Abstract
Vascular tumors commonly arise in the breast or overlying skin. Although classification as benign or malignant is usually straightforward in resection specimens, rendering a definitive diagnosis on core biopsy samples is often difficult because of limited sampling. Whereas benign vascular lesions are well circumscribed and lack endothelial hyperplasia, severe cytologic atypia, and anastomosing vasculature, malignant vascular tumors are characterized by complex, anastomosing vascular channels that infiltrate the dermis and/or breast parenchyma. Included within this morphological spectrum are atypical vascular lesions associated with prior radiation therapy. As with other differential diagnoses in the setting of breast core biopsies, correlation with clinical and radiologic findings is critical. It is also important to remember that complete diagnostic characterization of some vascular lesions may be possible only after surgical excision. This chapter covers a multitude of benign and malignant vascular lesions of the breast and discusses their diagnostic features and differential diagnoses.
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Keywords
- Angiolipoma
- Angiomatosis
- Angiosarcoma
- Atypical vascular lesion
- Diffuse dermal angiomatosis
- Hemangioma
- Papillary endothelial hyperplasia
Benign Vascular Lesions
Overview
Benign vascular lesions of the breast may be encountered in the breast parenchyma or overlying dermis and subcutis. These lesions are typically incidental findings and rarely detected on routine screening imaging studies. Benign vascular lesions are seldom biopsied when there is strong clinical/radiographic evidence of the diagnosis. If biopsy is clinically indicated, an excisional procedure is preferred to reduce the risk of hemorrhage. Collectively, benign vascular lesions are well circumscribed and lack the cytologic atypia, endothelial hyperplasia, and anastomosing channels that characterize angiosarcoma. Morphologic variants recognized in the breast include perilobular, capillary, cavernous, and venous hemangioma; arteriovenous malformations and angiolipomas may occur in the breast rarely. There is no evidence to suggest that any of these types of hemangiomas develop into angiosarcomas over time. Other benign vascular lesions which may be rarely encountered in the breast include papillary endothelial hyperplasia and angiomatosis. The practical importance of recognizing these lesions is their distinction from angiosarcoma, which can be difficult on limited material such as in core needle biopsies (CNBs).
Clinical and Radiologic Features
Perilobular capillary hemangiomas are the most common vascular lesions of the breast and are observed in 1–12% of breast specimens [1]. They are almost always microscopic, incidental findings but may sometimes be detected clinically or by imaging. Capillary, cavernous, and venous hemangiomas appear as an oval or lobulated mass with well-circumscribed or microlobulated margins on mammogram and as an ill-defined, hyperechoic, or well-defined, hypoechoic mass on ultrasound. Most cases are superficial [2, 3]. By dynamic contrast-enhanced magnetic resonance imaging (MRI), hemangioma typically appears as a homogeneously enhancing mass with well-defined margins. The T1-weighted image shows intermediate signal, while in T2-weighted images the signal is intermediate to high [4, 5].
Angiomatosis occurs in young women and may be acquired or congenital [6, 7]. Clinically, angiomatosis presents as breast swelling or a large mass, in some cases measuring over 20 cm [6, 7], and is typically painless. Hyperpigmentation, discoloration, or papules of the overlying skin may be present [8]. Ultrasound examination shows large cystic spaces separated by septa with moderate blood flow [3]. MRI demonstrates a large septated mass, frequently with displacement and compression of the normal breast tissue. The cystic spaces are hypointense with respect to the glandular tissue on T1-weighted images and hyperintense compared to the glandular tissue on T2 images [3].
Microscopic Features
Perilobular hemangioma is a circumscribed proliferation of thin-walled capillaries lined by attenuated endothelial cells with small nuclei lacking atypia (Fig. 17.1a). Mitotic activity is absent. They may involve the intralobular or the extralobular stroma (Fig. 17.1b). Occasional lesions may be less circumscribed, raising concern for well-differentiated angiosarcoma on low-power examination; however, the endothelial cells lack atypia (Fig. 17.1c).
