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Angiosarcoma

Angiosarcoma is a rare and aggressive malignancy originating from endothelial cells that line blood and lymph vessels, accounting for 1% to 2% of all soft tissue sarcomas.^[1]^[2] It is characterized by rapid proliferation, a high propensity for local recurrence and distant metastasis, and an overall poor prognosis, with five-year survival rates often below 30% depending on stage and location.^[1] This vascular tumor can arise spontaneously or in association with specific risk factors, and it is classified as high-grade by definition due to its infiltrative and destructive behavior.^[1] Epidemiologically, angiosarcoma predominantly affects older adults, with a peak incidence in individuals over 60 years of age, and shows a slight male predominance, particularly among white populations.^[1] The most common site is the skin of the head and neck, especially the scalp, where it represents up to 50% of cases; however, it can also involve deeper tissues or visceral organs such as the liver, heart, breast, or spleen.^[1]^[2] Cutaneous forms are the most frequent overall, while visceral angiosarcomas are rarer and often diagnosed at advanced stages.^[1] Subtypes include hemangiosarcoma (from blood vessels) and lymphangiosarcoma (from lymph vessels), with secondary forms linked to prior medical interventions.^[1]^[2] Key risk factors for developing angiosarcoma include exposure to ionizing radiation, such as from previous cancer treatments, which accounts for a significant proportion of cases in irradiated fields like the breast or chest wall.^[1]^[2] Chronic lymphedema, often following mastectomy or lymph node dissection (known as Stewart-Treves syndrome), increases susceptibility, as does occupational or environmental exposure to chemicals like vinyl chloride (used in polyvinyl chloride production), arsenic, or thorium dioxide.^[1]^[2] Genetic predispositions, including mutations in BRCA1 or BRCA2 genes and syndromes such as neurofibromatosis type 1, have also been implicated in a subset of cases.^[1]^[2] Clinically, angiosarcoma often presents with nonspecific symptoms that delay diagnosis. In cutaneous manifestations, it typically appears as multifocal, bruise-like purple-red papules or nodules on the skin that enlarge, become raised, and may ulcerate, bleed, or cause swelling.^[2]^[1] Visceral involvement can lead to organ-specific signs, such as abdominal pain and weight loss in hepatic cases, shortness of breath or pericardial effusion in cardiac tumors, or painless masses in breast angiosarcoma.^[2]^[1] Due to its vascular nature, tumors frequently exhibit hemorrhage and necrosis, contributing to their aggressive course.^[1]

Overview

Definition and characteristics

Angiosarcoma is a rare malignant neoplasm originating from endothelial cells that line the blood or lymphatic vessels, representing approximately 1-2% of all soft tissue sarcomas.^[3] This vascular tumor is distinguished by its aggressive behavior, typically presenting as a high-grade malignancy with rapid cellular proliferation and an infiltrative growth pattern that lacks clear demarcation from surrounding tissues.^[4] It exhibits a strong propensity for early hematogenous metastasis, most commonly to the lungs, and in advanced stages, shows poor cellular differentiation with marked anaplasia.^[3] Histologically, angiosarcoma is characterized by the formation of irregular, anastomosing vascular channels and sinusoids lined by atypical, multilayered endothelial cells exhibiting nuclear pleomorphism, hyperchromasia, and increased mitotic activity.^[4] These features are often accompanied by extensive intratumoral hemorrhage, necrosis, and stromal lymphoid aggregates, reflecting the tumor's vascular origin and disruptive growth.^[3] Endothelial differentiation is a hallmark, demonstrable through immunohistochemical positivity for markers such as CD31, CD34, ERG, and factor VIII, which help confirm the diagnosis and distinguish it from other sarcomas.^[4] The rarity of angiosarcoma is evident in its estimated annual incidence of 0.1-0.2 cases per 100,000 individuals, predominantly affecting older adults.^[5] Its inherent aggressiveness contributes to a dismal prognosis, with median survival varying by site and stage, often 6-16 months overall with intervention; untreated cases progress rapidly, with survival typically in months.^[6]^[3]

Epidemiology

Angiosarcoma is a rare malignancy, with a global incidence estimated at 1-2 cases per million individuals per year, accounting for approximately 2% of all soft tissue sarcomas.^[7] Certain subtypes, such as hepatic angiosarcoma, exhibit higher incidence rates in specific populations exposed to environmental toxins like vinyl chloride.^[8] The disease predominantly affects older adults, with a median age at diagnosis of 65-70 years, and it is more common in individuals over 60 years of age.^[9] There is a slight overall female predominance or male-to-female ratio of about 1.2:1, with male predominance in cutaneous head and neck cases, and it occurs more frequently in Caucasians compared to other racial groups.^[10] Site-specific patterns show that cutaneous angiosarcomas comprise 50-60% of all cases, often presenting on the head and neck in elderly men.^[3] Breast angiosarcomas are frequently associated with prior radiation therapy, while hepatic cases are linked to occupational exposure to vinyl chloride among industrial workers.^[9]^[8] Incidence rates have increased slightly over time, with an annual rise of about 1.6% in the United States from 2001 to 2019, partly attributable to the growing use of radiation therapy in cancer treatment.^[11] The 5-year overall survival rate is approximately 30-40%, with variations by site and stage; for example, localized cutaneous angiosarcomas achieve around 50% survival, compared to about 10% for metastatic visceral forms.^[3]^[12]

