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Angiosarcomas are rare vascular tumors that comprise up to 3% of all adult soft tissue sarcomas. The majority of angiosarcomas occur in cutaneous sites, most frequently in the head and neck region. They can be caused by prior radiation, chronic lymphedema, or a history of exposure to vinyl-chloride chemotherapy (Bradford et al., 2010). Although one-fourth of these tumors arise in deep soft tissue, angiosarcoma has only rarely been described in the ovary. The first reported case was in 1931 and, to date, less than 35 cases have been published in the literature (Bösmüller et al., 2011). Angiosarcomas, regardless of anatomic site, demonstrate aggressive clinical behavior, with median survival ranging from 15 to 30 months, and fewer than 12% of patients alive at 5 years (Penel et al., 2007).
In general, patients with ovarian angiosarcoma present with advanced disease and have a very poor prognosis. Among those patients with FIGO stage III and IV disease, the median survival is 6 to 7 months, with an overall range of 1 to 30 months (Bradford et al., 2010). Typically, radical surgical excision is followed by any number of possible chemotherapeutic regimens. For metastatic soft-tissue sarcomas, anthracyclines and ifosfamide have proven to be the most effective chemotherapeutic agents. Additionally, taxanes have demonstrated promising results in angiosarcomas of the head and neck (Penel et al., 2008). We report a patient with stage IIIC ovarian angiosarcoma who had extended survival after primary cytoreductive surgery and adjuvant doxorubicin and ifosfamide chemotherapy.
A previously healthy 40-year-old woman presented to her primary care physician with a several-month history of fatigue and nausea. When her nausea did not respond to medical management, she was referred to a gastroenterologist. Upper endoscopy, colonoscopy, abdominal ultrasound, and HIDA (hepatobiliary iminodiacetic acid) scans were non-diagnostic, but her nausea resolved spontaneously. Three months later, she presented to a local community hospital emergency department with rapidly increasing abdominal girth. CT (computed tomography) scan of the abdomen and pelvis revealed an 11 × 6 cm pelvic mass, copious ascites, and omental nodularity. Serum CA125 was elevated at 1851 U/mL (normal range, < 35 U/mL). Due to the suspicion for ovarian malignancy, she was transferred to our institution for gynecologic oncology consultation.
She was counseled about primary cytoreductive surgery. At exploratory laparotomy, 5 L of chylous ascites was drained, omental caking was noted, and a 15 cm right adnexal mass was seen with confluent tumor that covered most of the pelvic peritoneum. Intraoperative frozen section of the right ovary and fallopian tube demonstrated a high-grade spindle cell neoplasm. Surgery included abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, ablation of implants, en bloc resection of the rectosigmoid with all surrounding pelvic peritoneum, and low pelvic anastomosis. No gross residual disease was present at the completion of the procedure.
The patient was discharged home on day 7 after an uncomplicated postoperative course. Four weeks after surgery, her CA125 had normalized to 26 U/mL. Final pathology demonstrated an ovarian angiosarcoma and chemotherapy was initiated. Doxorubicin (25 mg/m2) and ifosfamide (2.5 g/m2) were administered on days 1–3 of a three-week treatment cycle. Due to the risk of myelosuppression, pegfilgrastim (6 mg) was routinely given on day 4. She completed six courses of therapy with a single episode of neutropenic fever. A repeat CT scan of the chest, abdomen and pelvis showed no evidence of disease and her CA125 was 18 U/mL, thus she was presumed to be in clinical remission.
At a surveillance visit three months after completion of chemotherapy, her CA125 was still within normal range (16 U/mL). Two months later, she noted worsening abdominal discomfort that prompted a CT scan of the abdomen and pelvis. She was noted to have re-accumulation of ascites, peri-umbilical nodularity, and a 9 cm pelvic mass, concerning for recurrent disease. Her CA125 had increased to 54 U/mL. Weekly paclitaxel at 80 mg/m2 was initiated and a partial response was observed. She currently has progressive disease, but retains a good quality of life on palliative chemotherapy, 18 months after initial surgery.