Capillary hemangiomas are characterized by a circumscribed proliferation of small vascular spaces with a lobular appearance, similar to lobular capillary hemangioma (pyogenic granuloma) from other anatomic sites (Fig. 17.2a, b). The endothelial cells lining these spaces are flat to slightly cuboidal without evidence of atypia (Fig. 17.2c). In cavernous hemangiomas , the vascular spaces are composed of larger vessels with dilated lumens and thin walls (Fig. 17.3a, b). The endothelial cells are flat and lack atypia (Fig. 17.3c). Stromal calcifications may be present. Complex hemangiomas contain a mixture of small vessels characteristic of the capillary type and dilated vessels typical of the cavernous type. Venous hemangiomas are uncommon and are characterized by large venous channels with variably thickened muscular walls lined by flat endothelial cells without atypia [9] (Fig. 17.4). Thrombosis, with or without secondary changes thereof (i.e., organizing thrombus, dystrophic calcifications, papillary endothelial hyperplasia [see below]), may occur in any of the hemangioma subtypes. Otherwise, benign hemangiomas showing focal endothelial cell atypia or anastomosing vascular channels have been termed “atypical hemangiomas” and may represent degenerative changes as are sometimes seen in other long-standing soft-tissue tumors [10].
Papillary endothelial hyperplasia represents exuberant organization and recanalization of a thrombus. Its appearance in the breast is identical to that seen in other sites [9, 11, 12]. Histologically, papillary endothelial hyperplasia is a relatively circumscribed intravascular proliferation of endothelial cells lining hyaline papillary stalks [13] (Fig. 17.5a). The endothelial cells are usually attenuated and lack necrosis or atypia (Fig. 17.5b). Ectatic vascular spaces frequently observed surrounding the papillary endothelial nodule are suggestive of origin from or association with a preexisting cavernous hemangioma [13]. An intravascular location can often be confirmed by an elastic stain. As papillae fuse, anastomosing vascular channels can develop and mimic angiosarcoma [13]. However, lesional circumscription, purely intravascular growth, and absence of significant cytologic atypia, necrosis, aberrant mitotic figures, or foci of solid growth usually make the distinction straightforward. Excisional biopsy is certainly an adequate treatment.
Angiomatosis is an uncommon lesion in which cystically dilated, anastomosing vascular spaces involve large areas of the breast without infiltration of breast parenchyma [7] (Fig. 17.6a). The vascular spaces are lined by flat endothelial cells without atypia or mitotic activity (Fig. 17.6b). The walls between the spaces contain wispy smooth muscle fibers, scattered mononuclear cells, or lymphoid aggregates (Fig. 17.6c). Distinction from low-grade angiosarcoma may be difficult, as angiomatosis can be large and less circumscribed than other benign vascular lesions. However, in contrast to angiosarcoma, the vascular proliferation entraps mammary ducts and lobules, instead of aggressively infiltrating them. In addition, angiomatosis lacks prominent nuclei and endothelial multilayering seen in angiosarcomas. Extensive sampling may be required to exclude malignancy [7].
Diffuse dermal angiomatosis is a reactive cutaneous capillary proliferation, which may involve the breast [14,15,16,17,18,19,20] and also mimic angiosarcoma. It is a distinct disorder in the spectrum of cutaneous reactive angiomatoses. The typical patient is a middle-aged woman with macromastia, obesity, and a history of tobacco use and/or vasculopathic disorders. Diffuse dermal angiomatosis typically presents with reticulated erythematous to purple patches on large pendulous breasts, which may ulcerate easily. The pathogenesis is thought to be related to tissue hypoxemia resulting from subclinical torsion, compression, and increased venous hydrostatic pressure due to macromastia, which is further aggravated by coexistent ischemic conditions such as hypertension or diabetes. Mammography demonstrates diffuse cutaneous and trabecular thickening, raising concern for inflammatory breast carcinoma [18]. Histologically, diffuse dermal angiomatosis consists of a diffuse proliferation of benign endothelial cells between the collagen bundles throughout the dermis (Fig. 17.7a). A diffuse proliferation of bland endothelial cells and pericytes insinuates between dermal collagen bundles, forming rudimentary capillary-like vessels (Fig. 17.7b–d). Reduction mammoplasty is a viable treatment option, which can be considered in patients who fail conservative therapy.
