Breast

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 22, and is angiosarcoma of the breast.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

The H&E-stained sections demonstrate a poorly circumscribed lesion with infiltration into adjacent tissue. The tumor is composed of numerous anastomosing vascular channels that are lined by plump, spindled to epithelioid endothelial cells. The atypical endothelial cells have scant cytoplasm, large nuclei, variable pleomorphism, and mitoses. There is rare/focal necrosis in some sections. Vascular marker immunostains CD31, CD34, factor VIII, FLI1, and ERG are positive. These findings are diagnostic for angiosarcoma (AS).

AS are aggressive tumors of endothelial origin. The tumors most commonly present as cutaneous (head and neck), soft tissue, or visceral (breast, liver, spleen, heart) lesions. Breast is the most common site of visceral AS. AS of the breast can occur in a primary or secondary form. Primary AS occurs when there is no known inducing factor. Secondary AS most often develops following an extensive surgery or radiation therapy for a previous breast cancer, as in this case. Chronic lymphedema used to be a common risk factor for breast AS due to radical mastectomies involving the removal of significant numbers of axillary lymph nodes (Stewart-Treves syndrome). However, a recent change toward more conservative approaches, including partial mastectomies and radiation therapy, has led toward an increasing proportion of AS being radiation-induced.

Primary and secondary forms of AS are extremely rare compared to other breast malignancies (less than 1%). However, secondary AS of the breast from radiation therapy is a common form of radiation-induced sarcoma, accounting for nearly 40% of these tumors. Radiation-induced AS of the breast has a variable period of post-radiation presentation with an average peak between 5 and 10 years following therapy. Primary AS tends to present at an earlier age (approximately 40 years old) compared to the older age of secondary AS patients (approximately 70 years old).

Grossly, AS may present as nodules or plaque-like lesions with rapid growth and spread. They present as large, poorly circumscribed tumors with an average size of 5 cm. The overlying skin may show bluish nodules and dusky red discoloration. Microscopically, tumors are composed of dilated, anastomosing vascular channels lined by atypical endothelial cells with hyperchromatic nuclei. There is an infiltrative growth pattern, often invading adjacent breast lobules. The degree of atypia, mitoses, growth pattern, and presence of necrosis can be markedly variable within tumors and will impact overall grading. If poorly differentiated, AS can form solid growth without obvious vessel formation, making immunohistochemistry an important tool in these cases. Furthermore, papillary formations can be seen as well as large blood lakes from extravasated red blood cells. Since AS of the breast is more commonly found within the dermis, the overlying skin may or may not be impacted.

The positive immunohistochemistry profile for AS includes multiple vascular markers, including CD31, CD34, Factor VIII, FLI1, and ERG. Keratins, HHV8, ER, and PR stains are negative. Occasionally, EMA and focal/weak keratin staining may be present in epithelioid variants. MYC (8q24) and FLT4 amplification ​are ​common in the secondary form of breast AS but​ ​rare in the primary form and other common vascular lesions.

Overall, prognosis for this tumor is poor, with a median survival period of less than 5 years. Very large tumors, and those that are radiation-induced or deep-seated, appear to have a worse prognosis. No definitive reliable prognostic factors have been identified, including tumor grade, which does not appear to correlate with survival. AS grade does not affect the prognosis. It is important to recognize the features of low-grade AS, because they have a dire prognosis and can be mistaken for benign vascular lesions. High-grade lesions may be commonly misdiagnosed as breast carcinoma. AS most frequently metastasizes to the lungs, skin (including contralateral breast), liver, and bone.

Differential diagnoses include atypical vascular lesion, pseudoangiomatous stromal hyperplasia (PASH), spindle cell neoplasms of the breast, and benign vascular lesions.

