A rare case of rapidly progressing angiosarcoma of the breast with multiple metastases to the bone, liver, ovary, and gingiva

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1 Int Canc Conf J (2012) 1: DOI /s CASE REPORT A rare case of rapidly progressing angiosarcoma of the breast with multiple metastases to the bone, liver, ovary, and gingiva Michiyo Saimura Shoshu Mitsuyama Keisei Anan Kenichiro Koga Minoru Ono Satoshi Toyoshima Received: 11 December 2011 / Accepted: 15 March 2012 / Published online: 21 April 2012 Ó The Japan Society of Clinical Oncology 2012 Abstract We herein report a rare case of primary angiosarcoma of the breast. A 31-year-old pregnant woman noted a progressing mass in her left breast, and it was suspected to be a phyllodes tumor on the basis of images acquired after the delivery. The histological diagnosis by excisional biopsy was well-differentiated angiosarcoma, so she was referred to our hospital for further treatment. CT and MRI suggested that there was a residual lesion in the remnant breast and multiple bone metastases. She underwent a simple mastectomy, and chemotherapy was performed postoperatively. Four months after surgery, liver, ovary, and mandibular gingival metastases became apparent, although these metastatic lesions had not been distinguished at first. They rapidly progressed, and the regimen of chemotherapy was changed from weekly paclitaxel, MAID (mesna/ifosfamide/doxorubicin/dacarbazine) combination therapy, to docetaxel. Radiation therapy to the gingival tumor was relatively effective. However, the liver and ovary metastases continued to progress under chemotherapy and caused a fatal hemorrhage. Early diagnosis is very important in this highly aggressive disease, and a M. Saimura (&) S. Mitsuyama K. Anan K. Koga Department of Surgery, Kitakyushu Municipal Medical Center, Bashaku, Kokurakita, Kitakyushu, msaimura@med.kyushu-u.ac.jp M. Ono Department of Radiology, Kitakyushu Municipal Medical Center, Bashaku, Kokurakita, Kitakyushu, S. Toyoshima Department of Pathology, Kitakyushu Municipal Medical Center, Bashaku, Kokurakita, Kitakyushu, novel strategy for treatment is needed to prolong the survival and maintain the quality of life of such patients. Keywords Angiosarcoma Ovarian metastasis Gingival metastasis Weekly paclitaxel MAID Radiation therapy Introduction Primary angiosarcoma of the breast is a rare and highly aggressive tumor. It comprises 0.04 % of all the breast tumors and approximately 8 % of breast sarcomas [1]. It occasionally arises in young women, and can even develop during pregnancy. As a result of its rarity and typically unclear clinical findings on examination, the diagnosis of angiosarcoma can be difficult, particularly during lactation or pregnancy. These tumors have a high propensity for distant metastasis, and the overall prognosis is poor, with reported 5-year survival rates of approximately 10 % [2]. We herein present the case of a 31-year-old woman with primary angiosarcoma of the breast who was diagnosed just after delivering her baby; the disease progressed rapidly to distant metastases. Case report A 31-year-old woman noticed an enlarging mass in her left breast during pregnancy. She visited her primary physician with progressive pain and swelling of the left breast 1 month after delivering her baby. A physical examination revealed an elastic soft mass of 15 cm in diameter in her left breast. Ultrasonography revealed a huge lobulated mass with an irregular hypoechoic pattern, and mammography showed a high density mass occupying the whole left

