Clinical Features and Prognosis of Angiosarcomas of the Vulva and Vagina
Review of the literature revealed 2 cases of primary angiosarcomas of the vulva, and in addition to the case described in the introduction paragraph, there are 2 additional cases of angiosarcoma of the vagina.3–6 Most patients presented with a painless mass. The treatment was local excision and/or irradiation (Table 1). Follow-up information was available for the 3 patients. One patient had no evidence of distant or recurrent disease after 3 years; the other 2 patients died after 2 years and 4 months, respectively.
Clinical Features and Prognosis of Angiosarcomas of the Uterus
The most common symptoms of angiosarcomas of the uterus are abnormal vaginal bleeding and enlarged uterus presenting as pelvic mass. The mean age of the 18 patients with primary angiosarcoma of the uterus was 60 years (range, 17–81 years).7–20 All patients were initially treated by total abdominal hysterectomy with bilateral salpingo-oophorectomy. Follow-up information was available for 17 patients. Ten patients died of disease with a median survival of 12.2 months (range, 2–84 months); 6 patients had no evidence of disease, and 1 patient had recurrent disease. Survival did not statistically differ significantly among the different treatment modalities (P = 0.68, based on log-rank test). Mean age did not statistically differ significantly between the patients with no evidence of disease versus those who died of their disease (63 ± 7 vs 60 ± 18 years).
Clinical Features and Prognosis of Angiosarcomas of the Ovary
The most common clinical manifestations of angiosarcoma of the ovary are nonspecific gastrointestinal symptoms, of which abdominal pain and/or abdominal distention are most frequent. Review of the literature revealed 29 patients with primary angiosarcoma of the ovary, aged 19 to 77 years (mean age, 37 years; Table 1).16,21–30,31–39 Nine patients had no evidence of disease with a follow-up period that ranges from 2 months to 9 years. Sixteen patients died of disease with a median survival of 10.2 months (range, 18 days to 30 months). Mean age did not statistically differ significantly between the patients with no evidence of disease versus those who died of their disease (32.3 vs 36.6 years). Stages were known for 16 patients, including 5 patients with stage I and 11 patients with stage III or higher. Follow-up information was available for 3 patients with stage I disease. These patients had no evidence of disease with a follow-up period from 10 months to 9 years. Among 11 patients with stage III or higher, 9 died of their disease between 2 and 30 months of diagnosis. Two patients had no evidence of disease. However, follow-up period was short (2–12 months). Information on treatment was found in 22 patients. Overall, complete surgical resection was performed in 19 patients, a suboptimal debulking in 1 patient, a lung biopsy in 1 patient that showed a metastasis of an irresectable angiosarcoma of the ovary, and 1 patient had chemotherapy combined with radiotherapy as the primary treatment. Ten patients received adjuvant chemotherapy; 4 patients had no evidence of disease with a follow-up period of 2 to 12 months. The other patients died of their disease within 7 to 29 months. Follow-up of the patients without adjuvant chemotherapy showed no evidence of disease in 3 patients (2 months to 6 years). Furthermore, 7 patients died of their disease within 0.5 to 24 months. Interestingly, only 1 of the 22 patients with information about the treatment had a stage I disease. This patient received adjuvant chemotherapy.
Macroscopic and Microscopic Features of Angiosarcomas
Most angiosarcomas form a large, friable, hemorrhagic mass ranging from 2 to 29 cm in maximum dimension. The tumors have a hemorrhagic deep red to brown cut surface, often showing extensive necrosis and cystic degeneration. In the vulva and vagina, the tumor is predominantly solid with poorly defined margins and ulceration.6 Uterine angiosarcoma often grows diffusely and deeply into the myometrium. Occasionally, the tumor mimics a leiomyoma with hemorrhage, and other angiosarcomas are reported in association with leiomyomas. A single uterine angiosarcoma has been described as polypoid.11 In the ovary, angiosarcoma is usually unilateral, often invading the surrounding structures.31–33 Typically, they replace the entire ovary. Some ovarian tumors arose in the wall of a mature cystic teratoma,23,25 whereas rarely they have been described in association with mucinous cystadenoma.31
The histologic appearance varies from tumor to tumor, independent of its localization. Most angiosarcomas have a lobulated architecture with solid sheets, cystic spaces, hemorrhage, and necrosis. Closely packed, interanastomosing vascular channels alternate with a reticular, fascicular, or solid growth. A fine papillary pattern has been described in several uterine and ovarian angiosarcomas. The vascular spaces are irregular, slit-like to dilated, and are lined by highly atypical endothelial cells with large pleomorphic and hyperchromatic nuclei (Fig. 1). Some variants have a spindled or epithelioid morphology, making them hard to recognize as a vascular tumor. Binucleated and multinucleated giant cells may be present. Mitotic figures are usually numerous. Prominent stromal hyalinization may be seen. Immunohistochemically, the tumor cells stain for CD31, CD34, and/or factor VIII.8 Immunoreactivity for cytokeratins may be strong but only focal, more often in the epithelioid variant. Results for the immunohistochemical staining of S100, HMB45, CD99, desmin, h-caldesmon, EMA, and ER and PR are negative.