Angiolipomas are more often seen in the subcutis than in the breast parenchyma. As in other sites, they are often painful and may be multiple. Angiolipomas are well-circumscribed lesions composed of an admixture of mature adipose tissue and benign capillary hemangioma components (Fig. 17.8a). The presence of intravascular hyaline microthrombi is characteristic (Fig. 17.8b). Angiolipomas lack the infiltrative pattern and atypia of angiosarcoma. These benign vascular lesions do not require excision.
Differential Diagnosis
The most important differential diagnosis for all the vascular lesions described above is angiosarcoma, which is characterized by poorly circumscribed borders, an infiltrative growth pattern, anastomosing vascular channels, nuclear atypia, and often endothelial multilayering. It is well recognized, however, that these features may not be fully developed or represented in a CNB specimen. When sampling is limited, diagnostic features of angiosarcoma may not be present. Conversely, benign vascular lesions may be confused with angiosarcoma on the basis of pseudoinfiltrative areas, apparent lack of circumscription, or presence of exuberant papillary endothelial hyperplasia with slight cytologic atypia (see above). Thus, in cases with overlapping or equivocal features, excision may be necessary to accurately characterize the lesion.
Immunohistochemical Workup
Benign vascular lesions demonstrate immunoreactivity for a variety of conventional vascular markers (ERG, CD31, CD34, FLI1, factor VIII-related antigen). However, routine use of these markers is unnecessary for the diagnosis of an obviously vasogenic lesion.
Treatment and Prognosis
In the majority of cases, benign vascular lesions do not require excision. When the diagnosis is made on CNB and the entire lesion cannot be fully visualized, excision may be recommended to fully characterize the lesion. In contrast, complete excision with negative margins or simple mastectomy is recommended for angiomatosis, since there is significant potential for local recurrence if the lesion is incompletely excised [6, 7, 21].
Angiosarcoma
Overview
Angiosarcoma arises in the breast more than in any other site [1]. Mammary angiosarcoma is also the most common type of breast sarcoma, representing approximately 8% of all breast sarcomas [22]. With an annual incidence rate of 1.2 per million women, angiosarcoma accounts for only 0.04% of all malignant neoplasms of the breast [23]. Most angiosarcomas of the breast are secondary to prior radiation therapy or less commonly chronic lymphedema [24,25,26,27,28]. Conversely, primary mammary angiosarcoma is a very rare disease that typically affects younger patients (<50 years of age). Both primary and secondary angiosarcomas show aggressive clinical behavior similar to angiosarcomas arising in other cutaneous or soft-tissue sites. They carry a propensity for local recurrence and a high risk for metastasis and tumor-related death. For this reason, all angiosarcomas are considered of high histologic grade [29,30,31].
Clinical and Radiologic Features
Patients with primary angiosarcoma range in age from 17 to 70 years (median 38 years) [32]. All reported cases of postradiation angiosarcoma have occurred in women over 50 years of age, which is on average 20 years older than women with primary mammary angiosarcoma [33]. Most cases occur 2.5–11.5 years (median 4.5 years) after radiation therapy [34,35,36,37]. This latency period is substantially shorter than for other radiation-associated malignancies in which the time between radiation therapy and malignancy is often more than 10 years. Although radiation-associated mammary angiosarcoma is uncommon, the incidence has increased significantly given the trend for more conservative surgical therapy for breast cancer combined with adjuvant radiation therapy [34, 36, 38, 39]. The estimated risk of either cutaneous or parenchymal disease following radiation therapy is approximately 0.3–0.4% [37, 40].
