Annals of Oncology Advance Access originally published online on October 31, 2007
Annals of Oncology 2007 18(12):2030-2036; doi:10.1093/annonc/mdm381
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© 2007 European Society for Medical Oncology
sarcomas |
Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases
1 Hospices Civils de Lyon, Université Lyon1, Hôpital Edouard. Herriot, Oncologie Médicale, Pavillon E, Lyon
2 Unité Institut National de la Santé et de la Recherche Médicale 590, Université Lyon 1, Centre Léon Bérard, Lyon
3 Santé Publique, Centre Léon Bérard, Lyon
4 Oncologic Médicale Institut Curie, Paris
5 Oncologic Médicale Service de Chirurgie Institut Gustave Roussy, Villejuif
6 Service de Chirurgie
7 Service d'anatomo-pathologie, Institut Curie, Paris
8 Service d'Anatomo-Pathologie, Institut Bergonié, Bordeaux, France
* Correspondence to: Dr J. Fayette, Hospices Civils de Lyon, Université Lyon1, Hôpital E. Herriot, Oncologie Médicale, Pavillon E, 5 place d'Arsonval, 69003 Lyon, France. Tel: +33-472-117398; Fax: +33-472-117328; E-mail: jfayette{at}9online.fr
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Abstract |
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Background: Angiosarcomas are rare, heterogeneous and a retrospective study was conducted to describe their natural history.
Patients and methods: We reviewed 161 files of angiosarcoma treated in three institutions of the French Sarcoma Group from 1980 to 2004. Survival and prognostic factors for survival were analyzed.
Results: Median age was 52 years. Primary sites were the breast (35%), skin (20%) and soft tissues (13%). At initial diagnosis, 31 (19%) had metastases. Surgery was the first treatment in 121 (75%) patients combined with chemotherapy or radiotherapy in 34 and 32, respectively. Ninety (74%) of these 121 patients relapsed, mostly locally (50). With an average time since initial diagnosis of 8.1 years, 123 (76%) patients progressed and 76 (47%) died. Median survival was 3.4 years [95% confidence interval (CI) 2.4–5.8], and the 5-year overall survival (OS) rate was 43% (95% CI 33–53). In multivariate analysis, liver primary site [relative risk (RR) = 12.62], performance status (PS) of two or more (RR = 3.83), presence of metastases at diagnosis (RR = 2.50), soft tissue tumor (RR = 0.31) were correlated to OS. PS, liver and soft tissue tumors were identified as independent prognostic factors for progression-free survival.
Conclusions: Angiosarcomas have an overall poor outcome, but with a clearly distinct prognosis depending on the primary site.
Key words: angiosarcoma, retrospective study, sarcoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Angiosarcomas are rare sarcoma subtypes in which malignant cells express the morphological and functional properties of endothelial cells [1]. They represent <1% of all sarcomas [2], with no series exceeding 67 cases in the published literature. The presentation and the clinical behavior of these tumors differ according to their primary site [3–5] or histological subtype.
Angiosarcomas are ubiquitous and seldom arise from the large vessels or the heart. Contrary to soft tissue sarcomas, the most common primary sites include the skin and organs [1]. Because of their rarity, the outcome of angiosarcoma patients has not been clearly described, given the rarity of the disease. Their prognosis is generally considered poor, and their clinical behavior unpredictable [1].
In order to gain more insight into the disease, we elaborated and analyzed a large database of all angiosarcomas observed in three large French cancer centers (Institut Gustave Roussy, Institut Curie in Paris and Centre Léon Bérard in Lyon). We present here the results of this retrospective study.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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retrieval procedure and file selection
The data of 204 patients with angiosarcoma hospitalized or requesting a second opinion from January 1980 to April 2004 in three French cancer centers, Institut Gustave Roussy, Institut Curie in Paris and Centre Léon Bérard in Lyon, were collected retrospectively. Kaposi sarcomas were excluded. The diagnosis of angiosarcoma was based on histological analysis by a member of the pathology working party of the French Sarcoma Group. Tumors were stratified by histological grade according to the scoring system of the Fédération Nationale des Centres de Lutte contre le cancer that includes differentiation, necrosis and proliferation index [weak (0–9 mitosis per 10 fields of magnification x40), medium [10–19] and high (
20)] [6]. Tumors were classified as multifocal when multiple contiguous nodules were histologically detected. Of the 204 indexed patients, seven were excluded because of unconfirmed diagnosis, and 36 excluded because of missing clinical or follow-up data; 161 files were retained for analysis.