Classification

Cutaneous angiosarcoma

Cutaneous angiosarcoma represents a subtype of angiosarcoma originating from the vascular endothelium of the skin, distinct from deeper visceral or soft tissue forms. Cutaneous angiosarcoma is the most common subtype of angiosarcoma, accounting for about 60% of cases. These tumors typically arise idiopathically in the skin without underlying visceral involvement and are characterized by aggressive local growth and a propensity for multifocal spread within the dermal and subcutaneous layers.^[3] Primary cutaneous angiosarcoma, the idiopathic form, predominantly affects elderly individuals, with a mean age at diagnosis around 70 years and a notable male predominance. It most frequently occurs on the head, neck, and scalp, presenting initially as multifocal bruise-like violaceous patches or plaques that can evolve into nodules, tumors, ulceration, and bleeding. These lesions often mimic benign conditions due to their subtle onset, leading to extensive skin involvement in up to 60% of cases at presentation. This subtype comprises the majority of cutaneous cases and is not associated with prior radiation or lymphedema. Lymphedema-associated angiosarcoma, known as Stewart-Treves syndrome, develops in areas of chronic lymphedema, most commonly the upper limb following mastectomy and axillary lymph node dissection for breast cancer. It typically emerges after a latency period of 5 to 10 years, though intervals up to 20 years have been reported, in the setting of persistent lymphatic obstruction that promotes neoplastic transformation of endothelial cells. Presentation involves erythematous or violaceous nodules and plaques on the edematous limb, which may ulcerate and exhibit rapid progression. This variant is rarer than the primary form but carries similar aggressive behavior, often complicating long-term survivors of breast cancer. Diagnosis of cutaneous angiosarcoma poses significant challenges due to its nonspecific and deceptive clinical appearance, frequently resulting in initial misdiagnosis as a hematoma, infection, cellulitis, or benign vascular lesion. Early lesions may be overlooked or attributed to trauma, delaying biopsy and histopathological confirmation, which is essential and reveals irregular vascular channels lined by atypical endothelial cells. The multifocal nature and subtle progression contribute to diagnostic delays averaging several months, exacerbating the risk of local spread. Prognosis for cutaneous angiosarcoma remains guarded, with 5-year overall survival rates ranging from 30% to 50%, influenced by early detection and complete surgical excision. Local recurrence is common, occurring in 60% to 80% of cases, often within the first two years, due to the tumor's infiltrative margins and difficulty achieving negative surgical borders in cosmetically sensitive areas like the scalp. Factors such as tumor size greater than 5 cm and multifocality at diagnosis portend worse outcomes, though multimodal approaches can improve local control in select patients.

Visceral angiosarcoma

Visceral angiosarcoma refers to a rare and aggressive subtype of angiosarcoma that arises within the parenchymal tissues of internal organs, often leading to organ-specific dysfunction and rapid progression. These tumors originate from endothelial cells lining blood vessels in visceral sites such as the breast, heart, liver, and brain, and they are characterized by their vascular nature, which predisposes them to early dissemination. Unlike more superficial forms, visceral variants typically present with insidious symptoms related to mass effect or vascular compromise, complicating early detection and contributing to their dismal prognosis. Primary breast angiosarcoma occurs de novo, predominantly affecting premenopausal women in their thirties or forties, represents approximately 0.05% of all malignant breast tumors, and is one of the most common types of breast sarcomas.^[13] Clinically, it manifests as a rapidly enlarging, painless palpable mass, often exceeding 4 cm, which may be accompanied by rare instances of purple-blue skin discoloration due to underlying vascular proliferation. In contrast, secondary breast angiosarcoma develops as a radiation-induced malignancy following treatment for primary breast cancer, with a latency period typically ranging from 5 to 15 years after exposure. The risk is elevated in patients who underwent breast-conserving surgery combined with radiotherapy, with reported cumulative incidences of 0.05% to 0.5% within this timeframe, highlighting the iatrogenic etiology of this subtype. Primary cardiac angiosarcoma is the most common primary malignant tumor of the heart, accounting for 30-40% of all primary malignant cardiac tumors (which comprise about 25% of primary cardiac neoplasms), and it predominantly originates in the right atrium in nearly 90% of cases.^[14] This location often leads to obstructive symptoms, including right-sided heart failure due to inflow obstruction or pericardial tamponade from tumor invasion and hemorrhage. The tumor's aggressive local growth and propensity for pericardial involvement necessitate urgent intervention, though complete resection is frequently unattainable due to its central position and multifocal spread. Primary hepatic angiosarcoma, a mesenchymal malignancy comprising 0.1-2% of primary liver cancers, is strongly associated with environmental exposures such as thorotrast (a historical contrast agent) and vinyl chloride monomer, with latencies extending up to 20 years following exposure. These tumors often present as multifocal lesions throughout the liver, carrying a high risk of spontaneous rupture and life-threatening intraperitoneal hemorrhage. Incidence has become extremely rare since the 1980s, following international bans on thorotrast and stringent regulations on vinyl chloride use in industry. Primary brain angiosarcoma is an exceedingly uncommon intracranial neoplasm, representing less than 1% of primary central nervous system sarcomas, and it typically appears as an aggressive, vascular mass that can mimic more benign entities like meningioma on imaging due to its dural-based or extra-axial location. Despite its rarity, the tumor's rapid growth and infiltrative behavior lead to significant neurological compromise, often requiring multimodal management for control. Overall, visceral angiosarcomas exhibit poor resectability owing to their deep-seated locations and anatomical constraints, with early hematogenous metastasis to distant sites such as the lungs and bones occurring in the majority of cases at presentation. This metastatic potential, combined with high-grade histology, results in 5-year survival rates below 30%, underscoring the need for aggressive surgical, chemotherapeutic, and targeted approaches despite limited efficacy.

