PubMed and ASCO abstracts were searched for articles in English using search terms including “angiosarcoma”, “hemangiosarcoma”, “malignant hemangioendothelioma”, “lymphangiosarcoma”, and “radiotherapy”, “chemotherapy”, “drug therapy”, “prognosis”, “aetiology”, “pathogenesis”, “biology”, “angiogenesis”, “VEGF”. We included papers published between January, 1989, and September, 2009, and earlier landmark studies.
ReviewAngiosarcoma
Introduction
Angiosarcomas are a subtype of soft-tissue sarcoma and are aggressive, malignant endothelial-cell tumours of vascular or lymphatic origin (figure 1). Treatment is challenging in many cases and the prognosis is poor. Although the development of several vascular-targeted therapies has stimulated interest in identifying the molecular pathogenesis of angiosarcomas and clinical testing of these molecules. In this review we aim to give an overview of angiosarcoma and its current management, with a focus on clinical trials investigating the treatment of advanced disease.
Much of the published data on these rare tumours are based on case series, which causes difficulty in interpretation of results, because reporting may be selective, datasets incomplete, and treatment approaches diverse, even within the same institution. There have been no phase 3 and few phase 2 treatment trials in angiosarcomas. Furthermore, angiosarcomas are commonly included as a handful of cases within wider studies on soft-tissue sarcomas. As histological and anatomical classifications are replaced by molecular classifications, guidelines for diagnosis and treatment will likely be clarified.
Section snippets
Classification
Angiosarcomas are subdivided into cutaneous angiosarcoma, lymphoedema-associated angiosarcoma, radiation-induced angiosarcoma, primary-breast angiosarcoma, and soft-tissue angiosarcoma, and most reports include several angiosarcoma subtypes.1 There is some evidence that tumour behaviour might depend on site of origin,2, 3 although whether differences between cutaneous, radiation induced, breast, and visceral angiosarcomas are caused by biological differences or differences in clinical
Epidemiology
About 2% of soft tissue sarcomas and 5·4% of cutaneous soft tissue sarcomas are angiosarcomas.4, 5 The incidence of angiosarcoma has risen over the past 30 years, but whether this is a true increase is unclear. The rise could be related to greater use of radiotherapy, improved medical awareness, or a refined histopathological definition. Angiosarcomas have a similar distribution between sexes, can develop at any age, and are more common in older patients; with the cutaneous form most common in
Aetiology
Most angiosarcomas arise spontaneously, but there are a few reports of malignant transformation within pre-existing benign vascular lesions.10 Several well described risk factors exist (panel 1). Chronic lymphoedema of any origin is associated with the development of angiosarcoma; a phenomenon known as Stewart-Treves syndrome. Lymphoedema is one causal aetiological factor in the development of breast angiosarcomas after treatment for breast cancer.11 Lymphoedema caused by Milroy's disease and
Clinical presentation
Cutaneous angiosarcoma can initially resemble a bruise, or a raised purplish-red papule, is typically multifocal (figure 1) and can be mistaken for a simple benign lesion leading to delayed presentation and diagnosis. With increasing tumour size, tissue infiltration, oedema, tumour fungation, ulceration, and haemorrhage can develop.1 Tissue infiltration and multifocal disease can result in contaminated resection margins despite radical surgery.7, 9, 26 Deeper soft tissue and visceral lesions
Differential diagnosis
Angiosarcomas are included within the broad category of vascular tumours (panel 2).1 Clinical history may provide clues but a precise diagnosis requires expert histological assessment.
Capillary haemangiomas typically develop during infancy and present as solitary, well-circumscribed protuberances. After radiation, atypical vascular lesions arise in areas of skin contained within treatment fields. Most of these lesions develop within 3 years of radiotherapy and, while benign, could predict an
Pathology
The histological features of angiosarcoma can vary both within and between cases. Morphological differences can be subtle, and distinguishing a malignant vascular tumour from a benign proliferative or inflammatory lesion with light microscopy can be difficult. Angiosarcomas are infiltrative and do not have a capsule or a clear border separating normal from abnormal tissue.
Abnormal, pleomorphic, malignant endothelial cells are the hallmark of angiosarcoma and can be rounded, polygonal, or
Molecular biology
No comprehensive studies of molecular changes in angiosarcoma have been published. Reports typically explore the expression of one or two markers in a small series of tumours with limited correlation to clinical or pathological features, and are insufficient to compare subgroups such as cutaneous, visceral, or radiation-induced versus de-novo disease. Gene-expression microarray technology should help to identify unique molecular signatures for histological subtypes. This will improve the
Chromosomal abnormalities
Cytogenetic analyses of angiosarcomas have been published for nine patients.50 Most of the samples were derived from metastases, poorly differentiated angiosarcomas, or radiation-induced tumours and a wide range of disparate chromosomal abnormalities were identified, none of which are specific to angiosarcoma. Common abnormalities included trisomy 5, deletions on the short arm of chromosome 7, varied abnormalities on chromosomes 8, 20, and 22, and loss of chromosome Y.
Staging
Soft-tissue sarcomas are staged using the International Union Against Cancer and American Joint Committee on Cancer (UICC/AJCC) system.1 This is based on the TNM (tumour–node–metastatsis) staging system (panel 3),51 with an additional notation for histological grade. Angiosarcomas are high-grade tumours by definition, so histological grading is not used in staging.29
Although many patients with angiosarcoma (50–80%) present with localised disease,7, 8, 9 some (20–45%) have metastatic disease at
Prognostic factors
Primary soft-tissue sarcomas are associated with a 5 year survival of 50–60%,52 but angiosarcomas have an overall 5 year survival of about 35%.3, 6, 9 Even with localised disease, the most optimistic survey suggests only 60% of patients survive for more than 5 years, with a median survival of 7 months.7 However, there are reports of some long-term survivors with metastatic disease,9 but which prognostic factors are important is unclear. Consistent with data for other soft-tissue sarcomas,
Diagnostic assessment
Size of the primary lesion and presence or absence of distant metastases are the most useful determinants of treatment options. Diagnostic assessment includes biopsy, to confirm histology, and MRI to delineate the extent of the primary lesion before surgery. CT imaging of the thorax is done to exclude metastatic disease, and PET imaging may be useful to detect metastases when radical surgery is being planned.56 Although angiosarcomas can spread through the lymphatic system, the value of
Treatment
There are no randomised trials and few prospective studies, most published reports of angiosarcoma treatment are retrospective case series. Treatment has been included in management guidelines for other soft-tissue sarcomas, such as those published by the European Society for Medical Onocology (ESMO) and the National Comprehensive Cancer Network (NCCN). No evidence-based recommendations can be made for specific angiosarcoma subtypes and patients with this rare disease should be referred to
Conclusion
Current treatment options are limited, particularly in radiation-induced angiosarcomas, with surgery as the main curative treatment option. However, wide resection margins are required, and local control is improved with adjuvant radiotherapy. Despite a substantial risk of subsequent metastatic disease there is no compelling evidence for adjuvant chemotherapy. Palliative chemotherapy is hampered by toxicities and poor response rates, and on the basis of available evidence, treatment with
Search strategy and selection criteria
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