Mesenchymal Tumors of the Breast

Clinical Presentation

Hemangiomas of the breast may be identified at any adult age, with only rare cases reported in children and men. Perilobular hemangiomas are usually found incidentally in CNBs or surgical excisions performed for other indications. Other larger hemangiomas are palpable or detected by imaging. A breast hemangioma has been reported in a patient with Kasabach-Merritt syndrome.

Clinical Imaging

Perilobular hemangiomas are usually occult on imaging, although vascular lesions are being increasingly detected by MRI. Hemangiomas are often superficially located in the breast. On mammography, larger hemangiomas can be detected as well-circumscribed, oval or lobulated lesions with similar density as the adjacent breast and an average size of 1 to 2 cm. Calcifications may be present but are not common. On ultrasound, hemangiomas are well-circumscribed, lobulated, solid masses that are hypoechoic or hyperechoic. Some clinically or mammographically evident lesions are occult on ultrasound. The radiological findings are not specific and can mimic fibroadenoma. On MRI, hemangiomas can appear as lobulated masses with fibrous septa, which are isointense to the adjacent tissue on T1-weighted images and homogeneously hyperintense on T2-weighted images. Lesions with intense enhancement can mimic angiosarcoma.

Gross Pathology

Perilobular hemangiomas are microscopic, generally smaller than 2 mm, and not grossly identifiable. Gross evaluation of larger hemangiomas reveals a well-circumscribed, firm, dark red or brown mass, usually measuring less than 2.5 cm. Venous hemangiomas up to approximately 5 cm in size have been reported. Cavernous hemangiomas exhibit a spongy texture.

Microscopic Pathology

A key feature of all hemangiomas is the presence of circumscribed borders. No endothelial proliferation, such as piling up, tufting, or papillary growth, is present, nor is there nuclear atypia or mitotic activity. Perilobular hemangiomas are nonanastomosing proliferations of small, dilated capillaries filled with red blood cells, typically associated with a terminal duct lobular unit (TDLU) ( Fig. 31.5 ). The appearance of the capillaries has been described as a fine meshwork pattern. The endothelium is in single layers with bland nuclear features. The capillary walls are thin and without smooth muscle. Stromal lymphocytes may be present. Perilobular hemangiomas can be single or multiple and may be bilateral. Other hemangioma types occur in extralobular stroma. Cavernous hemangiomas are composed of large, dilated, nonanastomosing vascular spaces filled with red blood cells ( Figs. 31.6A and 31.6B ). Fibrous stroma may be present between the spaces and may calcify. Capillary hemangiomas are characterized by densely packed small capillary-sized blood vessels with a lobular appearance ( Figs. 31.6C and 31.6D ). Venous hemangiomas are composed of large, irregularly dilated vascular spaces with variably thickened muscularized walls ( Figs. 31.6E and 31.6F ). These lesions are considered vascular malformations rather than true hemangiomas. A feeder vessel with a muscularized wall is often present within or adjacent to the hemangioma. Thrombosis, recanalization, or papillary endothelial hyperplasia may be present within the vascular lumina of any hemangioma.

Some lesions with features otherwise indicative of hemangioma but with nuclear atypia or minimal vascular anastomoses have been termed “atypical hemangiomas.” However, surgical excision and clinical follow-up have shown no upgrade or progression to angiosarcoma.

Hemorrhage and infarction may occur in hemangiomas after CNB. Although these changes may resemble blood lakes or necrosis seen in angiosarcoma, recognition of the circumscribed lesional borders and lack of nuclear atypia, mitoses, or solid proliferation allows for distinction from angiosarcoma (see also “Differential Diagnosis” under “Angiosarcoma”).

Treatment and Prognosis

Hemangiomas are benign, and no treatment is needed if low-grade angiosarcoma can be excluded. Given their small size, incidental perilobular hemangiomas are often removed by the CNB procedure. Historically, prompt excision of vascular lesions of the breast was advised to exclude angiosarcoma. More recent studies of hemangiomas without atypical features on CNB have found no recurrences or clinical events in nonexcised lesions and no upgrades to angiosarcoma in excised lesions, suggesting that excision is not necessary in select cases with careful radiological-pathological correlation. Hemangiomas with atypical features should be excised to exclude angiosarcoma. Similarly, for cases with limited sampling, the significance of focal endothelial hyperplasia, anastomosing vascular channels, mitotic activity, or border irregularity may not be readily assessed. For cases with ambiguous features on CNB, a descriptive diagnosis of atypical vascular proliferation can be utilized with deferral to the anticipated excision specimen.