Soft tissue angiosarcoma

Soft tissue angiosarcoma arises from endothelial cells within deep soft tissues, such as skeletal muscle, subcutaneous fat, and connective tissues, distinct from superficial skin or organ-based tumors. These neoplasms predominantly occur in the extremities (particularly the lower limbs), retroperitoneum, and trunk, where they manifest as deep-seated, painless masses that progressively enlarge and may cause local discomfort due to mass effect.^[4]^[15] In rarer instances, they can involve the mediastinum or mesentery, often appearing as ill-defined, hemorrhagic lesions on imaging.^[16] Representing approximately 10% of all angiosarcomas, soft tissue variants are relatively uncommon compared to cutaneous forms, though they account for a notable subset of vascular sarcomas in musculoskeletal sites.^[15] Many cases arise idiopathically without identifiable predisposing factors, but associations have been reported with prior trauma, such as chronic injury or surgical intervention, and radiation exposure, particularly in previously irradiated fields.^[4]^[17] These secondary forms highlight potential environmental triggers in endothelial cell transformation, though the majority lack such history.^[1] At diagnosis, soft tissue angiosarcomas are characteristically large, often exceeding 5 cm in diameter, and exhibit high-grade histology with aggressive features including necrosis and high mitotic activity.^[4] Approximately 50% of patients present with distant metastases, most commonly to the lungs, reflecting the tumor's propensity for hematogenous spread from the outset.^[16] Local recurrence is frequent due to infiltrative margins, complicating complete resection.^[15] Distinguishing soft tissue angiosarcoma from benign vascular lesions, such as hemangiomas or vascular malformations, is critical and hinges on histopathological evidence of infiltrative growth dissecting through surrounding tissues, alongside cytologic atypia featuring pleomorphic endothelial cells, hyperchromatic nuclei, and anastomosing vascular channels.^[4] Immunohistochemical markers like CD31, CD34, and ERG positivity further confirm malignant endothelial differentiation, aiding in differentiation from reactive or benign proliferations that lack such atypia and invasion.^[1]

Pathophysiology

Cellular and molecular features

Angiosarcoma originates from the malignant transformation of endothelial cells lining blood or lymphatic vessels, resulting in aggressive proliferation that forms irregularly anastomosing vascular channels, including characteristic slit-like spaces lined by atypical, plump endothelial cells exhibiting high mitotic rates and marked nuclear pleomorphism.^[4] These histological features reflect the tumor's endothelial differentiation, with tumor cells often displaying spindle, epithelioid, or primitive morphologies that infiltrate surrounding tissues.^[3] At the molecular level, angiosarcomas harbor recurrent genetic alterations that drive oncogenesis, including MYC amplification in approximately 42% of cases (ranging from 11% to 90%), with particularly high prevalence in secondary angiosarcomas associated with radiation exposure.^[18] Overexpression of vascular endothelial growth factor (VEGF) is observed in 86% of cases, promoting aberrant angiogenesis through autocrine and paracrine mechanisms.^[18] Common mutations include TP53 alterations in 27% of cases (10-69%, varying by anatomic site such as 35% in head and neck angiosarcomas), KDR (encoding VEGFR2) mutations in 12% (7-73%), PTPRB deletions or mutations in 18% (11-29%), and less frequent involvement of FLT1 (VEGFR1).^[18]^[19] Cutaneous subtypes often display an ultraviolet (UV) radiation mutational signature in up to 50% of head and neck cases, characterized by high tumor mutational burden and COSMIC Signature 7a.^[20] Immunohistochemical profiling confirms endothelial origin, with strong positivity for CD31 (91% of cases), CD34 (68%), ERG (96%), and FLI1 (97%), typically showing membranous or nuclear staining patterns that highlight vascular channels.^[18] These markers aid in diagnosis, while angiosarcomas are generally negative for cytokeratins, helping to distinguish them from epithelial carcinomas, although focal cytokeratin expression may occur in epithelioid variants.^[4]

Tumor behavior and metastasis

Angiosarcomas exhibit highly infiltrative growth patterns, characterized by irregular borders and a lack of encapsulation, which allows the tumor to permeate surrounding tissues such as dermis and subcutaneous layers without clear demarcation.^[1] This infiltrative behavior often involves extensive lymphovascular invasion, facilitating early dissemination, with perineural invasion also commonly observed in aggressive cases.^[4] As a result, achieving complete surgical margins is challenging, contributing to the tumor's local aggressiveness. Metastasis in angiosarcoma primarily occurs via hematogenous routes, with the lungs being the most frequent site, affected in 63-85% of cases presenting with pulmonary nodules or cysts.^[21] Other common distant sites include the liver and bones, where lesions often appear as multiple hypoattenuating or lytic foci, respectively, while lymphatic spread is less prevalent except in cutaneous variants.^[21] This pattern underscores the endothelial origin of the tumor, promoting vascular dissemination over lymphatic pathways in most instances. Angiosarcomas are considered high-grade malignancies by default, with the majority classified as FNCLCC grade 3, reflecting their inherent aggressiveness and rapid progression from localized disease to widespread metastasis, often within months of diagnosis.^[1] Molecular drivers such as MYC amplification may further enhance this aggressive behavior, though detailed mechanisms are addressed elsewhere. Post-resection recurrence is common, with local rates ranging from 45-64% and distant metastasis occurring in 27-42% of cases, necessitating vigilant surveillance.^[22]