Whereas primary mammary angiosarcoma is typically a solitary, painless mass (usually >5 cm [1], range < 1.0 cm to >20 cm [41]) located deep in the mammary parenchyma [42], most postradiation angiosarcomas are multifocal and cutaneous (but may secondarily invade subjacent breast parenchyma) [34, 43,44,45]. If the lesion is located deep in the breast, there may be no external features to suggest angiosarcoma. More superficial tumors may show purple-blue discoloration of the skin due to hemorrhage and vascularity (Fig. 17.9). Mammography in primary angiosarcoma typically shows architectural distortion without microcalcifications or a large ill-defined density within the breast parenchyma [5, 46]. Radiation-associated cutaneous angiosarcoma presents as erythematous plaques, papules, or nodules within the field of radiation. MRI can be useful in defining the size in postradiation angiosarcoma [5].
Gross and Microscopic Features
Grossly, angiosarcomas are hemorrhagic masses. Areas of necrosis and cystic degeneration may be seen, especially in larger tumors [41]. The classic mammary angiosarcoma is characterized microscopically by complex, anastomosing vascular channels that infiltrate the dermis and/or underlying breast parenchyma (Fig. 17.10). Angiosarcoma has a variety of histologic appearances ranging from well-differentiated, obviously vasoformative lesions to solid, poorly differentiated neoplasms requiring immunohistochemistry (IHC) for classification. In addition, the histologic features and degree of cellular differentiation can vary considerably within a given lesion. At the well-differentiated (low-grade) end of the spectrum, the vascular spaces are well defined and lined by cells with prominent nuclei that protrude into the vascular lumen (Figs. 17.11a, b). Endothelial tufting is minimal, and papillary formations are absent [32, 47]. Well-differentiated angiosarcoma may subtly permeate adipose tissue simulating angiolipoma (Fig. 17.12). Solid or spindle cell foci, blood lakes, mitoses, and necrosis are typically absent as well. Less differentiated variants [32, 47] (intermediate- and high-grade tumors) show prominent endothelial cell tufting, papillary formations (Fig. 17.13), or multilayered growth of obviously malignant, mitotically active endothelial cells (Fig. 17.14a, b). Focally, the papillary formations may mimic papillary endothelial hyperplasia, a potential diagnostic pitfall in a CNB where sampling may be limited (Figs. 17.15a, b). The anastomosing vascular channels of angiosarcoma commonly dissect around lobular units, a feature facilitating diagnosis on core biopsy (Fig. 17.16a, b). Solid or spindle cell foci, blood lakes (Fig. 17.17a, b), and necrosis (Fig. 17.18a, b) are usually present in poorly differentiated tumors, and some may show limited evidence of vascular differentiation (vasoformation). Occasionally poorly differentiated angiosarcomas have an epithelioid appearance resembling carcinoma (see below).
For many years, considerable effort was extended in grading mammary angiosarcoma [32, 47], since early studies suggested a relationship between histologic grade and outcome [32, 47, 48]. However, a more recent study by Nascimento and coworkers with strict morphologic criteria indicated that angiosarcomas of the breast behave poorly regardless of grade, with 60% of patients developing distant metastases at a mean follow-up of 49 months [30].
Most cases of radiation-associated angiosarcoma are solid with an epithelioid morphology (see below), spindle cell morphology (Fig. 17.19a, b), or a mixture of the two patterns (Fig. 17.20). Occasionally, lesions with structural patterns typical of well- or moderately differentiated tumors are seen, but the malignant cells have marked nuclear hyperchromasia and conspicuous mitotic activity [1] (Fig. 17.21). Variable numbers of slit-like spaces containing intraluminal or extravasated erythrocytes or interstitial hemorrhage with the formation of blood lakes are often present in poorly differentiated lesions.
Epithelioid Angiosarcoma
Epithelioid angiosarcoma is a rare variant of angiosarcoma composed predominantly or exclusively of large “epithelioid” endothelial cells with ill-defined cell borders, abundant amphophilic to eosinophilic cytoplasm, and large vesicular nuclei (Fig. 17.22c). It has been reported to occur in diverse sites but uncommonly in the breast [1, 30, 49,50,51,52,53]. When arising at this site, epithelioid angiosarcoma is almost exclusively seen in patients with a history of radiation therapy [1, 30, 50,51,52,53]. Histologically, epithelioid angiosarcoma is a poorly circumscribed, infiltrative process which may extensively involve the deep dermis, mammary parenchyma, or both (Fig. 17.22a). When the lesion involves the mammary parenchyma, solid islands of tumor infiltrate around or obliterate acinar structures (Fig. 17.22b). Mitoses, including atypical forms, are abundant. Vascular spaces, blood lakes, or slit-like spaces containing extravasated erythrocytes are infrequently apparent. Therefore, IHC may be an important adjunct to reaching the correct diagnosis (see discussion below and Fig. 17.22d–f).