statistical analysis
Chi-square and Fisher's exact tests were used for descriptive analyses. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last news; progression-free survival (PFS) was calculated from the date of diagnosis to the date of first local or metastatic progression, or death, or else to the date of last news, using the method of Kaplan–Meier. Survival curves were compared using a log-rank test. Univariate and multivariate analyses using Cox's model were carried out to identify the prognostic factors. The data were analyzed using SAS 8.02 and SPSS 11.0.2 software (SAS Institute Inc., Cary, NC).
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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diagnosis
description of the series and clinical presentation.
Patient and tumor characteristics are described in Table 1. There were 104 women and 57 men with a median age at diagnosis of 52 years (range 0.2–91 years). No peak of incidence according to age was detected. The most frequent primary sites were the breast (n = 57; 35%), skin (n = 32; 20%) and soft tissues (n = 20; 13%). Clinical presentation varied considerably with primary site. Initially, cutaneous angiosarcomas presented as limited bruises, frequently were mistaken for benign tumors. These were localized to the head and neck (11 of 32), the upper limb (10 of 32), the lower limb (5 of 32) and the trunk (5 of 32). Angiosarcomas of the soft tissues presented as soft tissue masses located on the trunk (n = 9/20), the head and neck (n = 6/20) or the limbs (n = 4/20). Splenic (n = 7; 4%) or hepatic sites (n = 7; 4%) were often painful, whereas cardiac angiosarcomas (n = 8; 5%) were generally diagnosed at the time of a compressive pericardial effusion (n = 6/8; 75%). Angiosarcomas of the breast were observed only in women at a median age of 52.4 years (range 17.0–85.8 years).
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stage at diagnosis.
At diagnosis, 128 (79.5%) patients had localized disease, whereas 31 (19%) had metastases. A total of 55 metastases were reported, which is more than usually reported in sarcomas. The most common metastatic sites at initial diagnosis were the lungs (n = 14/55; 25%), bone (n = 12/55; 22%) and liver (n = 9/55; 16%). Of note, none of patients with liver metastases had a primary liver tumor. One hundred and thirty-two of 138 (96%) patients in whom this information was available had a performance status (PS) of zero or one. The most frequent predisposing conditions were radiotherapy (n = 40; 25%) and lymphedema (n = 13; 8%), both frequently associated with previous treatment of breast cancer. Among the 57 patients with breast angiosarcoma, 27 (47%) had had breast cancer (all had been irradiated and three developed lymphedema). The average time interval between the predisposing condition and the diagnosis of angiosarcoma was 17.6 years (range 7.2–36.4 years) for patients with lymphedema and 10.5 years (range 2.3–36.4 years) for patients with radiotherapy.
histological findings.
Thirty-nine (24%) tumors were biopsied before primary treatment. Most tumors were reported to be poorly limited, which frequently caused incomplete initial surgical removal: resection was R0, R1, and R2 in 85, 11 and 14 patients, respectively (Table 2). Actually, 33 patients (20%, but 112 data were missing) had multifocal sites upon histological examination of the primary tumor. Most tumors for which this parameter was documented were pT2 (>5 cm) (36 patients; 22%, but 125 missing data), 34 (21%, 127 missing data) had necrosis and 37 (13%, 124 missing data) had high histological grade according to the World Health Organization classification [6].
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initial treatment and results
Surgical resection was the first treatment in 121 (75%) patients (Table 2). R0 resection was achieved in one or two steps in 85 of 121 (70%) cases. After surgery, 32 of 121 (26%) patients received adjuvant radiation with doses ranging from 50 to 60 Gy. Sixty-one patients received chemotherapy: 16 were treated in the adjuvant setting after complete or R1 resection (n = 16/121; 13%) or in the neo-adjuvant setting (n = 9/121; 8%). Chemotherapy was also given after incomplete removal of the tumor in nine patients who could not be proposed for additional resection (n = 9/121; 8%). In addition, inoperable, locally advanced or metastatic angiosarcomas were given palliative chemotherapy (n = 27/61; 44%). The most common regimens were doxorubicin single agent (n = 23/61; 44%), ifosfamide single agent (n = 3/61; 5%) or a combination of the two drugs (n = 28/61; 46%). Response to chemotherapy in inoperable or R2 resected disease was assessable in only 17 patients of this retrospective study: the best outcome was complete response in three patients (18%), partial response in seven (41%), disease stabilizations in two (12%) and progression in five (29%).
