mm in diameter, in previously irradiated skin.82,83,90,94,95 The latency following radiotherapy ranges from 12 to 240 months (median 66 months) in the largest single series.96

Histologically, there is a proliferation of dilated vascular spaces with an anastomotic, branching pattern within the superficial dermis (Figure 6).83,90,94,95,97 The lesion is circumscribed, with a wedge-shaped appearance at low power and without infiltration into the underlying subcutis. The vessels are lined by a single layer of plump endothelial cells. Nuclei may show some mild hyperchromasia, but lack significant atypia, nucleoli or mitotic figures. Papillary projections, formed by the underlying stroma, may be present, but there is no multilayering of endothelial cells. The vascular spaces do not contain red blood cells and there is no haemorrhage or extravasation of red blood cells. AVLs are usually associated with a chronic inflammatory cell infiltrate. Associated stromal fibrosis and interstitial mucin have been described.94 Features of high-grade AS such as necrosis, blood lakes and areas of solid growth are not seen. Features useful in distinguishing between AVLs and low-grade AS are summarized in Table 2; however, these two entities form a clinical and histological spectrum and some cases show intermediate features that are difficult to classify.83,94,97 Areas with the appearance of AVL can be found at the periphery of AS, and in the series of Mattoch et al. five of 11 cases diagnosed as AVL on incisional biopsy were reclassified as AS following complete excision.97 Thus, diagnosis of such lesions, particularly on small samples, should be undertaken with caution.

image

Figure 6.  Atypical vascular lesion. A, Low-power view shows a circumscribed proliferation of dilated vascular spaces within superficial dermis. There is a patchy associated chronic inflammatory infiltrate. B, At higher power, the spaces are lined by flattened to slightly plump endothelial cells without any nuclear atypia. Case courtesy by Dr S. Wu, the Ipswich Hospital.

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Table 2.   Histological features useful in discriminating atypical vascular lesions from low-grade angiosarcoma
Histological featuresAtypical vascular lesionsLow-grade angiosarcoma
  1. Adapted from Fineberg and Rosen.90

Infiltration into subcutisAbsentOften present
Multilayering of endothelial cellsAbsentPresent
Prominent nucleoliAbsentPresent
MitosesAbsentMay be present
Significant cytological atypiaAbsentPresent
Haemorrhage/red cell extravasationAbsentMay be present
Dissection of dermal collagenMay be present focallyPresent
Chronic inflammationUsually presentUncommon
Wedge shaped, circumscribedYesNo
Stromal projections into lumenPresentAbsent

AVLs are believed to arise as a result of lymphatic obstruction following surgery and/or radiotherapy, causing acquired dilation of superficial vascular channels. On immunohistochemistry they are CD31+, D2-40+ and factor VIII+, with focal or absent reactivity for CD34.83,94,95 They are smooth muscle actin- and Ki67-negative.94 On electron microscopy they show a discontinuous endothelial lining with absent pericytes and poorly developed intercellular contacts, in keeping with lymphatic origin.95

Follow-up data on these lesions are limited, but they seem to follow a benign course. The majority have no further disease, but up to 31% develop further lesions locally or elsewhere within the radiation field.83,94,96 A single case with progression to low-grade AS over 3 years has been described.83 Complete excision of all lesions and biopsy of any new lesions is recommended to exclude low-grade AS.93,97

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lesions of apparent vascular origin
  5. Perilobular, cavernous and capillary haemangioma
  6. Atypical haemangioma, angiomatosis, papillary endothelial hyperplasia and angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma)
  7. Haemangiopericytomas and epithelioid haemangioendotheliomas
  8. Angiosarcoma
  9. Primary AS
  10. Differential diagnosis of primary AS
  11. Prognosis of primary AS and management
  12. Secondary AS
  13. Other radiotherapy-associated lesions
  14. Atypical vascular lesions
  15. References
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