—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 4 - Epithelioid Angiosarcoma Arising in the Setting of Prior Radiation Therapy for Breast Cancer

Melinda E. Sanders, Vanderbilt University Medical Center, Nashville, TN





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Clinical History
The patient is a 56 year old female who is status post left lumpectomy and sentinel node biopsy followed by radiation therapy for invasive breast cancer in 2003, who presented in 5/2010 with a 2 month history of left breast enlargement, hyperpigmentation and multiple hard, painful skin nodules. Mammography at that time revealed a non-palpable spiculated nodule in the right breast suspicious for carcinoma and a suspicious thickening/mass of the left breast parenchyma and skin involving the anterior, inferior and medial aspects. Clinically, the left breast was described as having a peau d' orange appearance. Bilateral core needle biopsies were performed. The right needle core biopsy revealed invasive mammary carcinoma, no special type (ductal), low combined histologic grade, low proliferative rate. The biopsy on the left was read as fat necrosis and considered non-diagnostic. The decision was made to proceed with an incisional biopsy of the left breast for definitive diagnosis.


Case 4 - Figure 1
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Case 4 - Figure 4

Case 4 - Figure 5
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Case 4 - Figure 7

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
A low power photomicrograph of this woman's incisional biopsy of the left breast (figure 1) shows a poorly circumscribed, infiltrative process extensively involving the deep dermis and mammary parenchyma. Cords of tumor cells aggressively splay the collagen bundles of the dermis. Solid tumor islands are also present which involve both the dermis and subadjacent mammary parenchyma. At slightly higher magnification (figure 2), the highly infiltrative nature of the tumor cells can be better appreciated. Figures 3 and 4 show solid islands of tumor infiltrating around acinar structures. Figures 6 and 7 show the solid areas infiltrating the mammary parenchyma. On high power, the epithelioid morphology of the tumor is best appreciated (Figure 5). The tumor cells are highly pleomorphic with round to ovoid vesicular nuclei with prominent nucleoli. The tumor cell cytoplasm is eosinophilic and abundant. Mitoses and atypical mitoses are numerous. Vascular spaces, blood lakes or slit-like spaces containing extravasated RBC's are not apparent.

A series of immunohistochemical stains were ordered. Tumor cells were strongly and diffusely positive for CD31, CD34, Factor VIII, FLI-1, and D2-40. Tumor cells showed moderate positivity for p63 in approximately 50% of cells. Tumor cells were negative for CK AE1/3, PanCK, CK903, CK5/6, LCA (CD45), CD20, MPO, synaptophysin, chromogranin, ER, PR, Her2/neu, S-100, melan-A, HMB45 and INI-1.

Differential Diagnoses:
Taking into consideration both the clinical history and histologic appearance, the top differential diagnostic consideration for this lesion would be an epithelioid angiosarcoma. However, other considerations for this high grade epithelioid malignancy include poorly differentiated carcinoma, either primary to the breast or metastatic, high grade lymphoma, melanoma, or less likely proximal type epithelioid sarcoma.

Epithelioid angiosarcoma typically demonstrates expression of vascular markers including Factor VIII, CD31, CD34, D2-40 and FLI-1. In addition, moderate expression of p63 in approximately 50% of tumor cells was observed. Focal to patchy staining for epithelial cytokeratins and EMA has been reported in up to 40% of angiosarcomas but this strong staining is highly unusual and we found no reports of p63 positivity in angiosarcoma in the literature. However, in the face of multiple positive vascular markers and the clinical history, we were not swayed from the diagnosis of angiosarcoma.

Misdiagnosis of a poorly differentiated carcinoma, either primary to the breast or metastatic is an important pitfall for epithelioid angiosarcomas, as they may express multiple keratin markers (although usually patchy and faint) and vascular channel formation may be absent or missed. Careful attention to the clinical history is critical to avoiding this mistake. As mentioned above, in the face of positivity for multiple vascular markers and negativity for multiple other cytokeratins, the p63 expression was not considered to support a diagnosis of carcinoma.

A high grade lymphoma is an important consideration given the sheet-like growth pattern, vesicular nuclei and the splaying of dermal collagen. Peripheral T-cell lymphoma and diffuse large B cell lymphoma would be the primary considerations, although the degree of atypia is somewhat high for a diffuse large B cell lymphoma. Negativity for LCA and CD20 excludes these possibilities.

Although somewhat more unlikely, the possibility of malignant melanoma might also be entertained give the epithelioid nuclei. Since there is no epidermal component, the presumption would then be that this represents a metastatic lesion. The infiltrative nature of the process rather than a nodular lesion would also be unusual for melanoma. In this case, tumor cells were negative for S-100, Melan-A and HMB-45 essentially excluding this possibility.

