Teaching Case

A 47-year-old female presented with a breast angiosarcoma. In the past year, the patient had been treated with a 28-day cycle of estradiol and estradiol plus norethisterone. The patient had also undergone clinical and mammographic check ups once a year. At the last clinical check up, a soft breast tumor was found in the lower inner quadrant of the patient's left breast.

Mammographs and focused echographs of the patient did not highlight any focal lesions at the site of the clinical mass. According to the clinical findings and despite no focal lesions having been detected on mammography and echography, the patient was sent for a 6-month check up, and she returned after 8 months. At this time, the clinical examination revealed that the left breast tumor was still soft but had increased in size and had a slightly hyperchromatic overlying skin. The mammography investigation done in the same quadrant showed the presence of a tumor mass with a mixed density and ill-defined contours having a maximum size of 4 cm. Ultrasonography tests when done revealed that the patient had a tumor mass with well-defined contours, both hypoechogenic and anechogenic areas and a hypervascular color-doppler pattern suggestive of a vascular tumor. The patient underwent an ultrasonography-guided fine needle aspiration biopsy (FNAB) with a 21 gauge needle, which gave no significant results as it was of composed of only blood. According to these findings, a surgical biopsy of the tumor mass was performed in the lower inner quadrant. The histological examination performed during the surgical procedure (anatomical piece sized 6x4 cm, including two soft blue areas with ill-defined contours sized 2.3 x 1.5 cm and 0.5 x 0.5 cm, respectively) revealed the presence of a sarcoma-like tumor mass. Based on this finding, the surgeon performed a left Madden mastectomy followed by a left axillary lymphadenectomy. The following histological examination revealed the presence of a grade II angiosarcoma with disease-free edges. All the lymphnodes were found to be disease-free. Microscopy test evidenced variously anastomized vascular channels and gaps with blood inside, with an atypical endothelium composed of polygonal and/or stretched cells with big, hyperchromic nuclei. Immunohistochemical analyses revealed the presence of markers on the surface of endothelial cells for CD 34, CD 31 and antifactor VIII, while there was a negative response for the following markers: epithelial cell-wall antigen (EMA), Pankeratin 56 kD, anti-melanoma HMB45 and Actin-L. Of the tumor cells 25--30% showed the growth marker Ki-67 (MIB-1), suggesting a high mytotic index for the angiosarcoma. Before chemotherapy, a staging procedure was performed based on a CT study of the chest and an ultrasonographic evaluation of the abdomen, which were found to be negative for metastases. The patient underwent five cycles of chemotherapy following the schema 4EPI-IFO/CNR (4 Epirubicina 60 mg/m², days 1 and 2; Ifosfamide 3000 mg/ m², Mesna equidose days 1--3). The 6-month follow-up consisted of breast ultrasonography and Magnetic Resonance (MR) for the study of wall-chest recurrence; abdomen ultrasonography, chest radiography and right breast mammography. Up to now, these examinations have shown that the patient is free from local recurrence and systemic disease.

A primary breast angiosarcoma is believed to be a rare connectival tumor which is more frequently found in patients in their third-fourth decades of life, whereas breast carcinomas are thought to arise later. In the study conducted by Rosen and coworkers, 6% of the patients showed a correlation between pregnancy and breast angiosarcomas, suggesting the hormone-dependent nature of the tumor. This evidence was weak because the low receptor density was not enough to give a hormone-dependent signal to tumor cell growth. The onset of breast angiosarcomas during hormone therapy seems to suggest a relation between the tumor and endocrine stimulation; though in some cases estrogen receptors on the tumor cells were found, the evidence in the literature is still weak. Histological differential diagnoses for angiosarcomas are the following: stretched cell sarcoma (fibrosaroma, malignant fibrous histiocytoma), fusocellular melanoma, carcinoma with a sarcoma-like component, when tumor endothelial cells show a sarcoma-like architecture, as in the case described. Merino and coworkers have supported the role of antifactor VIII antigen, produced by endothelial cells, in differentiating vascular tumors from other tumors. Histological grading on three degrees (good, medium and poor differentiation) depends on the differentiation of the vascular structures and on the number of sarcoma-like, undifferentiated areas. From a clinical viewpoint, a primary breast angiosarcoma is a soft or elastic tumor, painless, unfixed on deep chest muscles which depends on the tumor size and staging, appears sometimes with an overlying pigmented skin (violet), suggesting its vascular nature. On the other hand, some authors (Masathoshi et al. 20) have reported cases of breast angiosarcomas of a big size, that are tough, strongly adherent to deep muscles, are painless, with overlying pigmented skin. In the case described, according to the literature, the tumor was painless and with an overlying pigmented skin. Mammography findings showed a tumor mass with ill-defined contours and a mixed density, without having the typical features of a breast carcinoma (i.e. micro-calcifications, distortion and ill-defined contours). Focused ultrasonography using a 7.5 MHz linear probe, showed a tumor mass with a mixed hypo-anechogenic structure; the color-Power-Doppler study revealed a high signal intensity from the gap-anechogenic areas, supporting the vascular nature of the gaps and discriminating them from cysts. When considering the multicentricity of the tumor and the difficulty in defining its contours, the elective surgical approach to angiosarcomas is radical mastectomy. According to the literature, homolateral axillary lymphadenectomy is not required; however, it is often performed as in the case reported. The role of chemotherapy is still under investigation. Clinical evidence supports the role of chemotherapy in grade III angiosarcomas to increase chances of survival whereas in grades I and II, benefit/toxicity assessment is required. In conclusion, it can be said that a breast angiosarcoma is a rare tumor with a difficult histological diagnosis, and is similar to other anatomo-clinical entities, such as hemangiomas, phylloid cystosarcomas, carcinoma metastases, myoepitheliomas and other sarcoma-like tumors. The angiosarcoma is painless, which is the main and more common clinical evidence; the other features such as the overlying skin pigmentation; are not constant; moreover, the tumor may be either soft or even tough. The diagnosis is based on clinical data, history, bilateral mammography (independent of the patients’ age), ultrasonography and color-doppler, and is concluded by performing a biopsy.