Clinical presentation

Cutaneous symptoms

Cutaneous angiosarcoma most commonly presents on the head and neck, particularly the scalp and face, as ill-defined, bruise-like ecchymosis or red-purple macules that may initially appear innocuous.^[3] These lesions often mimic benign conditions such as cellulitis, hematoma, or dermatitis, leading to delayed recognition.^[23] Satellite lesions or multifocal disease may be seen in 41-46% of cases, with multiple discrete or coalescing patches that can span large areas of the skin.^[24] Over time, the lesions progress to raised nodules or plaques, which may become violaceous or bluish in hue.^[25] As the disease advances, cutaneous lesions frequently develop ulceration, persistent bleeding, and surrounding edema, contributing to local tissue destruction.^[26] Associated symptoms include pain, pruritus, crusting, or nonpitting edema, though some cases remain asymptomatic until significant involvement occurs.^[2] In lymphedema-associated subtypes, such as Stewart-Treves syndrome following mastectomy, symptoms often include progressive arm swelling alongside the characteristic skin changes.^[23] The onset is typically insidious, evolving over several months, with median diagnostic delays of 5-7 months due to the deceptively benign initial appearance.^[27]

Visceral and soft tissue symptoms

Visceral angiosarcomas arise in internal organs and often manifest through symptoms of mass effect, compression, or vascular disruption, leading to organ-specific dysfunction that can be insidious and nonspecific until advanced stages. In the breast, primary angiosarcoma typically presents as a firm, tender mass causing swelling or a sensation of fullness, potentially accompanied by discolored rash or bruise-like skin changes on the breast surface.^[28]^[29] Secondary forms, often post-radiation, may similarly feature a painful lump with overlying skin alterations.^[1] Cardiac angiosarcoma, most frequently involving the right atrium, produces symptoms related to hemodynamic compromise, including dyspnea and chest pain as prominent early features due to obstruction of blood flow.^[30] Arrhythmias may arise from myocardial infiltration, while right heart involvement can precipitate pericardial effusion culminating in sudden cardiac tamponade, a life-threatening emergency.^[30]^[1] Hepatic angiosarcoma commonly causes right upper quadrant abdominal pain from tumor expansion, alongside hepatomegaly detectable on physical examination and jaundice due to hepatic dysfunction.^[31] In cases of rapid growth, tumor rupture may occur, resulting in hemoperitoneum with acute abdominal distention and hemodynamic instability.^[31]^[2] Soft tissue angiosarcomas in deep locations, such as the limbs or trunk, often present as painless enlarging masses or swelling due to local expansion, though some may cause discomfort from compression of adjacent structures.^[1]^[32] Bleeding into the tumor can lead to anemia, manifesting as fatigue and weakness, particularly with acute hemorrhage.^[16] Across visceral and soft tissue sites, advanced angiosarcoma frequently elicits general systemic symptoms, including unexplained weight loss and malaise, reflecting tumor burden and metastatic spread.^[25]^[2]

Risk factors and etiology

Environmental and iatrogenic factors

Environmental exposures and iatrogenic interventions represent significant acquired risk factors for angiosarcoma, particularly in the liver and skin. Therapeutic radiation is a well-documented cause, with angiosarcomas often arising in irradiated fields such as the breast following treatment for breast cancer. The latency period between radiation exposure and tumor development typically ranges from 5 to 25 years, with a median of around 7 years in reported cohorts. Cumulative radiation doses exceeding 10 Gy have been implicated in elevating risk, though the absolute incidence remains low relative to the benefits of radiotherapy. For instance, post-radiation angiosarcomas of the breast exhibit aggressive behavior and poor prognosis, underscoring the need for vigilant long-term surveillance in irradiated patients. Chemical toxins also play a prominent role, notably vinyl chloride monomer exposure among workers in the polyvinyl chloride (PVC) industry, which is causally linked to hepatic angiosarcoma. This occupational hazard induces liver angiosarcoma through chronic exposure, with standardized mortality ratios for the tumor reaching up to 2.87 in exposed cohorts, and even higher associations with cumulative dose. Historically, iatrogenic administration of thorotrast (thorium dioxide), a radiographic contrast agent used until its ban in the 1950s, has been strongly associated with hepatic angiosarcoma, often manifesting decades after injection due to alpha-particle radiation from thorium decay. Arsenic exposure, common in mining and pesticide production, further contributes to hepatic angiosarcoma risk, as evidenced by cases following prolonged medicinal or environmental ingestion. Additional iatrogenic factors include chronic immunosuppression, particularly in solid organ transplant recipients on regimens involving calcineurin inhibitors, which predisposes to de novo angiosarcomas in various sites, including the skin, liver, and vascular access fistulas. Retained foreign bodies, such as shrapnel fragments from trauma, can provoke local angiosarcoma development through chronic inflammation, as seen in war veterans with embedded metal. Prolonged use of anabolic-androgenic steroids, often for performance enhancement, is linked to hepatic angiosarcoma, frequently in conjunction with peliosis hepatis, a vascular liver lesion that may progress to malignancy. These factors highlight the importance of exposure history in risk assessment for this rare sarcoma.