Differential Diagnosis
The differential diagnosis of well-differentiated angiosarcoma includes hemangioma, atypical vascular lesion, pseudoangiomatous stromal hyperplasia (PASH), and angiolipoma. In contrast to the infiltrating growth pattern, anastomosing vascular channels, and endothelial atypia seen in angiosarcoma, conventional hemangiomas and angiolipomas are well-circumscribed lesions that show no evidence of dissection through normal structures, anastomosing growth patterns, or cytologic atypia. Atypical vascular lesions may show anastomosing vascular spaces, but nuclear atypia and endothelial multilayering are absent. Finally, PASH may resemble well-differentiated angiosarcoma at low power, but it is not a true vascular lesion; the cells lining the pseudovascular spaces are instead fibroblasts and/or myofibroblasts that may express CD34 and SMA, but not endothelial markers.
The differential diagnosis of poorly differentiated angiosarcoma of the breast includes high-grade invasive mammary carcinoma of no special type, high-grade spindle cell metaplastic carcinoma, malignant melanoma, and epithelioid or other pleomorphic sarcomas. Distinction between epithelioid angiosarcoma and these other entities is greatly assisted by IHC (discussed below).
Immunohistochemistry and Molecular Alterations
Angiosarcoma typically demonstrates strong immunoreactivity for multiple vascular markers including CD31 [54,55,56], CD34 [55,56,57], factor VIII-related antigen [54,55,56], VEGFR-3 [56,57,58], D2–40 [59], FLI1 [60], and ERG [61], but use of IHC is only necessary for characterization of poorly differentiated tumors with limited or absent vasoformative areas. Since poorly differentiated angiosarcomas may demonstrate limited expression of endothelial cell markers, use of a battery of markers for endothelial differentiation in conjunction with other appropriate markers to resolve the differential diagnosis cannot be overemphasized.
CD31 and, more recently, ERG [61,62,63,64] (Fig. 17.23) are the gold standard for demonstrating endothelial differentiation in angiosarcoma. ERG is as sensitive and more specific for endothelial differentiation than CD31 [61]. Although CD31 and CD34 are both commonly used endothelial markers, CD31, while rather specific (it can be positive in intratumoral macrophages), is not particularly sensitive and is often lost or poorly expressed in angiosarcoma. In contrast, while CD34 is very sensitive (positive in >90% of vascular tumors), it is certainly not specific for endothelial cells, as it is expressed by many other mesenchymal cell types. ERG, a transcription factor that regulates angiogenesis, is a sensitive and relatively specific nuclear marker for endothelial cells (particularly clones directed at the N-terminus of the protein [65]). Thus far, the only other consistently ERG-positive tumor is prostatic adenocarcinoma [66]. A minority of Ewing sarcomas [67], epithelioid sarcomas [65, 68, 69], and acute myeloid leukemias [63] express ERG. These tumors show distinct clinical as well as morphologic and additional IHC profiles compared to angiosarcoma. A number of lymphatic-associated antibodies have also been recently developed (D2–40, Prox-1, and VEGFR-3) [56,57,58] and shown to be frequently expressed in angiosarcoma, suggesting that lymphatic or mixed lymphatic/blood vascular differentiation is common in malignant vascular tumors.