Atypical vascular lesion (AVL) is a vascular lesion that develops postradiation, similar to angiosarcoma, with a median age of approximately 55. However, AVL is benign and does not recur if excised completely. The lesion should be small, superficial, and well-circumscribed, often in a wedge pattern, without an invasive periphery as previously described in AS. The lesion does not extend into parenchymal tissue of the breast. AVL histology demonstrates dilated vessels that anastomose within the dermis but are lined by only single cells without mitoses, pleomorphism, or necrosis. The nuclei may be slightly plump but are bland in comparison to AS, and nucleoli are absent. Although vascular markers will be positive, neither MYC nor FLT4 will show amplification.

Hemangiomas may be present in various forms, which includes capillary, cavernous, and anastomosing. These lesions are well-circumscribed without infiltrative borders. The lining endothelial cells in hemangiomas lack atypia, pleomorphism, or more than a single layer. Capillary hemangiomas demonstrate numerous diminutive vessels and occasionally a distinctly larger vessel at the periphery feeding the lesion. Cavernous hemangiomas contain fibrous septae separating enlarged and dilated vasculature that may develop thromboses and revascularization. Intravascular papillary endothelial hyperplasia (Masson hemangioma) is characterized by papillary proliferations, which may be seen focally in any vascular lesion. Anastomosing hemangiomas show architectural complexity mimicking AS, but no cytologic atypia.

Metaplastic spindle cell carcinoma is a type of metaplastic breast carcinoma that presents with a wide variety of patterns, such as fibromatosis-like and undifferentiated pleomorphic sarcoma-like. In addition, the cytologic appearance can be highly variable, with a range from bland appearance to severe pleomorphism. Diagnostic clues are the presence of an in-situ component and areas showing gland formation and/or squamous differentiation. The tumors often express broad-spectrum keratin, p63, and SMA but will be negative for ER, PR, HER2, and vascular markers. Prognosis for spindle cell carcinoma is also poor despite infrequent lymph node metastasis.

Myofibroblastoma (MF) is a well-circumscribed benign mammary stromal tumor composed of fibroblasts and myofibroblasts. MF occurs in older men and post-menopausal women and is a member of the 13q/Rb family of tumors (which includes spindle cell lipoma, extramammary myofibroblastoma, and cellular angiofibroma), with loss of Rb expression. Microscopically, short fascicles of bland spindle cells are present with intervening dense hyalinized collagen bands and adipose tissue. Scattered mast cells and perivascular infiltrates may be seen. By immunohistochemistry, ER, PR, AR, and SMA are positive. Tumor cells also stain for BCL2, CD34, CD10, and CD99, while other vascular markers and Rb are negative.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign myofibroblastic proliferation that imitates a vascular disorder by formation of broad clefts. The clefts are empty but may intersect into lobules, simulating invasion. Since PASH is myofibroblastic in origin, spindled cells are sometimes present that appear as an endothelial lining. However, these cells will be negative for vascular markers present in true vascular lesions (CD31, Factor VIII), while being positive for hormonal and myofibroblastic markers (ER, PR, CD34, and smooth muscle myosin heavy chain). The surrounding stroma contains a very dense stroma that has been described as keloid-like. There is no atypia, necrosis, or mitoses. 

1. Which of the following is more likely to be present in secondary angiosarcoma than primary angiosarcoma?
   
   
   1. ER/PR positivity
   2. Factor VIII staining
   3. HHV8 positivity
   4. MYC​ amplification​
   5. Younger patient age
2. Which of the following is the cell of origin for pseudoangiomatous stromal hyperplasia (PASH)?
   
   
   1. Endothelial cells
   2. Epithelial cells
   3. Myofibroblasts
   4. Neural cells
   5. Skeletal muscle cells
3. Which of the following spindle cell breast tumors show a wide variability of histologic patterns with positive staining for p63?
   
   
   1. Atypical vascular lesion
   2. Metaplastic spindle cell carcinoma
   3. Myofibroblastoma
   4. PASH
   5. Secondary angiosarcoma of the breast

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1. MYC​ amplification​ (d)
2. Myofibroblasts (c)
   
3. Metaplastic spindle cell carcinoma (b)