Proximal type epithelioid sarcoma is a recently recognized aggressive variant of epithelioid sarcoma which develops predominantly in the pelvis, peritoneum and genital tract so the breast would certainly be an unusual location. Most are deep-seated and occur at an older age than the classic type which typically occurs in adolescents and young adults. Histologically, proximal type epithelioid sarcoma has a multinodular pattern consisting of large epithelioid carcinoma-like cells with marked cytologic atypia, vesicular nuclei and prominent nucleoli. Proximal type epithelioid sarcoma is positive for high and low molecular weight cytokeratins and /or EMA. Approximately 50% of cases are CD34 positive. In addition, epithelioid sarcomas loose nuclear immunoreactivity for INI-1, a tumor suppressor gene which controls transcription. In combination with the other immunohistochemical stains, positivity for INI-1 excludes proximal epithelioid sarcoma.

Final Diagnosis:
Epithelioid Angiosarcoma Arising in the Setting of Prior Radiation Therapy for Breast Cancer.

Case Discussion:
Angiosarcoma arises in the breast more than in any other site [1] . Mammary angiosarcoma is the most common type of breast sarcoma with an incidence of 5.8 per 5 million women [2] , represents approximately 8% of all breast sarcomas and 0.04% of all malignant neoplasms of the breast [3] .

Angiosarcomas in the breast can be divided into 3 categories: 1) primary mammary angiosarcoma, 2) cutaneous angiosarcoma associated with prior radiation therapy and 3) angiosarcoma arising in association with lymphedema (Stewart-Treves syndrome), usually affecting the upper limb after radical mastectomy [4] . Because of the increase in conservative treatment for breast carcinoma including partial mastectomy and sentinel lymph node biopsy as well as improvement in operative and radiation techniques Stewart-Treves syndrome is now very uncommon.

Primary Mammary Angiosarcoma
The age range of patients with primary angiosarcoma ranges from 17 to 70 years (median 38 years) [5] . These tumors are typically a deep, solitary mass in the mammary parenchyma but can involve the overlying skin [6] . The initial clinical finding is usually a painless mass ranging in size from less than 1.0 cm to greater than 15 cm, but most are at least 5.0 cm [1] . The presence of purple-blue discoloration of the skin reflects hemorrhage and vascularity in superficial tumors. If the lesion is deep seated there may be no external features to suggest angiosarcoma. Grossly, well differentiated angiosarcomas have a spongy appearance where as high grade tumors are typically solid, ill defined and fibrous, indistinguishable from other sarcomas [7] . Mammography in primary angiosarcoma typically shows architectural distortion without microcalcifications [8, 9] .

Histologically, angiosarcomas are characterized by anastomosing vascular channels that infiltrate the dermis and/or the breast parenchyma. Angiosarcoma may be categorized as low intermediate or high grade based on presence or absence of specific histologic features [5, 10] . The histologic grade can be variable within a given lesion. In low grade angiosarcomas the vascular spaces are well defined and lined by cells with prominent nuclei. Endothelial tufting is minimal and papillary formations are absent. Solid and spindle cell foci, blood lakes and necrosis are absent. Mitoses are rare to absent. Intermediate grade angiosarcoma shows increased cellularity, endothelial tufting, focal presence of papillary formations, rare if any spindle cell foci and absence of blood lakes and necrosis. The papillary areas are typically characterized by obvious mitotic activity. High grade angiosarcomas are characterized by prominent endothelial cell tufting, papillary formations with obviously malignant endothelial cells and numerous mitoses. Solid and spindle cell foci, blood lakes and necrosis are almost always present. Occasional high grade angiosarcomas have an epithelioid appearance which resembles carcinoma as discussed below. Primary angiosarcoma demonstrates strong expression of multiple vascular markers including Factor VIII, CD31, CD34, D2-40, FLI-1, ulex europaeus agglutinin-1, and B72.3 but their use is typically only necessary in high grade lesions as discussed below.

Post-Radiation Mammary Angiosarcoma
Mammary angiosarcoma arising in the post irradiation setting usually involves the skin with or without invasion of the subadjacent breast parenchyma [11, 12, 13] . Most tumors are multifocal and m ore than 50% of cases involve the skin only [7] . Radiation-associated mammary angiosarcoma is uncommon with approximately 100 cases reported in the literature, although the incidence is increasing with increased use of conservative therapies for breast cancer [11, 14, 15, 16] . The estimated risk of cutaneous or parenchymal disease following radiation therapy is 0.3% to 0.4% [17, 18] . All reported cases of post radiation angiosarcoma have occurred in women >50 years of age which is on average 30 years older than women with primary mammary angiosarcoma [19] . Most cases occur 2.5 to 11.5 years (median 4.5 years) post irradiation [11, 16, 18, 20] . This latency period is substantially shorter than for other radiation-associated malignancies in which the time between radiation therapy and malignancy is often > 10 years.

MRI can be very useful in defining the size in post radiation angiosarcomas [8] .

In contrast to primary mammary angiosarcoma, most cases of radiation-associated angiosarcoma are high grade regardless of the architectural pattern [1] . Most are solid with an epithelioid morphology (see below), a spindle cell morphology, or a mixture of the two patterns. Occasionally, lesions with the structural patterns more typical of low to intermediate grade lesions are seen but the malignant cells have poorly differentiated nuclei, vesicular chromatin, prominent nucleoli and mitotic activity consistent with a high grade angiosarcoma [1] . Variable numbers of slit-like spaces containing intraluminal or extravasated RBCs and even hemorrhage with the formation of blood lakes are typically present but occasionally may be entirely absent in the most poorly differentiated cases.