Clinical Presentation

Angiolipoma of the breast is uncommon and usually involves the subcutaneous tissue rather than the breast parenchyma. Angiolipoma presents as a mass, with a mean size of less than 2 cm, although reported sizes range up to 20 cm. Like angiolipomas at other sites, these lesions are often painful.

Clinical Imaging

Mammographic and sonographic features are similar to those for hemangioma, although some cases may have irregular margins.

Gross Pathology

Angiolipomas are usually well-circumscribed and often encapsulated. The cut surface is yellow and lobulated, similar to lipoma. With increased vascular components, these tumors may appear red and firm.

Microscopic Pathology

Angiolipomas consist of a circumscribed proliferation of capillary-sized vascular spaces distributed within fibrous stroma in a lipomatous background. Intravascular fibrin thrombi are often prominent, and cytological atypia is absent ( Fig. 31.7 ). The amount of vasculature can vary considerably between cases, and cellular angiolipomas show a prominent vascular component with little to no admixed adipose tissue ( Fig. 31.8 ). Mitotic activity is typically absent to low, but may be more overt in cellular cases. The diagnosis of conventional, adipose-predominant angiolipoma is typically straightforward, but cellular lesions may overlap morphologically with hemangioma and low-grade angiosarcoma on CNB (see also “Differential Diagnosis” under “Angiosarcoma”).

Treatment and Prognosis

Angiolipomas are benign and do not recur. Definitive diagnosis on CNB does not require excision.

Clinical Presentation

Few cases of angiomatosis have been reported in the breast, many as case reports. Aside from a case of angiomatosis in a 7-year-old boy, all patients have been female, with a wide age range (0–59 years) and a mean age of 51 years in the largest series. Most patients present with a mass, palpable irregularity, or breast enlargement, and less frequently with MRI enhancement. The overlying skin may be hyperpigmented or papular. Angiomatosis as an incidental imaging finding has been reported. All reported lesions have been unilateral, with the upper outer quadrant or axilla being most often involved.

Clinical Imaging

Mammography may show an ill-defined mass or density. Ultrasound typically demonstrates a hypoechoic, irregular mass, potentially with multiple circumscribed spaces separated by thin septa. MRI shows a T2 hyperintense and T1 isointense mass and/or enhancement.

Gross Pathology

Angiomatosis is ill-defined, cystic, and/or spongy on gross examination. Published cases have ranged from 2 to more than 20 cm. The cystic spaces contain hemorrhagic or serosanguineous material.

Microscopic Pathology

Angiomatosis is characterized by a diffuse distribution of large, dilated, anastomosing vascular spaces in the extralobular stroma ( Fig. 31.9 ). Red blood cells can be identified in some spaces but not others, and immunohistochemistry (IHC) with CD31 and D2-40 supports the presence of lymphangiomatous and hemangiomatous vessels. The vascular spaces are lined by flat endothelial cells without atypia or mitotic activity. The lesional borders are ill defined, and the vascular spaces tend to incorporate and entrap breast ducts and lobules, without infiltration into the intralobular stroma of the TDLUs. Sparing of the intralobular stroma helps differentiate angiomatosis from low-grade angiosarcoma, which can invade and destroy the intralobular stroma. Scant smooth muscle strands may be identified in the vascular walls of some cases, but well-muscularized vessels, as in venous hemangioma, are not seen. Lymphoid aggregates can be present.

Treatment and Prognosis

Surgical excision is required for definitive diagnosis. Complete excision with negative margins is recommended, as incompletely excised cases have a risk of local recurrence. Metastasis or malignant transformation has not been observed.

Clinical Presentation

Most patients with papillary endothelial hyperplasia of the breast present with a superficial, firm mass, and some have reported trauma to the area. The overlying skin may show red to blue discoloration. In one series, patients with papillary endothelial hyperplasia were on average older (mean age 62 years) than patients with primary angiosarcoma (33 years). Some reports have been in men.

Clinical Imaging

Papillary endothelial hyperplasia is seen as a circumscribed nodule on mammography, in some cases associated with calcifications.

Gross Pathology

Gross examination reveals a rounded nodule that may be either rubbery or friable, and red or tan. The lesions are small (<2 cm) and overlapping in size with other vascular lesions.