High-grade sarcomas, malignant mixed müllerian tumors (including low-grade müllerian adenosarcoma when it exhibits sarcomatous overgrowth), and poorly differentiated or sarcomatoid carcinomas enter the differential diagnosis because of the broad histologic spectrum of angiosarcomas.8 ,31 Primary angiosarcomas of the FGT should also be distinguished from metastatic angiosarcoma and less frequently benign vascular lesions.33 Vulvar and vaginal epithelioid angiosarcoma can easily mimic malignant melanoma.6 In the uterus and ovary, a spindled or epithelioid leiomyosarcoma should be considered in the differential diagnosis. In the ovary, other mimics include yolk sac tumor, clear cell carcinoma, and choriocarcinoma.31
Unfortunately, there is lack of consensus on optimal treatment and prognostic factors for angiosarcomas of the FGT. We described a case of a primary angiosarcoma of the vagina (2 previous case reports exist) and performed a review of all published studies of primary angiosarcomas of the FGT to better delineate (1) the risk factors for poor outcome and (2) the best approach for management. This review supports the use of primary surgery and adjuvant radiotherapy for localized angiosarcomas of the vulva, vagina, and uterus. Furthermore, it was shown that adjuvant chemotherapy for patients with ovarian angiosarcomas showed improved survival (Fig. 2).
The rarity and histopathologic diversity may contribute to the lack of consensus on the risk factors for poor outcome. In general, angiosarcomas have an overall 5-year survival of about 35%.1 ,40 This was in line with the 5-year overall survival rate for angiosarcomas of the FGT, as found in the current review (Fig. 3). Unfortunately, no evidence-based treatment recommendations are available for specific angiosarcoma subtypes. Radical surgery with complete resection is the primary treatment of choice. Wide resections are required because of the invasive and multifocal nature of angiosarcomas. Adjuvant radiotherapy with large doses (>50 Gy) and wide treatment fields is recommended.1 ,41,42 No formal radiotherapy trials have been done, but retrospective series suggest that it improves local control and overall survival.41,43 The findings of this review are in line with these recommendations; the median survival of patients with tumors of the vulva, vagina, and uterus with adjuvant radiotherapy after surgical resection (n = 9) was more than 4 years (SE, 14 months), whereas the median survival in patients without radiotherapy (n = 10) was about 1 year (SE, 5 months) (P = 0.23, log-rank test).
There is no convincing evidence that supports the use of chemotherapy in the neoadjuvant or adjuvant setting after definitive surgery and radiotherapy for angiosarcoma with local disease.44–46 The estimated 5-year survival rate of the patients with adjuvant chemotherapy (n = 15) in this review was 27% (SE, 20%), and 7 patients had no evidence of disease after a follow-up period up to 1 year (censored observations), whereas 11 of 14 patients without adjuvant treatment had died within the first year of follow-up. Unfortunately, numbers for patients with localized disease versus metastatic disease could not be summarized, because information about the stage was not available for most patients. It has been suggested that cytotoxic chemotherapy is the primary treatment option for metastatic angiosarcoma, although its evidence is limited.1 Indeed, in the current review, adjuvant chemotherapy for patients with stage III or IV ovarian angiosarcomas showed improved survival. However, numbers are limited, and results have to be interpreted in this light. Table 1 shows that ovarian angiosarcomas are treated with various different approaches and regimens. Therefore, comparing efficacy of the different chemotherapeutic approaches and regimens is difficult. In general, the main drug groups used for metastatic angiosarcomas are anthracyclines, ifosfamide, and taxanes.47 Doxorubicin and ifosfamide show response rates of 16% to 36% as single drugs in soft tissue sarcomas.48 Combination chemotherapy is not associated with better outcomes.48 In patients with advanced angiosarcoma receiving chemotherapy with various regimens, but mostly doxorubicin based, 64% had a partial response.45 Response rates of taxanes are between 17% and 63%.1 Retrospective comparisons suggest similar response and survival rates with anthracycline and taxane chemotherapy.40
There are some important limitations to note. Although the results of the current review suggest that large tumors (>5 cm) and old age at presentation might predict poor outcome, the statistical power to detect differences in survival among subgroups is low with the number of cases reported and so is the precision of point estimates. Therefore, pooled tests and stratified analysis of survival were not considered because it does not follow a sound clinical basis having different primary sites. Furthermore, numbers were small, with a substantial risk of being a surrogate for stage that is missing in many cases. Thus, there seems to be a tendency that size of more than 5 cm carries poorer prognosis, which cannot be objectively verified because of the aforementioned reasons. Negative results of this review should be interpreted with caution.
We describe a patient with a primary angiosarcoma of the vagina that was treated initially by local resection and adjuvant radiotherapy. This review supports the use of surgical and adjuvant radiotherapy for angiosarcomas of the vulva, vagina, and uterus, whereas the most optimal management of angiosarcomas of the ovary seems to consist of debulking surgery with adjuvant anthracycline-, ifosfamide-, or taxane-based chemotherapy. Unfortunately, the number of patients is too small to be able to make conclusions for the different stages.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Angiosarcomas; Female genital tract; Treatment; Review; Prognostic factors