Cytokeratin (CK) and epithelial membrane antigen (EMA) immunoreactivity is not infrequent in angiosarcomas and may lead the pathologist toward an erroneous diagnosis of carcinoma. Weak to moderate or rarely strong expression of pankeratin (CAM5.2 and AE1/AE3) in a minority of tumor cells has been reported in 3–20% of non-epithelioid angiosarcomas [70, 71] and up to 50% of epithelioid angiosarcomas. EMA expression of similar distribution and intensity has been reported in 10–35% of non-epithelioid angiosarcomas and 25% of epithelioid angiosarcomas [70, 71]. Cautious interpretation of such expression in conjunction with the characteristic clinical and morphologic features of the tumor and expression of endothelial cell antigens will avoid this potential pitfall. High-grade invasive mammary carcinoma of no special type (ductal) is the most common differential diagnostic consideration for CK-expressing, high-grade angiosarcomas. However, carcinoma will usually show much stronger and more diffuse CK immunoreactivity and be negative for endothelial markers. Angiosarcomas composed of predominantly spindle cells may mimic a high-grade spindle cell metaplastic carcinoma. In angiosarcoma, the spindle cells form lobulated nests, whereas in metaplastic carcinoma the spindle cells form linear arrays with ill-defined, infiltrative borders.
The spindle cells of metaplastic carcinoma usually show moderate to strong expression of p63 [72] and its isoform p40 (∆N p63), but the latter is less useful given its lower sensitivity [73, 74]. Spindle cell metaplastic carcinoma also shows patchy moderate to diffusely strong expression of high-molecular-weight CKs (CK5/6, CK34βE12) throughout the lesion and lacks expression of endothelial markers.
The proximal type of epithelioid sarcoma typically has a multinodular growth pattern and may occasionally show a pseudovascular appearance that can be mistaken for abortive attempts at vasoformation. Cytologically, the cells are large and epithelioid with marked cytologic atypia, vesicular nuclei, and prominent nucleoli. A significant proportion of epithelioid sarcomas also express endothelial markers, including N-terminal ERG, CD34 (up to 50%), FLI1, and D2–40, further complicating distinction from angiosarcoma [63]. Although epithelioid sarcoma is typically strongly CK positive (75% of cases) [65], it should be recalled that malignant vascular tumors may aberrantly express CKs. However, in contrast to angiosarcoma, epithelioid sarcoma is negative for CD31 and often shows loss of nuclear INI1/SMARCB1 expression [75,76,77].
Melanoma metastatic to the breast frequently demonstrates epithelioid histology, thus falling within the differential diagnosis of epithelioid and poorly differentiated angiosarcoma. Most melanomas strongly express S-100 protein, SOX10, Melan-A, and HMB45, whereas angiosarcomas are negative for these markers; the importance of thorough clinical history cannot be overemphasized.
At the opposite end of the clinical spectrum, lower grade angiosarcomas arising in the postradiation setting must be distinguished from atypical vascular lesions. This distinction is important given the significant difference in clinical management and prognosis. However, their distinction can be exceptionally challenging and in some cases impossible to resolve with certainty on CNB material given their histomorphologic and immunophenotypic overlap. It is also important to note that angiosarcomas may contain peripheral atypical vascular lesion-like areas (Fig. 17.24a, b). The discovery that the c-MYC locus is amplified in over half of postradiation angiosarcomas [26, 78,79,80,81] and a variable fraction of non-radiation-associated angiosarcomas [26, 81,82,83,84], but not in atypical vascular lesions, now allows resolution of this differential diagnosis in most cases (Fig. 17.25a–f). IHC for c-MYC shows nearly 100% concordance with c-MYC fluorescence in situ hybridization (FISH) [24, 82, 85]. However, it should be noted that c-MYC amplification is not detected in all cases of radiation-associated angiosarcoma, especially when the lesion is well differentiated and unfortunately more likely confused with an atypical vascular lesion; therefore, lack of expression does not exclude angiosarcoma [26, 84,85,86,87].
The FLT4 gene is co-amplified with c-MYC in 18–25% of secondary angiosarcomas, but not in primary angiosarcomas or atypical vascular lesions [78, 83], and is detectable by both FISH and immunohistochemistry. FLT4 encodes the vascular endothelial growth factor receptor-3 (VEGFR3) [26, 88,89,90,91]. The high sensitivity and specificity of FLT4 immunohistochemistry are of therapeutic interest, since it may be a rapid screening tool to identify patients who would benefit from kinase inhibitor therapy. For example, pazopanib, a multikinase inhibitor with activity against VEGFR-1/2/3, was recently approved for soft-tissue sarcomas previously treated with chemotherapy [92, 93].