Microscopic Pathology

Papillary endothelial hyperplasia is usually superficially located, involving the deep dermis or subcutis. The lesion consists of a well-circumscribed intravascular proliferation of flat endothelial cells lining thin and branching papillary hyaline stalks ( Fig. 31.10 ). The endothelial cells lack cytological atypia, and there is no necrosis. Mitotic figures are absent to rare. Thrombus may be evident. Elastin stain can help highlight the intravascular location of the proliferation. The complex branched and fused papillary stalks of papillary endothelial hyperplasia can mimic the anastomosing and papillary endothelial growth of angiosarcoma. However, the circumscription of the lesion, intravascular location, and lack of other features of angiosarcoma, such as significant cytological atypia, necrosis, or solid growth, can facilitate the diagnosis (see also “Differential Diagnosis” under “Angiosarcoma”).

Treatment and Prognosis

Papillary endothelial hyperplasia is benign and does not recur after excision.

Clinical Presentation

Primary angiosarcoma typically arises in younger women with a median age of 40 years, although a wide age range has been reported. A few cases have been reported in men. Most patients present with a large (>5 cm), painless, and rapidly growing breast mass or with diffuse breast swelling. If the tumor is superficial, the skin may show red, violaceous, blue, or black discoloration ( Figs. 31.11A and 31.11B ). A few cases of bilateral angiosarcomas have been reported.

Clinical Imaging

On mammography, most angiosarcomas are seen as a noncalcified mass, with ill-defined density, or focal symmetry within the breast parenchyma. Some tumors may not be detectable by mammography. Ultrasound typically reveals a solid hyperechoic mass or an architectural distortion of hyper- or hypoechogenicity. On MRI, the mass is heterogeneously enhancing with malignant pattern washout characteristics.

Gross Pathology

Gross examination reveals an ill-defined, firm, hemorrhagic, spongy mass within the breast tissue, although smaller tumors may present with only hemorrhagic discoloration ( Fig. 31.11 ). Poorly differentiated tumors have more solid and fleshy areas with or without necrosis. Primary angiosarcomas are usually solitary, in contrast to secondary angiosarcomas that are more often multifocal. Mean tumor size is approximately 6 to 7 cm, but size can range from less than 1 cm to more than 20 cm. The gross mass may underestimate tumor size due to infiltrative growth identified microscopically. Consistent with this, adjacent breast parenchyma may in some cases show punctate or irregular zones of hemorrhage. Liberal sampling, especially of hemorrhagic tissue, is advised to adequately assess margin status and tumor stage. Some angiosarcomas may show only an ill-defined induration or thickening on gross examination.

Microscopic Pathology

Primary angiosarcomas often occur within the breast parenchyma, in contrast to radiation-associated angiosarcomas that are usually more superficially centered within the dermis and subcutis. A broad spectrum of histological features can be seen, ranging from obviously vasoformative proliferations with little nuclear atypia to poorly differentiated solid tumors lacking an obvious vascular growth pattern ( Fig. 31.12 ). The malignant endothelial cells may be flat, plump, spindled, or epithelioid, with a range of nuclear pleomorphism ( Fig. 31.13 ). The histological appearance can be heterogeneous within a given tumor ( Figs. 31.14 and 31.15 ). At one end of the spectrum, well-differentiated angiosarcomas have a well-developed vasoformative growth pattern, characterized by variably dilated, complex interanastomosing vascular spaces with irregular contours ( Figs. 31.13A, 31.13B , and 31.16 ). The endothelial cells can be bland or slightly enlarged and hyperchromatic, and hobnail into the vascular lumen. The tumor infiltrates the extralobular stroma and fat in a haphazard pattern, and may invade the intralobular stroma and completely surround and engulf TDLUs ( Fig. 31.16 ). The density of the neoplastic vascular spaces can be heterogeneous and may decrease toward the periphery, which can make margin evaluation challenging ( Fig. 31.17 ). Recognition of the infiltrative growth pattern facilitates the diagnosis of malignancy. Primary angiosarcomas more often show well-formed vasoformative architecture compared to secondary angiosarcomas. Some angiosarcomas may also infiltrate as dense proliferations of small capillaries. In some cases, compression of the vascular spaces of a well-differentiated angiosarcoma can mimic PASH, but infiltrative growth and better-defined vasoformative areas nearby are helpful clues to the diagnosis. Less-differentiated angiosarcomas have areas of papillary endothelial growth ( Figs. 31.12B and 31.12C ), which refers to a spectrum of features ranging from multilayering and tufting of the endothelial cells into vascular lumens to complex papillary architecture that may expand and fill the space. Nuclear atypia may be subtle and mitoses can be rare in the papillary endothelial proliferations, which can result in a deceptively bland appearance. The endothelial cells may be more plump or spindled with increasing transition to cellular solid growth. Poorly differentiated angiosarcomas have areas of solid or spindle cell growth patterns, hemorrhage (“blood lakes”), or necrosis, and in some cases may show no or little evidence of vasoformative growth ( Figs. 31.18 and 31.19 ).