survival analysis and prognostic factors
After a median follow-up from initial diagnosis of 97 months, 85 patients were alive and 123 had progressed. Median survival was 42 months [95% confidence interval (CI) 29–70] (Figure 1A and Table 3): 12 months for metastatic patients, 51 for patients with localized tumors (Figure 1B). At 5 years, OS was 43% (95% CI 33–53). The survival curve reached a plateau with 20% of long-term survivors beyond 10 years (Figure 1B). Interestingly, 20% of patients with initially metastatic disease were long-term survivors.
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The PFS of the series was 16 months (Figure 2A): 19 and 8 months for localized and metastatic tumors, respectively (Figure 2B). Relapses were observed beyond 8 years in a significant proportion of long survivors and PFS beyond this date was not significantly different in patients with metastatic or localized initial disease.
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As expected, in univariate analysis, PFS and OS were significantly worse in metastatic patients as compared with patients with local disease (Table 3). PFS and OS were also significantly impacted by primary site, PS and presence of necrosis in the initial tumor sample. Liver, bone and heart angiosarcomas were associated with particularly poor prognosis.
In multivariate analysis, the same parameters were found independently correlated to OS and PFS: primary site in the liver, presence of metastases and PS were correlated to poor OS, whereas soft tissue primary tumors independently correlated to better survival (Table 4). Of note, PS over zero at initial diagnosis was strongly associated with cardiac primary site; when removing PS from the model, cardiac site was retained as independently predictive of prognosis, thus confirming that the site of the primary tumor and the presence of metastases are the principal parameters influencing OS.
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Regarding PFS, only three independent prognostic factors were identified, i.e. liver or soft tissue sites and PS. Again, when PS was removed from the model, cardiac primary site was confirmed as an independent adverse prognostic factor for PFS. The presence of metastasis at initial diagnosis was not an independent prognostic factor for PFS in this series.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The goal of this retrospective study was to describe the outcome of patients with angiosarcoma. The results reported in 161 patients show that angiosarcomas represent a distinct entity among soft tissue sarcomas, both in terms of primary tumor sites and of clinical behavior, including relapse, sites of metastases, long-term outcome after metastases and prognostic factors.
Primary tumors likely develop in specific organ sites; a high proportion of breast angiosarcomas (35%) was observed in this series, which is more than in previous series in which skin (33%) and soft tissue (24%) primaries tend to represent the majority of tumors [1, 7]. This overrepresentation of breast angiosarcomas may result from the specific breast cancer accrual of one of the three participating centers or from the increasing proportion of patients undergoing primary breast-conserving therapy with lumpectomy and radiation, a treatment strategy associated with a >1000 times higher relative risk (RR) of developing breast angiosarcomas [8]. Indeed, previous lymphedema and radiotherapy, both well-known recognized risk factors for angiosarcoma [9–11], were reported in 8 and 25% of the patients in this series. Of note, the majority of patients with lymphedema included here were irradiated, thus enhancing the correlation between these two predisposing conditions. Indeed, within the 122 991 women treated for a breast cancer from 1958 to 1992 in Sweden and in whom 116 sarcomas, including 40 angiosarcomas, were diagnosed, the incidence of angiosarcoma correlated with lymphedema with a RR of 9.5 (range 3.2–28), but not with irradiation [12].
The present series shows that angiosarcomas are actually a family of tumors with distinct behavior. In marked contrast with other sarcomas [13], PFS and OS are influenced almost exclusively by the primary site of the disease, with liver, heart, bone and splenic angiosarcomas being associated with the worse survival. Conversely, although the median OS of metastatic angiosarcomas is short (1 year), the 5-year survival rate in our series was 23% (3–43), which is significantly better than the usual 5%–8% rate reported for patients with metastatic soft tissues sarcoma [14]. In soft tissues sarcoma, a close to 20% 5-year survival can be achieved after complete surgical resection of metastases; however, in this study metastatic angiosarcomas were found to have unresectable metastases. Another study has reported that among metastatic sarcomas, angiosarcomas classify in the group with the best survival [14]. Due to the limited number of cases, this point deserves further investigations though and this parameter was not identified as an independent parameter [14]. It is noteworthy that PFS was not independently influenced by the presence of a metastasis at initial diagnosis, and that relapses were observed in a significant proportion of long-term survivors beyond 8 years.