On gross examination, the right ovary measured 15 × 11 × 2 cm and weighed 400 g. The surface was predominantly smooth, tan to purple, with foci of fresh hemorrhage. The tumor had a soft, nodular, bosselated cut surface [Fig. 1, A]. On microscopic examination, anastomosing vascular spaces with slit-like lumina were interspersed with solid fascicular areas [Fig. 1, B–C]. Higher magnification demonstrated pleomorphic, epithelioid to focally spindled cells, some displaying intracytoplasmic lumina [Fig. 1, D–E]. Brisk mitotic activity (> 10 mitoses/10 high power fields), necrosis, and hemorrhage were present. Immunohistochemical studies showed strong positivity for CD31 and CD34 (vascular markers) [Fig. 1, F], while keratin, EMA and WT-1 were negative. The morphologic and immunohistochemical findings supported a diagnosis of spindle and epithelioid angiosarcoma, grade 3 of 3, primary of the right ovary with secondary involvement of uterine and appendiceal serosa, muscularis propria of the rectosigmoid colon, and omentum (FIGO stage IIIC).
Ovarian angiosarcoma is an extremely rare tumor, with less than 35 cases reported in the literature (Bösmüller et al., 2011). Similar to the more common epithelial ovarian cancers, angiosarcomas are associated with non-specific symptoms and often present with advanced stage. Ovarian angiosarcoma occurs in all age groups, with reported cases including patients ranging in age from 7 to 81 years old, with a mean age of 37 (Bösmüller et al., 2011).
Angiosarcomas are malignant and infiltrative vascular tumors. They can be pure or part of mixed malignant müllerian tumors, adenosarcomas, teratomas, or surface epithelial tumors. Histologically, they range from well- to poorly-differentiated. Well-differentiated angiosarcomas demonstrate more organization as they are often comprised of well-formed vascular spaces. In contrast, poorly-differentiated angiosarcomas, as found in our patient, may be a diagnostic challenge as organizational architecture devolves and cellular atypia rises. The differential diagnosis includes poorly-differentiated carcinoma, other more common sarcomas such as leiomyosarcoma, adenosarcoma with sarcomatous overgrowth, carcinosarcoma, or even malignant melanoma, yolk sac tumor, and choriocarcinoma. Metastatic lesions, including metastatic angiosarcoma, must be ruled out (Bösmüller et al., 2011; Young et al., 2010). Immunohistochemical analysis may be helpful to establish a diagnosis of angiosarcoma. Immunohistochemical studies commonly used to include vascular markers, more commonly CD34 and CD31 (Young et al., 2010).
Once accurately diagnosed, management of ovarian angiosarcoma is largely by extrapolation, as this is a very unusual tumor in the ovary. Unlike previous reports (Bradford et al., 2010), our patient had a complete response to therapy with extended survival, which presumably, was due to a combination of her initial radical debulking surgery and the aggressive adjuvant chemotherapy regimen. Doxorubicin is an anthracycline that is commonly used for soft tissue sarcomas, including angiosarcomas, yielding objective response rates of 20 to 30% in advanced disease (Eriksson, 2010). The mustard alkylating agent, ifosfamide, is the only other agent with comparable response rates (Eriksson, 2010; Penel et al., 2011). Numerous trials in the soft-tissue sarcoma population have investigated doxorubicin and ifosfamide combination therapy. The dual regimen appears to demonstrate a synergistic effect with tumor response rates of up to 50%, but with greater toxicity (Penel et al., 2007; Eriksson, 2010; Quesenberry et al., 2005). Using pegfilgrastim to lessen bone marrow suppression, our patient tolerated the regimen very well.
Taxanes are generally considered non-effective in the treatment of soft-tissue sarcomas, with the exception of angiosarcoma. Specifically, paclitaxel has been shown to be active against the vascular-derived Kaposi's sarcoma and, more recently, cutaneous angiosarcoma of the head and neck (Penel et al., 2007, 2008, 2011; Eriksson, 2010). Weekly low-dose administration increases the anti-angiogenic effect and dose intensity, without significantly increasing the toxicity profile. The anti-angiogenic activity is particularly potent in angiosarcomas, which have been shown to overexpress pro-angiogenic factors, including VEGF, flt-1, flk1, and ets-1 (Penel et al., 2007; Young et al., 2010). Sorafenib, imatinib, bevacizumab or other novel anti-angiogenic biologic molecules are currently under investigation and have also shown some response against angiosarcomas (Penel et al., 2011). These small molecules may play a future therapeutic role in targeting the signaling pathways associated with excess vascular proliferation and tumor growth.
In summary, aggressive cytoreduction to no gross residual use paired with the novel use of paclitaxel has resulted in a sustained partial response for our patient.
The authors declare that there are no conflicts of interest.