Historically, angiosarcoma has been classified as low, intermediate, or high grade, based on a combination of histological features including endothelial tufting and papillary growth, solid/spindled growth, mitotic activity, and blood lakes or necrosis (Rosen grade). In this system, low-grade tumors lack all of these features or have only focal endothelial tufting and rare mitotic figures, whereas all the features are present in high-grade tumors. Intermediate-grade tumors have endothelial tufting with only focal papillary proliferation that may be mitotically active, or focal solid foci. Whereas grade correlated with clinical outcome in earlier studies, more recent studies in primary angiosarcomas have shown conflicting results, with one major report failing to show such an association, suggesting that outcomes are poor irrespective of grade, and another finding an association with outcome, using both the three-tier and a simplified two-tier system. For reporting, some consider it useful to describe the microscopic findings of angiosarcoma as a function of grade, as tumors can show considerable heterogeneity ( Figs. 31.14 and 31.15 ), and a low-grade descriptor may convey a deceptively bland appearance and can be helpful for clinicopathological follow-up.

Epithelioid angiosarcomas are rare in the breast and are significantly more common in postradiation angiosarcomas than primary angiosarcomas. These tumors are predominantly or entirely composed of solid sheets of large epithelioid tumor cells with abundant amphophilic cytoplasm, large vesicular nuclei, and abundant mitotic activity, with little to no vasoformative growth ( Figs. 31.13G and 31.13H ). The histological features can mimic high-grade invasive ductal carcinoma (IDC), and IHC with vascular markers and keratin is useful to establish the diagnosis.

Intratumoral morphological heterogeneity of some angiosarcomas poses several potential diagnostic pitfalls. First, a well-differentiated angiosarcoma with bland nuclear features may be misinterpreted as a benign vascular lesion, such as hemangioma or angiolipoma, on scant CNB material. Second, heterogeneity increases the effect of sampling bias, and CNBs may therefore not be representative of the tumor at excision. And third, tumor size and margin status may be underestimated in cases where scattered bland vascular spaces of a well-differentiated tumor permeate and blend imperceptibly with the adjacent fat.

Treatment and Prognosis

The prognosis of primary angiosarcoma of the breast is poor. These tumors have a predilection for local recurrence, distant metastasis, and disease-related death, with overall short survival. The median time to recurrence is as low as 5 months, and median disease-free survival is approximately 1 to 2 years. Frequent sites of metastasis include the lung, liver, and bone, as well as contralateral breast and other skin and soft tissue sites. Although early studies suggested a correlation between a three-tiered grading system and clinical outcome, more recent studies have yielded conflicting results. Nodal metastasis is uncommon.

Mastectomy is the primary treatment in most studies, although rates of breast conserving surgery (BCS) are increasing. There have been no clinical trials comparing BCS with mastectomy or assessing optimal margin width. Axillary lymph node sampling is variable, but dissection is not routinely performed due to low rates of lymph node metastasis. Although multimodal management is common in treating angiosarcoma of the breast, there are no clinical trials to definitively guide therapy. The use of adjuvant chemotherapy and/or radiotherapy varies across studies, most of which are limited by small sample size and lack of systematic treatment approach. Anthracycline and taxane-based regimens are commonly used as front-line therapy.