Genomic sequencing has identified activating mutations in KDR gene, which encodes vascular endothelial growth factor 2 in approximately 10% of mammary angiosarcomas, regardless of radiation exposure [94]. Mutations in PTPRB and PLCG1 (genes related to angiogenesis) have also been described in some angiosarcomas [95]. While c-MYC amplification may be seen in tumors with KDR mutations, FLT4 amplification appears to be mutually exclusive with KDR alterations [83]. Collectively, these findings suggest that therapeutic targeting of these angiogenic pathways may improve outcomes in these typically chemo- and radiation therapy-resistant tumors [86, 87].
Treatment and Prognosis
Total mastectomy is the treatment of choice for angiosarcoma as wide excision alone results in an unacceptable rate of local recurrence [96]. Axillary dissection is not necessary since metastases rarely involve these lymph nodes [96]. Occasionally, a small lesion (with respect to total breast volume, typically <2 cm) may be completely excised by lumpectomy. Nearly all studies to date conclude that radiotherapy and chemotherapy are largely ineffective for both primary and post-radiotherapy angiosarcomas [31, 97, 98]; thus, the current interest in the employment of targeted agents to improve outcome is high (as discussed above). One recent study suggested that only patients with radiation-associated angiosarcoma derive benefit from chemotherapy [99], while another found chemotherapy benefit for patients with tumors >5 cm [100]. Immunotherapy may also be effective in some patients [101].
As with angiosarcoma of other anatomic sites, those arising in the breast (both primary and secondary to radiation therapy) are highly aggressive neoplasms with a poor prognosis. Indeed, most patients die shortly after diagnosis [102], and the median survival of patients with mammary angiosarcoma is only 1–2 years [33, 34]. Local recurrence is common, even after surgical resection with negative margins [39, 85, 103]. Metastases generally occur in the lungs, bone, liver, contralateral breast, and distant skin and soft tissues [85, 97]. Although older studies suggested a relationship between histologic grade and patient outcome for primary mammary angiosarcoma [32, 47], more recent data derived from the well-annotated cases reported by Nascimento and others failed to demonstrate an association between grade and outcome [30], analogous to angiosarcomas arising at other anatomic sites and those secondary to radiation therapy [34]. In Nascimento’s series, 10 of 41 (24%) patients experienced local recurrence, 24 (59%) developed metastasis, and 18 (44%) died. Stratification of the tumors by histologic grade using Rosen’s 3-tiered grading system showed no significant differences in relapse-free or overall survival [32, 47]. This result was subsequently replicated by Taffurelli et al. in a series of 112 patients [31].
Atypical Vascular Lesions
Overview
Atypical vascular lesions are most commonly seen in the skin of the breast following radiation therapy for breast cancer [24, 36, 38, 39, 44, 104]. They are thought to arise as a consequence of lymphatic obstruction after surgery and radiation, causing superficial dilatation of vascular channels [85, 105]. These lesions are not frankly malignant, and their potential to transform into angiosarcoma is low [106]. However, they are surrogate markers for exposure to radiation.
Clinical and Radiologic Features
The typical age at presentation is the sixth and seventh decades of life. Most patients present with a solitary, small, red, brown, or pink erythematous papule or plaque, but between 20% and 50% of patients have multiple synchronous or metachronous lesions [27, 38, 85, 86, 107]. Atypical vascular lesions are typically <5 mm, but some as large as 20 mm or more have been reported [27, 38]. Compared to postradiation angiosarcomas, atypical vascular lesions tend to occur in slightly younger patients and within a shorter time interval (average 3–4 years) following radiation exposure [85, 108].