2 160 Int Canc Conf J (2012) 1: breast. CT revealed a heterogeneously enhanced mass in the left breast. MRI showed a multilobulated mass in the left breast, high intensity in the center for T1-weighted images and a nearly heterogeneous high intensity for T2-weighted images (Fig. 1a, b). Dynamic contrast-enhanced MRI revealed an irregular enhancing mass with a rapid plateau pattern (Fig. 1c, d). PET scans showed a large hypermetabolic lesion in the left breast with no metastases. A phyllodes tumor was suspected, and because both aspiration cytology and a core needle biopsy failed to provide sufficient information to make a diagnosis, the patient underwent an excisional biopsy. Macroscopically, the tumor measured cm in the greatest dimensions, and was encapsulated and dark red with blood and hematoma (Fig. 2). The histological findings were irregular vascular channels lined with atypical endotheliallike cells with frequent mitotic figures (Fig. 3). The results of the immunohistochemical analysis revealed that the tumor cells were highly positive for CD34 and CD31, and negative for AE1/AE3 and asma. The tumor was diagnosed histopathologically as angiosarcoma. MIB-1 index was 80 %. ER and PgR were negative. The patient stopped breast feeding after the diagnosis. She came to our hospital for treatment 2 months after the initial examination. CT and MRI after the excisional biopsy revealed small enhanced nodules in the remnant breast, which were suspected to be residual lesions. In addition, bone MRI revealed multiple metastases on the spine, sternum, and clavicle. She underwent a simple mastectomy, and the histological finding was no residual tumor in the left breast. Weekly paclitaxel (80 mg/m 2 ) was administered postoperatively for the bone metastases. Two months after surgery, MRI demonstrated the right ovary to be swollen to a size of 3 cm in diameter, and the patient was suspected to have endometriosis. Four months after surgery, CT revealed the presence of an enhanced mass 4 cm in diameter behind the uterus, which suggested ovarian metastasis (Fig. 4a). At the same time, liver metastases became apparent, which were also difficult to distinguish from hemangioma at first. In addition, a dark red nodule that was 5 mm in diameter appeared in the mandibular gingiva and was suspected to be metastasis (Fig. 5a). The regimen of chemotherapy was changed to MAID therapy [mesna (1200 mg/m 2 )/ifosfamide (2500 mg/m 2 )/doxorubicin (20 mg/m 2 )/dacarbazine (300 mg/m 2 ), days 1 3 every 4 weeks]. However, by 6 months after surgery, all metastatic lesions had rapidly increased in size. The gingival tumor had grown to 7 cm in diameter and was symptomatic, including pain, bleeding, and difficulty chewing Fig. 1 MRI showed a multilobulated mass in the left breast. a High intensity in the center for T1-weighted images. b A nearly heterogeneous high intensity for T2-weighted images. c, d Dynamic contrast-enhanced MRI showed an irregular enhancing mass with a rapid plateau pattern

3 Int Canc Conf J (2012) 1: Fig. 2 Macroscopically, the tumor measured cm in the greatest dimensions, and was encapsulated and dark red with blood and hematoma Fig. 3 Histological findings were irregular vascular channels lined with atypical endothelial-like cells with mitotic figures Fig. 4 a Enhanced CT revealed the presence of an enhanced mass 4 cm in diameter behind the uterus, suggesting ovarian metastasis 4 months after surgery. b The tumor had grown to 14 cm in diameter 7 months after surgery (non-enhanced CT)

4 162 Int Canc Conf J (2012) 1: Fig. 5 a A dark red nodule that was 5 mm in diameter appeared in the mandibular gingiva 4 months after surgery. b The gingival tumor had grown to 7 cm in diameter 6 months after surgery (Fig. 5b). The chemotherapy regimen was changed to docetaxel (70 mg/m 2, every 3 weeks), and external photon beam radiotherapy was delivered at a total dose of 30 Gy (30 Gy/10 fractions) for 2 weeks to treat the gingival metastasis. Although the gingival tumor shrunk following the radiation, the liver and ovary metastases continued to progress (Fig. 4b). About 8 months after the referral, the patient died of disseminated intravascular coagulation caused by bleeding from the metastatic tumors of the liver and ovary. Discussion Primary angiosarcoma of the breast is a rare malignancy with a poor long-term prognosis. It seems to have an overall clinical course similar to other types of angiosarcoma arising in the skin or soft tissue; it carries a moderate risk of local recurrence, and a high risk of distant metastasis and death. We herein described a case of primary angiosarcoma of the breast which rapidly progressed to metastases after the excisional biopsy. Although the subsequent mastectomy made it possible to achieve good local control, the distant metastases were not responsive to chemotherapy. Because of its rarity and the limited characteristic findings on imaging examinations, angiosarcoma of the breast is difficult to diagnose in the early stage. In most of the cases reported in the literature, the tumor size was greater than 4 cm in diameter. The few patients with tumors less than 4 cm at diagnosis had a better survival rate [1]. Another report indicated that the gross tumor size did not correlate with patient survival [3]. Our patient succumbed to extensive metastases to the bone, liver, ovary, and gingiva 8 months after referral. The tumor size at excisional biopsy had reached 15 cm in diameter. A diagnosis of angiosarcoma may be suggested in a specimen obtained by fine needle aspiration which contains malignant spindle cells and papillary clusters, but it is sometimes difficult to make a correct diagnosis even with a core needle biopsy. An incisional biopsy can provide sufficient material for the diagnosis of mammary angiosarcoma, but unless it contains a high-grade lesion, the findings may be misleading with respect to grade. In our case, the excisional biopsy resulted in a correct diagnosis of angiosarcoma. The optimal treatment of angiosarcoma is an early and complete surgical excision, with special care taken to obtain tumor-free surgical margins, because the neoplasm often extends microscopically beyond its gross limits. Axillary lymph node metastases are exceedingly uncommon at the time of primary therapy, and therefore routine axillary dissection is not indicated. According to a review of 47 patients reported between 1932 and 2007 in Japan [4], a mastectomy was performed for 42 patients (89 %). Although axillary lymph node dissection was performed for 27 patients (57 %), no axillary lymph node metastasis was reported. In general, adjuvant chemotherapy may be offered to patients with angiosarcoma of the breast, but its effectiveness remains controversial, and there are still no clearly established chemotherapeutic regimens. There are also no standard chemotherapeutic regimens for metastatic angiosarcoma. National Cancer Comprehensive Network guidelines recommend single agents and regimens with activity in angiosarcoma including paclitaxel, docetaxel, and MAID therapy with evidence-leveled category 2A. Sher et al. [5] reported that the overall response rate for metastatic angiosarcoma to cytotoxic chemotherapy was 48 %. Adriamycin-based regimens, which remain the treatment of choice for metastatic soft tissue sarcomas, typically resulted in response rates of %, with an overall survival time of 12 months [6, 7]. Some previous retrospective studies suggested that paclitaxel was effective in patients with angiosarcomas, especially those with face and scalp angiosarcomas. In addition, phase II trials have shown striking results, even complete responses, following treatment with paclitaxel [8, 9]. In our case, weekly