Differential Diagnosis

The differential diagnosis of well-differentiated angiosarcoma includes benign vascular lesions such as hemangiomas, angiolipomas, angiomatosis, and papillary endothelial hyperplasia; atypical vascular lesions (AVLs); and PASH. Hemangiomas, angiolipomas, and papillary endothelial hyperplasia lack cytological atypia and are generally circumscribed without infiltrative growth, in contrast to angiosarcomas. Hemangiomas and angiolipomas additionally lack anastomosing growth. The vascular spaces of AVLs are anastomosing, but there is no overt endothelial cell atypia, tufting, or multilayering. The complex papillary stalks of papillary endothelial hyperplasia can mimic the anastomosing vasoformative growth of angiosarcoma. An elastin stain may be helpful to highlight the intravascular location. Most hemangiomas are less than 2 cm in size, whereas angiosarcomas are usually larger than 2 cm. A thick-walled feeder vessel can be seen in hemangiomas, and mural smooth muscle can be recognized in venous hemangiomas, but neither is present in angiosarcomas. The diffuse anastomosing vascular spaces of angiomatosis can be very concerning for angiosarcoma. However, angiomatosis lacks cytological atypia and characteristically spares the intralobular stroma, whereas angiosarcoma can infiltrate the intralobular stroma and dissect between the TDLUs. In summary, significant endothelial atypia; endothelial proliferation; piling up, tufting, or papillary growth; and destructive infiltration are not features of a benign vascular lesion and should raise concern for angiosarcoma. Of course, these features may not be developed in a limited CNB sample, and excision may be necessary for full characterization.

The differential diagnosis of poorly differentiated angiosarcoma with solid or spindled growth includes high-grade IDC, metastatic carcinoma, metaplastic spindle cell carcinoma, acantholytic squamous cell carcinoma, malignant melanoma, malignant phyllodes tumor with extensive stromal overgrowth, and other sarcomas. Ancillary IHC can be useful in this context. Angiosarcoma is generally positive for multiple endothelial markers, including CD34, ERG, CD31, D2-40, and Factor VIII, although staining can be limited in some cases ( Figs. 31.18D and 31.20 ). Of these, ERG is considered a highly sensitive and relatively specific marker for endothelial differentiation. CD34 is sensitive but not specific for endothelial differentiation and can be expressed in a number of other mesenchymal neoplasms, notably including a subset of malignant phyllodes tumors. The use of multiple endothelial markers is suggested in suspected poorly differentiated angiosarcoma. Invasive carcinoma is typically diffusely positive for keratin and epithelial membrane antigen (EMA), whereas angiosarcoma is often negative. However, some poorly differentiated angiosarcomas can be keratin and/or EMA positive. Careful interpretation with the aid of endothelial cell marker expression, clinical context, and morphological features can avoid a misdiagnosis. Metaplastic spindle cell carcinoma and acantholytic squamous cell carcinoma can form areas with pseudovascular spaces that can mimic the vasoformative growth of angiosarcoma. Conversely, solid and spindled growth in poorly differentiated angiosarcoma can mimic the solid, spindled growth of spindle cell carcinoma. Metaplastic spindle cell carcinoma frequently expresses p63 and high molecular weight keratins and is negative for endothelial markers. In contrast to melanoma, angiosarcoma is negative for melanocytic markers, such as S100 protein, SOX10, HMB45, and Melan-A.

Clinical Presentation

Whereas primary angiosarcoma often presents as a breast mass, postradiation angiosarcoma more commonly presents as cutaneous discolored patches, plaques, papules, or nodules within the irradiation field of women with a history of radiation therapy for breast cancer. Lesions can be solitary or multifocal. Presentation with skin thickening or dimpling or a palpable mass has been described. The average clinical size is 4 to 5 cm, but can range from less than 1 cm to 20 cm. Tumors can arise after BCS or mastectomy with radiation. The median interval between radiation and development of angiosarcoma is approximately 6 years, but can range from about 1 year to 11.5 years. The associated risk appears to increase up to 3 decades after breast cancer diagnosis. The median patient age is 70 years, which is about 20 years older than patients with primary angiosarcomas.

Clinical Imaging

Mammographic findings include skin thickening, parenchymal trabecular thickening, or an asymmetric mass. The features may be difficult to separate from surgical and radiation-induced changes. On MRI, an enhancing, circumscribed nodule may be seen in the skin. Some cases are radiographically occult.

Gross Pathology

The gross appearance of postradiation angiosarcoma varies from hemangioma-like to a solid mass with hemorrhagic and necrotic central portions and spongy peripheral areas. As in primary angiosarcomas, the tumor extent cannot be reliably assessed on gross examination. In one study, 40% of cases had no grossly identifiable lesion.

Microscopic Pathology

In contrast to primary angiosarcoma that typically occurs within the breast parenchyma, postradiation angiosarcoma is predominantly centered in the dermis ( Fig. 31.21 ). Some tumors invade deeper into the breast parenchyma. The histological appearance (vasoformative, spindled, and/or solid growth patterns) is similar to primary angiosarcoma, although secondary angiosarcomas are more commonly solid or spindled and poorly differentiated, including epithelioid morphology.