Microscopic Features
On a well-oriented and adequate skin biopsy, atypical vascular lesions appear as a wedge-shaped aggregation of variably dilated, thin-walled vascular spaces lined by a single layer of cytologically bland endothelial cells limited to the dermis resembling lymphangioma (Fig. 17.26a). Rarely, the deep aspect of the reticular dermis or underlying subcutis may be involved [38, 85, 106, 108,109,110]. Small narrow vessels are also present and may show a focally anastomosing pattern with dissection through dermal collagen. Nuclear hobnailing and hyperchromasia are frequently observed (Fig. 17.26b, c). However, overt nuclear atypia, endothelial multilayering, and mitotic activity are not seen in atypical vascular lesions and if present should heighten the concern for well-differentiated angiosarcoma [109]. Thin projections of endothelium-covered stroma commonly project into the vascular spaces [86, 109]. Subtypes of atypical vascular lesion have been described based on the vascular lining cells: lymphatic type, vascular type, and those with mixed features [108]. The lymphatic type consists of empty, variably ectatic vessels resembling lymphangioma [109] (Fig. 17.27a–d). The vascular type is reminiscent of a capillary hemangioma and is composed of irregularly arranged, variably attenuated capillaries lined by hobnail endothelial cells [108, 110] that may demonstrate mild cytologic atypia [108] (Fig. 17.28a–d). There is no evidence that the subtypes differ in their very low rate of malignant progression [85, 86, 108]; thus, their distinction is only of academic interest.
On CNB, atypical vascular lesions can be difficult to differentiate from angiosarcoma. Features suggestive of atypical vascular lesion include small size, lack of overt endothelial atypia, and confinement to the dermis, without involvement of subcutaneous or breast parenchymal structures. Although the presence of anastomosing vascular spaces lined by plump endothelial cells is concerning, recognition of lesional circumscription and limited extent of the dissecting growth pattern will prevent overdiagnosis.
Differential Diagnosis
Distinction of atypical vascular lesions from angiosarcoma is critical to avoid excessive surgery and inappropriate prognostication as discussed in detail above in the differential diagnostic considerations for angiosarcoma. The histologic differential diagnosis also includes dermal vascular ectasia due to radiation and scar.
Immunohistochemistry
The endothelial cells of both the lymphatic and vascular types of atypical vascular lesion are positive for a variety of vascular markers including factor VIII-related antigen, ERG, CD31, CD34, and FLI1. The lymphatic type is also positive for D2–40 [108, 110]. Staining for smooth muscle myosin demonstrates the vessels of the vascular type with circumferential pericytes [108, 110]. Importantly, IHC for MYC has been shown to resolve the differential diagnosis of atypical vascular lesion and angiosarcoma with high specificity (Fig. 17.25 c, d) [24, 82, 85].
Treatment and Prognosis
The majority of these lesions pursue a benign clinical course, with only a few reported cases of progression to angiosarcoma [27, 34, 38, 40]. However, since these lesions are a surrogate marker for prior radiation exposure and may indicate a higher propensity to develop malignant vascular tumors, atypical vascular lesions diagnosed on CNB should be excised with the aim of obtaining negative margins. In addition, a small subset of these lesions may be upgraded to angiosarcoma on excision [108, 111].
A series of ten radiation-induced intradermal vascular lesions with micropapillary tufts and architectural and/or cytologic atypia have been reported [106]. In contrast to angiosarcoma, the neoplasms were described as relatively well circumscribed and did not recur after complete excision. Although these authors concluded that atypical postradiation vascular lesions are characterized by a benign clinical course, others report that these types of lesions may have a higher incidence of local recurrence or malignant progression [38, 108]. In summary, it would appear that the risk of tumor progression is associated with atypical morphological features such as complex vascular architecture, involvement of deeper dermal and subcutaneous structures, and cytologic atypia [108]. Thus, excision with negative margins and close clinical follow-up for lesions lacking c-MYC amplification/overexpression remains warranted.
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Sanders, M.E., Cates, J.M. (2022). Vascular Lesions of the Breast. In: Shin, S.J., Chen, YY., Ginter, P.S. (eds) A Comprehensive Guide to Core Needle Biopsies of the Breast . Springer, Cham. https://doi.org/10.1007/978-3-031-05532-4_17
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