Epithelioid angiosarcoma
Epithelioid angiosarcoma is a rare variant of angiosarcoma composed of predominantly or exclusively of large "epithelioid" endothelial cells with abundant amphophilic to eosinophilic cytoplasm and large vesicular nuclei, which has been reported in diverse sites such as deep soft tissue [21] , uterus [22] , small bowel [23] , lung [24] , thyroid [25] , adrenals [26] , pharynx, prostate, skin [27] and bone [28] but also very rarely in the breast [4, 29, 30, 31, 32, 33] . In the breast, epithelioid angiosarcoma is almost exclusively seen in the post radiation setting with only 5 definitive cases of primary mammary epithelioid angiosarcoma reported in the literature [29, 30, 31, 32, 33]. The recent series by Nascimento also reports 5 cases of epithelioid angiosarcoma although they do not explicitly state whether all are primary [4] . Many cases express keratin in addition to endothelial markers. Its principal significance is the close mimicry of carcinoma.

Recognition of epithelioid angiosarcoma and its distinction from poorly differentiated carcinoma, melanoma, and proximal type epithelioid sarcoma is greatly assisted by immunohistochemistry as well as the rarity of these lesions in the breast. Epithelioid angiosarcoma typically demonstrates expression of vascular markers including Factor VIII, CD31, FLI-1, ulex europaeus agglutinin-1 and B72.3 but typically not CD34 [33] . Negativity for S-100, Melan-A and HMB-45 essentially exclude melanoma. Positivity for INI-1 excludes proximal epithelioid sarcoma [34, 35] . Focal to patchy staining for epithelial cytokeratins and EMA may be seen in up to 40% of angiosarcomas but these cases are also invariably positive for at least 1 vascular marker. In contrast carcinomas will stain positively for keratins and EMA but negatively for the vascular markers.

Treatment
Total mastectomy is the treatment of choice for angiosarcoma as wide excision alone is associated with high recurrence rates [36] . Axillary dissection is not necessary as metastases rarely involve these lymph nodes [36] . Occasionally, a small lesion may be completely excised by quadrantectomy. Radiotherapy and chemotherapy are ineffective for both primary and post-radiotherapy angiosarcomas [37] .

Prognosis
Angiosarcoma is a highly aggressive neoplasm with a poor prognosis with most patients dying shortly after diagnosis [38] . The mean survival of patients with mammary angiosarcoma is 1 to 2 years. Older studies have suggested a relationship between grade and outcome [5] for primary mammary angiosarcoma. However, the most recent data derived from the well-annotated cases reported by Nascimento et al. demonstrates no correlation between histologic grade and patient outcome [4] , analogous to angiosarcomas at other sites and following radiation therapy in the breast [11] . In the series by Nascimento et al. follow-up was available on 41 of 49 patients (83.7%) over a median duration of 29 months. During that time 10 patients (24.4%) experienced local recurrence, 24(58.5%) were found to have metastases and 15 showed no evidence of disease. The median time interval between diagnosis and metastasis was 34 months. At the time of the manuscript, 18 (44%) of patients had died of disease which is comparable to angiosarcomas arising in other sites and a similar follow-up interval. Stratification of the tumors by grade using Rosen's 3-tiered grading system [5, 10] showed no statistically significant differences in relapse-free and overall survival. The median recurrence free and overall survival rates for the entire cohort were 2.8 and 5.7 years, respectively. Similarly, no statistically significant correlation between tumor size and the likelihood of local recurrence or dying of disease was identified (P > 0.05). Vorburger et al compared the prognosis of 32 primary mammary angiosarcomas and 23 radiation therapy-associated angiosarcomas and found similarly poor disease-free and overall survival [19] .

The prognosis of radiation therapy-associated mammary angiosarcomas is similar to angiosarcomas arising elsewhere and is independent of tumor grade [11] . It carries a moderate risk of local recurrence and high risk of metastasis and death. Metastases are mainly to lungs, bone and liver [7] . Uniformly the prognosis is poor.

Prognosis for primary epithelioid angiosarcomas is very poor. Among the 5 reported definitive cases, 1 was alive with local recurrence, 1 was alive with axillary recurrence, two were dead of metastatic disease while one was alive free of disease at 9 months.

Conclusions/key points :
Primary mammary angiosarcoma is a rare disease that affects relatively younger patients. Angiosarcomas arising in the post radiation therapy setting affect older women with all reported patients greater than 50 years of age. Both lesion types show aggressive clinical behavior similar to angiosarcomas of soft tissue. They carry a moderate risk of local recurrence and a high propensity for metastasis and tumor-related death, irrespective of grade. They have an overall similar clinical course as other types of angiosarcoma arising in skin or soft tissue.

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