Amplification of MYC at 8q24 is a consistent molecular hallmark of secondary angiosarcoma, present in more than 90% of cases. Fluorescence in situ hybridization (FISH) and IHC can be used to detect MYC amplification or protein overexpression, respectively, and facilitate the diagnosis ( Fig. 31.22 ). Only rare reports of MYC -amplified primary breast angiosarcoma exist, and AVLs have been consistently negative. Loss of histone H3K27 trimethylation (H3K27me3) by IHC has been observed in postradiation angiosarcoma.

Treatment and Prognosis

The prognosis of secondary angiosarcoma of the breast is poor. Local recurrences are common, occur in more than 50% of patients, and may be multiple. The median disease-free survival is less than 3 years, and five-year survival rates range from 28% to 55%. Sites of metastatic spread are similar to primary angiosarcoma and include lung, liver, bone, and contralateral breast.

Treatment for postradiation angiosarcoma is similar to primary angiosarcoma. Mastectomy is often the primary treatment, although some patients undergo wide local excision. Adjuvant radiotherapy and chemotherapy are variably used. Recent reports of pathologically complete response (pCR) with neoadjuvant therapy may suggest promise in select cases.

Clinical Presentation

AVLs present as a circumscribed brown to red, erythematous papule, or less commonly plaque or nodule, on irradiated skin. Lesions may be solitary or multiple and usually measure up to 0.5 cm, although AVLs measuring multiple centimeters have been reported. On average, AVLs tends to present approximately 3 to 4 years after radiation treatment, but some may appear as early as 1 year after radiation. The median preceding radiation dose is 50 Gy. Patients usually present in the late sixth to early seventh decade and may be slightly younger on average than patients presenting with postradiation angiosarcoma.

Microscopic Pathology

An AVL is a circumscribed and often wedge-shaped vascular proliferation, usually centered in the superficial and mid-dermis but rarely involving the deep dermis ( Fig. 31.23 ). Rare examples may involve the subcutis. Two histological subtypes have been described: lymphatic subtype and vascular subtype, with overlapping features seen in some cases. The more common lymphatic subtype is characterized by irregularly dilated, angulated, thin-walled vascular spaces with a branching and focally anastomosing growth pattern. Focal dissection through collagen bundles may be seen. Proteinaceous fluid may be present in the vascular spaces and may contain red blood cells or occasional lymphocytes. The vascular spaces are lined by a single layer of flat, plump, or hobnailed endothelial cells, which may have hyperchromatic nuclei. There is no true cytological atypia, mitotic activity, or endothelial multilayering. The endothelial cells express ERG, D2-40, CD31, and to a variable degree, CD34. The vascular subtype is composed of small capillary vessels with flat or hobnailed endothelium arranged more haphazardly and lacking a lobular growth pattern. These lesions can resemble capillary hemangioma or hobnail hemangioma. The endothelial cells express ERG, CD31, and variably CD34.

Some studies have reported rare AVLs with cytological or architectural atypia, which included nuclear or nucleolar enlargement and piling up of endothelial cells. In one series of 10 such cases, none of the lesions recurred, whereas subsequent development of high-grade angiosarcoma was reported in one of four cases with endothelial atypia in another study.

Treatment and Prognosis

AVLs overall have a benign clinical course. Rare cases with progression to angiosarcoma have been reported, and this remains controversial. AVLs may recur, or additional AVLs may develop over time. AVLs should be surgically excised with the goal of achieving negative margins. Close clinical follow-up with biopsy of additional lesions is warranted.

Differential Diagnosis

The most important differential diagnosis of AVL is angiosarcoma. This distinction can be made in most cases if the lesion is entirely excised and evaluated. Features of angiosarcoma include lack of circumscription and infiltrative growth, extensive involvement of subcutis, endothelial tufting or papillary growth, overt cytological atypia, mitotic figures, blood lakes, and necrosis. However, the leading edge of angiosarcomas can be histologically bland and resemble AVLs, which can lead to underrecognition of angiosarcoma in CNB specimens but can usually be resolved by evaluation of the excised lesion. In contrast to postradiation angiosarcomas, AVLs are negative for MYC amplification or MYC protein overexpression, as assayed by FISH and IHC, respectively. Similarly, IHC detection of H3K27me3 has recently been found to be preserved in AVLs but lost in radiation-associated breast angiosarcomas. These ancillary tests can be useful to reach the correct diagnosis.