5 Int Canc Conf J (2012) 1: paclitaxel was administered first to examine the potential activity of the single drug, and combination therapy followed. The metastatic disease in our case was refractory to several systemic chemotherapeutic regimens, and the patient finally succumbed to the disseminated disease. Angiosarcoma of the breast is a rare disease that affects relatively younger patients. Coexistent pregnancy was present in 4 of 63 (6 %) cases in one series [10]. Some mammary angiosarcomas have low or negligible levels of hormone receptors [11]. The high rate of having the onset of the lesions during pregnancy and the coincidence of the peak age incidence of the patients with the peak age of reproduction suggest that the tumor may be hormone dependent [2]. However, there is no evidence that these tumors are hormone dependent. Hormone receptors were negative in the tumor investigated in our case. Rosen et al. [10] reported that there was a statistically significant correlation between the grade of angiosarcoma and prognosis in a series of 63 patients. The tumor grade was categorized as high, intermediate, or low, and 25 of the patients (40 %) had low-grade lesions, 12 had intermediate grade tumors (19 %), and 26 had high-grade angiosarcomas (41 %). Estimated probabilities of disease-free survival 5 years after initial treatment were as follows: low-grade 76 %, intermediate grade 70 %, and high grade 15 % [10]. The median length of disease-free survival was also correlated with the tumor grade (low, greater than 15 years; intermediate, greater than 12 years, high 15 months) [10]. The most commonly used systems for adult soft tissue sarcomas are the French grading and the National Cancer Institute grading [12]. Both are 3-grade systems that are mainly based on histologic type and subtype, tumor necrosis, and mitotic activity. The tumor in the current case showed well-differentiated angiosarcoma with high mitotic activity and at most 50 % tumor necrosis, and therefore the histological grade was high. Tumor dissemination occurs early via the bloodstream. The most common sites of metastases are the bone, lung, liver, contralateral breast, skin, brain, and ovary [2]. Three unusual instances of clinically significant metastasis in the gingiva have been reported [13]. The recognition and management of local manifestations are important for maintaining the patient s quality of life. In our case, palliative radiotherapy was performed because of increasing pain and bleeding from the gingival lesion, and it was relatively effective for controlling these symptoms. Although a resection may be the treatment of choice for metastatic tumors when the primary lesion is under control, surgery for the metastatic lesions was impossible in our case because the disease was disseminated and had progressed in multiple organs. In our case, the tumor was clinically highly aggressive. The patient developed multiple metastases soon after the excisional biopsy, and died of progressive disease which was extremely chemoresistant. It is very important to become familiar with the clinical and histological features of this entity to avoid both a misdiagnosis and a delay of definitive treatment, and a novel strategy for treatment is urgently required to prolong the survival and maintain the quality of life of such patients. Acknowledgments We thank Dr. Tadatoshi Shigeta, from the Department of Surgery, Saiseikai Shimonoseki General Hospital, for his valuable clinical support in both the diagnosis and treatment. Conflict of interest References No author has any conflict of interest. 1. Donnel RM, Rosen PP, Lieberman PH et al (1981) Angiosarcoma and other vascular tumors of the breast. Am J Surg Pathol 7: Chen KTK, Kirkegaard DD, Bocian JJ (1980) Angiosarcoma of the breast. 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