Genetic and syndromic associations

Angiosarcomas are predominantly sporadic tumors, with approximately 70-80% of cases lacking identifiable hereditary or syndromic predispositions. However, a small subset, estimated at around 3%, arises in the context of gene-associated familial syndromes, underscoring the role of germline alterations in vascular tumorigenesis. These associations highlight the importance of genetic screening in patients with relevant syndromic features or family histories of vascular malignancies.^[3] Germline mutations in DNA repair and tumor suppressor genes contribute to familial predispositions. Mutations in BRCA1 and BRCA2 genes, associated with hereditary breast and ovarian cancer syndrome, have been linked to an increased risk of angiosarcoma, particularly radiation-associated cases in the breast, as evidenced by case reports and genetic analyses of affected patients.^[33] Several rare congenital syndromes confer an increased risk of angiosarcoma development, often through underlying vascular malformations or hamartomatous lesions that predispose to malignant transformation. Neurofibromatosis type 1 (NF1), an autosomal dominant disorder caused by mutations in the NF1 gene, is linked to vascular tumors, including angiosarcomas, with patients facing an approximate 50-60% lifetime risk of cancer development overall, though specific vascular tumor risks are lower but elevated compared to the general population. In NF1, angiosarcomas may arise from benign neurofibromas or independently, as evidenced by case reports of peripheral nerve-associated lesions. Maffucci syndrome, characterized by multiple enchondromas and soft tissue hemangiomas due to somatic mosaic IDH1 or IDH2 mutations, carries a 15-20% risk of sarcomatous transformation, with angiosarcoma being a recognized outcome in affected tissues such as the extremities or viscera. Klippel-Trenaunay syndrome, involving congenital vascular malformations, lymphatic anomalies, and limb hypertrophy often linked to PIK3CA mutations, has been associated with angiosarcomas in malformed tissues, including rare cases of pleural or epithelioid variants, particularly in adolescents.^[7]^[34]^[35]^[36] Germline mutations in tumor suppressor genes further contribute to familial predispositions. PTEN hamartoma tumor syndrome (PHTS), encompassing Cowden syndrome and related disorders from PTEN germline variants, has been implicated in pediatric cutaneous angiosarcomas, as seen in case reports of concurrent neuroblastoma and vascular malignancies, reflecting disrupted PI3K/AKT signaling in endothelial cells. Familial clusters of cardiac angiosarcoma are notably tied to germline POT1 mutations, which impair telomere protection and promote genomic instability; these variants occur in Li-Fraumeni-like families without TP53 alterations, leading to a spectrum of tumors including sarcomas. While specific ATP-dependent DNA helicase mutations (e.g., in RECQL family genes) are not directly established for angiosarcoma, broader DNA repair defects in syndromes like Rothmund-Thomson may indirectly heighten vascular malignancy risks through chromosomal instability.^[37]^[38] In pediatric angiosarcoma cases, syndromic associations are more prevalent than in adults, with up to 20% linked to underlying genetic conditions such as those above, emphasizing a stronger hereditary component in childhood-onset disease. Somatic genetic alterations, like TP53 mutations, often overlap with syndromic drivers but are addressed in cellular pathophysiology. For high-risk families, genetic counseling and surveillance for vascular lesions are recommended to facilitate early detection.^[39]

Diagnosis

Imaging modalities

Ultrasound serves as an initial imaging modality for evaluating superficial angiosarcomas, particularly cutaneous or soft tissue masses, where it reveals heterogeneous echotexture and increased vascularity on Doppler imaging, indicating hypervascularity and irregular blood flow within the lesion.^[15] For visceral sites like the spleen or liver, ultrasound may show mixed echogenicity with potential septal zones and low-grade blood flow (grade 0-I), though it is limited for deep or ill-defined large masses.^[3] This non-invasive technique aids in early detection and local assessment but is less effective for staging due to its restricted field of view. Computed tomography (CT) and magnetic resonance imaging (MRI) are preferred for characterizing deep-seated, visceral, or soft tissue angiosarcomas, demonstrating heterogeneous masses with prominent contrast enhancement corresponding to irregular vascular channels and potential necrosis or hemorrhage.^[15] On CT, lesions appear as hypoattenuating nodules with ring-like or progressive enhancement, facilitating identification of local invasion and regional spread.^[3] MRI provides superior soft tissue contrast, showing T2-hyperintense signals due to vascular components and edema, intermediate T1 signal, and avid gadolinium enhancement, which helps delineate tumor extent and differentiate from mimics like hemangiomas.^[15] Positron emission tomography-computed tomography (PET-CT) using 18F-FDG is highly useful for staging angiosarcoma, as the tumor exhibits marked FDG avidity reflecting its aggressive metabolic activity, with high sensitivity and specificity for detecting distant metastases, often present at diagnosis.^[40] It excels in identifying occult spread to lungs, bones, or lymph nodes, where sensitivity for metastatic disease approaches 80-90% in soft tissue sarcomas including angiosarcoma, guiding systemic evaluation beyond anatomical imaging.^[41] Site-specific imaging enhances diagnostic precision; for cardiac angiosarcoma, transthoracic echocardiography is the initial modality with approximately 75% sensitivity for visualizing right atrial masses, often showing irregular, mobile lesions with pericardial effusion, complemented by CT or MRI for detailed morphology.^[42] In hepatic angiosarcoma, MRI is particularly valuable for assessing multifocality, revealing multiple progressive-enhancing nodules or a dominant mass in nearly all cases (up to 74% with at least 10 lesions), highlighting the tumor's diffuse intrahepatic spread.^[43]