The long-term outcome of patients with soft tissue or breast angiosarcomas included in this series was favorable. Such a favorable outcome has not been consistently reported for breast angiosarcomas [15]. Two different reports have associated these tumors with poor prognosis [16–18] with a 2-year OS of only 10%. Of note, the precise nosological definition of breast angiosarcoma remains to be accurately established; in the present series, authentic angiosarcomas of the mammal gland, known to be of poor prognosis, were mixed with cutaneous angiosarcomas, good prognosis tumors developed on the breast after preserving treatment. It was not possible to differentiate between these two entities from the data available. Nevertheless, this point is crucial and deserves additional investigations in a prospective study. There was no significant difference between de novo and post-radiotherapy breast angiosarcomas. This point supports the use of an aggressive approach for the treatment of radiation-induced breast angiosarcomas.
Despite missing data, size and histological grade were found to be prognostic factors for OS in the series. In the literature, tumors <5 cm have a better prognosis [19–21] (i.e. a 5-year survival of 32% versus 13% for larger tumors). Conversely, histological grade has been identified as a poor prognostic factor in most recent studies [16, 20, 22]. Necrosis is part of the histological grade. In our study, necrosis seemed to be a strong adverse prognosis factor with no patient alive at 5 years. Because of missing data though, this factor could not be analyzed in multivariate analysis. Similarly, size could not be included in multivariate analysis. In this series, the sites of relapse were uncommon as compared with other types of sarcomas, with a high frequency of soft tissue, liver and bone metastases, which are rarely observed in other histotypes.
In view of the specific behavior of angiosarcomas that varies with the site of the primary tumor, it remains unclear whether the general rules used for the management of sarcomas should apply to this subtype. The analysis of the impact of treatment options in this series is obviously limited by its retrospective nature. We observed that the optimal treatment of primary localized angiosarcoma was R0 surgical resection which was the major parameter correlated to OS. Radiotherapy has been reported to be associated with improved survival in certain studies [19, 21, 23]. In our study, only 30% of the patients were irradiated, partly because of previous radiotherapy to the chest wall for cancer. The proportion was 37% in non-preirradiated angiosarcomas. No difference in outcome was observed in this series whether using adjuvant radiotherapy or not. Adjuvant chemotherapy remains an experimental option for localized completely resected soft tissue sarcomas [24, 25]. In the present series, no significant differences in terms of PFS or OS were observed in patients treated or not with adjuvant or neo-adjuvant chemotherapy. In this series, a single patient with Stewart–Treves angiosarcoma of the arm was treated with isolated tumor necrosis factor perfusion with long-term survival. Unfortunately, this technique can only seldom be proposed because most angiosarcomas are located in proximal sites or the trunk. Again, it must be stressed that because of the retrospective nature of our observations, no definitive conclusion can be made about the initial management of patients with angiosarcomas in this series.
In conclusion, angiosarcomas are a heterogeneous group of tumors with distinct clinical behavior, with a strong impact of disease site on outcome, frequent occurrence of metastatic lesions in unusual sites, frequent late relapses beyond 5 years and a generally poor outcome of the whole group, even though a 20% subset of metastatic patients may experience long-term survival. Drugs that target angiogenesis should be of particular interest in this malignant vascular tumor. Indeed, these drugs could have a double action, targeting tumoral vascularization and directly tumor cells. Recently, two studies with antiangiogenic approach illustrated this concept. Weekly paclitaxel in 30 patients with advanced angiosarcoma (chemonaive or pretreated) showed 70% (16 of 23) of clinical benefit [26]. Another phase II trial with sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, showed significant activity against angiosarcoma [27].
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The authors wish to thank B. Fontanière for help in data collection.
Received for publication January 23, 2007. Revision received June 28, 2007. Accepted for publication July 7, 2007.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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