Histopathology and immunohistochemistry

Diagnosis of angiosarcoma requires microscopic examination of tissue obtained through biopsy, as imaging alone cannot provide definitive confirmation. Core needle biopsy or excisional biopsy is recommended for accurate sampling, while fine-needle aspiration should be avoided due to high risk of sampling error and potential misdiagnosis.^[44]^[45] Histologically, angiosarcomas exhibit a range of patterns, primarily vasoformative and solid. In the vasoformative pattern, seen in well-differentiated tumors, irregular, anastomosing vascular channels lined by atypical endothelial cells predominate, often with papillary projections or tufting into lumina.^[3]^[46] The solid pattern, characteristic of poorly differentiated cases, features sheets of spindled, epithelioid, or primitive round cells with minimal vascular formation, high mitotic activity, and necrosis.^[3]^[47] Many tumors display a mixture of these patterns, reflecting their heterogeneous nature.^[48] Immunohistochemistry is essential for confirming the endothelial origin of angiosarcoma and distinguishing it from mimics. The most sensitive marker is CD31, which shows strong membranous staining in over 90% of cases and serves as the gold standard.^[3]^[49] CD34 and ERG are also commonly positive, with ERG providing nuclear staining that aids in specificity.^[50]^[51] The proliferation index, assessed by Ki-67, is typically elevated, often exceeding 20%, underscoring the tumor's aggressive biology.^[50]^[52] Angiosarcomas are uniformly considered high-grade malignancies, with most cases demonstrating marked cytologic atypia, mitoses, and necrosis regardless of differentiation level.^[1]^[53] In differential diagnosis, angiosarcoma must be distinguished from Kaposi sarcoma, which shares vascular features but is positive for HHV8 immunohistochemistry, unlike angiosarcoma.^[54]

Management and treatment

Surgical approaches

Surgical resection represents the primary curative approach for localized angiosarcoma, aiming to achieve complete tumor removal with negative microscopic margins (R0 resection) to optimize local control and survival outcomes.^[3] Wide local excision is the standard technique, incorporating a surrounding rim of normal tissue to account for the tumor's infiltrative growth pattern, with recommended margins typically ranging from 2 to 5 cm depending on the anatomical site.^[55] Achieving R0 margins is associated with improved recurrence-free survival, though positive margins occur frequently due to the tumor's aggressive biology.^[56] Site-specific considerations guide surgical planning to balance oncologic efficacy with functional preservation. For breast angiosarcoma, total mastectomy is preferred to secure wide margins exceeding 3 cm, as breast-conserving surgery often fails to achieve complete resection in this vascular malignancy.^[57] In hepatic angiosarcoma, partial hepatectomy is feasible for tumors confined to less than half the liver or measuring under 10 cm, offering potential survival prolongation when radical removal is possible.^[58] For extremity involvement, wide excision is attempted initially, but amputation may be necessary if the tumor is multifocal or encases critical neurovascular structures, preventing limb-sparing options.^[59] Neoadjuvant therapies play a role in select cases to reduce tumor burden and facilitate resectability, particularly for borderline resectable lesions, by enabling safer and more complete surgical intervention.^[60] Surgical challenges arise from angiosarcoma's propensity for multifocality and subclinical spread, which complicates margin assessment and contributes to incomplete resections in approximately 40% of cases, especially in cutaneous and scalp presentations.^[61] These factors often necessitate intraoperative frozen section analysis and multidisciplinary input to minimize local recurrence risks.^[62]

Systemic therapies

Systemic therapies for angiosarcoma primarily involve chemotherapy and targeted agents, aimed at controlling advanced or metastatic disease and, in select cases, preventing recurrence in high-risk localized tumors. First-line chemotherapy options include weekly paclitaxel, administered at doses such as 80 mg/m², which has demonstrated objective response rates (ORR) ranging from 40% to 60% across multiple studies in metastatic settings.^[63]^[64] Doxorubicin-based regimens, often combined with ifosfamide or as liposomal formulations to mitigate cardiotoxicity, represent another standard first-line approach, with comparable response rates of approximately 25-50% and median progression-free survival of 4-6 months in advanced disease.^[3]^[65] In high-risk localized angiosarcoma, such as cases with close or positive margins following resection, adjuvant systemic therapy is sometimes employed to reduce recurrence risk. Retrospective analyses indicate that adjuvant chemotherapy, typically with anthracyclines or taxanes, can decrease recurrence rates by 20-30% in these scenarios, though prospective data remain limited and it is not universally recommended.^[66]^[67] Targeted therapies focus on the vascular nature of angiosarcoma, particularly in tumors with high vascular endothelial growth factor (VEGF) expression. Multi-kinase inhibitors like pazopanib (800 mg daily) and sorafenib (400 mg twice daily) inhibit VEGF receptors and have shown modest activity, with ORR of 10-20% and disease stabilization in up to 50% of VEGF-overexpressing cases in phase II trials.^[68]^[69] Emerging immune checkpoint inhibitors (ICIs), such as anti-PD-1 agents including nivolumab, have demonstrated preliminary efficacy, particularly in cutaneous angiosarcoma. A multicenter phase II trial reported an ORR of 25% with nivolumab plus ipilimumab, with responses more pronounced in scalp and face primaries (three of five responders).^[70] Recent advances from 2024-2025 phase II studies highlight combinations of ICIs with chemotherapy for scalp and face subtypes, where paclitaxel plus nivolumab achieved ORR up to 73% in these anatomically challenging sites, suggesting improved control over chemotherapy alone.^[71]^[72]

Radiation and emerging treatments

Radiation therapy plays a key role in the management of angiosarcoma, particularly as an adjuvant treatment following surgical resection to enhance local control in high-risk cases. Adjuvant radiation is recommended for localized disease with close or positive margins, such as those less than 2 cm, where the risk of local recurrence is elevated due to the tumor's aggressive nature. Typical postoperative doses range from 60 to 66 Gy delivered in 1.8–2 Gy fractions, which has been associated with improved recurrence-free survival compared to surgery alone in retrospective analyses.^[73] For instance, in a multi-institutional study of scalp and face angiosarcomas, adjuvant or definitive radiation achieved a 5-year local control rate of 64%, with higher equivalent doses (>66 Gy) further enhancing outcomes.^[74] These benefits are attributed to the multimodality approach, though exact improvements vary; one analysis reported a hazard ratio of 0.27 for local recurrence with radiation addition, indicating substantial risk reduction.^[66] Palliative radiation therapy is employed for symptomatic relief in patients with metastatic angiosarcoma, targeting painful or functionally impairing lesions such as bone metastases or soft tissue masses. Hypofractionated regimens, often delivering 30–40 Gy in 10 fractions, provide durable symptom control and local control in up to 70% of cases, allowing breaks from systemic therapy without excessive toxicity.^[75] In a cohort of advanced sarcomas including angiosarcoma, palliative radiation yielded symptomatic benefits in the majority, with response rates exceeding 50% for pain palliation.^[76] Emerging treatments for angiosarcoma focus on novel modalities to overcome traditional limitations, including investigational radiation techniques and targeted combinations. Boron neutron capture therapy (BNCT), which selectively delivers radiation to boron-loaded tumor cells, has shown promise in phase I/II trials in Japan. A 2024 phase I trial in cutaneous angiosarcoma demonstrated a 70% overall response rate with a maximum tolerated dose of 18 Gy-Eq and a favorable safety profile, limited to transient grade 3 amylase elevation; phase II studies are ongoing to confirm efficacy in unresectable cases.^[77] Metronomic chemotherapy, involving low-dose continuous administration to target tumor vasculature, has been effective in advanced disease when combined with beta-blockers like propranolol. In a bench-to-bedside study of seven patients, vinblastine (6 mg/m² weekly) plus methotrexate (35 mg/m² weekly) and propranolol achieved a 100% response rate, with median progression-free survival of 11 months and overall survival of 16 months.^[78] Immunotherapy combinations, particularly immune checkpoint inhibitors with tyrosine kinase inhibitors (TKIs), represent another frontier for refractory angiosarcoma. Pembrolizumab paired with TKIs such as axitinib or lenvatinib has yielded objective response rates over 20% in real-world data from advanced sarcomas, leveraging vascular disruption and immune activation.^[79] For example, the axitinib-pembrolizumab regimen is emerging as a preferred option in vascular sarcomas, with ongoing trials evaluating its role in combination with other agents.^[80] Despite these advances, radioresistance remains a challenge in some angiosarcomas, often linked to intratumoral hypoxia resulting from abnormal vascular architecture. Hypoxic regions reduce radiation efficacy by limiting oxygen-dependent DNA damage, contributing to poorer local control in up to 50% of cases; this paradox in a vascular tumor underscores the need for hypoxia-modifying strategies.^[81]^[82]

Prognosis

Survival rates and prognostic factors

Angiosarcoma is associated with a poor prognosis overall, with 5-year survival rates typically ranging from 30% to 40% across large cohorts.^[3] Median overall survival is approximately 16 months for localized disease, compared to 8 to 12 months for metastatic cases at presentation.^[83]^[84] These outcomes reflect the aggressive nature of the tumor, with high rates of local recurrence and distant metastasis even after multimodal therapy. Survival varies significantly by primary site. For cutaneous angiosarcoma, 5-year survival rates are around 26% (95% CI 23–30%), benefiting from earlier detection in accessible locations.^[85] Breast angiosarcoma shows 5-year rates of approximately 38% to 44%, often influenced by prior radiation exposure in secondary cases.^[85] Cardiac angiosarcoma has a dismal 5-year survival of about 7% (95% CI 4–11%), limited by diagnostic delays and surgical challenges.^[86] Hepatic angiosarcoma fares slightly better among visceral sites, with 5-year rates near 33% to 39% in resectable cases, though most present advanced.^[87] Several prognostic factors influence outcomes in angiosarcoma. Tumor size greater than 5 cm is not significantly associated with overall survival (HR 1.10, 95% CI 0.52–2.35).^[10] Metastasis at diagnosis confers a markedly worse prognosis, with HR approximately 2.9 (95% CI 2.5–3.3) for survival, as distant spread drastically shortens median survival to under 1 year.^[85] Advanced age over 70 years is associated with poorer outcomes (HR 1.28 per decade), linked to comorbidities and reduced treatment tolerance.^[85] MYC gene amplification, present in up to 90% of certain subtypes like radiation-associated cases, correlates with aggressive behavior and worse survival (HR up to 20 for overall survival).^[88] Angiosarcomas are uniformly classified as high-grade (grade 3) tumors under the American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcomas, which integrates tumor size, nodal involvement, metastasis, and grade to determine stage.^[89] This high-grade designation underscores their rapid progression, with stage III or IV disease common at diagnosis and driving the majority of mortality.^[90]

Impact of site and stage

The prognosis of angiosarcoma varies substantially based on the primary tumor site, with cutaneous lesions in the head and neck region demonstrating superior outcomes compared to those in extremity soft tissue. Specifically, the 5-year disease-specific survival rate for sporadic cutaneous angiosarcomas of the head and neck is approximately 48%, attributed to higher resectability and earlier detection in accessible areas.^[91] In contrast, soft tissue angiosarcomas of the extremities exhibit a 5-year overall survival rate of around 33%, often due to challenges in achieving complete surgical margins amid deeper tissue involvement and larger tumor sizes.^[85] Disease stage at presentation further delineates survival disparities, with localized angiosarcomas (stages I-II) achieving 5-year survival rates up to 60% when amenable to aggressive local therapy.^[92] Conversely, metastatic disease (stage IV) portends a markedly poorer outlook, with 3-year survival rates of approximately 4%, and 5-year rates likely lower.^[93] Multifocality compromises prognosis by hindering curative resection and promoting early dissemination.^[94] Angiosarcomas arising in post-radiation sites, such as those following breast cancer therapy, often exhibit worse outcomes compared to primary tumors.^[95] A 2025 phase II trial of nivolumab for pretreated cutaneous angiosarcoma reported a median overall survival of 8.5 months (259 days) in stage IV cases but did not demonstrate significant efficacy improvements.^[96] As of 2025, multimodal approaches including surgery and systemic therapies continue to be explored for better outcomes in resectable cases.^[97]

Angiosarcoma in other animals

Canine hemangiosarcoma

Hemangiosarcoma, known as a highly aggressive vascular tumor in dogs, represents approximately 5-7% of all canine malignancies and is particularly prevalent in middle-aged to older large-breed dogs, with breeds such as German Shepherds and Golden Retrievers showing increased susceptibility.^[98]^[99]^[100] The condition most frequently arises in the spleen, accounting for over 50% of splenic tumors in affected dogs, followed by the heart or right atrium (around 25-40% of cardiac tumors) and the skin or subcutaneous tissues (about 14% of all hemangiosarcoma cases).^[101]^[102]^[103] Clinical presentation often involves nonspecific signs that escalate rapidly due to the tumor's propensity for rupture and internal hemorrhage, including acute collapse, severe weakness, lethargy, pale mucous membranes, and abdominal distension from blood accumulation.^[104]^[102] Dogs with untreated hemangiosarcoma typically face a poor prognosis, with a median survival time of 1-3 months, though rupture can lead to sudden death within days to weeks.^[101]^[105] Genetically, canine hemangiosarcoma shares molecular similarities with human angiosarcoma, particularly involving dysregulation of the PI3K/AKT signaling pathway, which promotes tumor growth and vascular abnormalities.^[106]^[107] This pathway's alterations, including mutations in PIK3CA, contribute to the disease's aggressiveness and are observed across predisposed breeds like Golden Retrievers, where genetic loci on chromosome 5 have been linked to higher incidence.^[108]^[109] Research as of 2025 has advanced targeted therapies for canine hemangiosarcoma. A University of Florida study published in January 2025 identified novel molecular insights into PIK3CA mutations and immune system interactions that could enhance treatment efficacy.^[110] Subsequent developments include the Morris Animal Foundation's selection of five new research proposals in June 2025 focused on diagnosis and treatment, a July 2025 Royal Veterinary College study reporting a median survival time of 9 days for diagnosed cases, an ongoing clinical trial for Paccal Vet chemotherapy starting in July 2025, and an October 2025 update from the Portuguese Water Dog Foundation on efforts toward curative outcomes.^[111]^[112]^[113]^[114] These initiatives build on explorations of vaccines and pathway inhibitors to address the cancer's rapid metastasis and improve survival beyond traditional surgery and chemotherapy.

Occurrence in other species

Angiosarcoma is a rare neoplasm in cats, accounting for less than 2% of all nonhematopoietic malignancies.^[115] It most commonly presents as cutaneous or subcutaneous forms (approximately 77% of cases), often affecting the head, limbs, or trunk, while visceral involvement, including the spleen and liver, occurs in about 19% of reported cases.^[115] Visceral angiosarcoma in cats carries a poorer prognosis compared to canine counterparts, with a median survival time of 77 days (range: 23–296 days) following diagnosis and treatment, primarily due to rapid multifocal dissemination.^[116] In horses, angiosarcoma predominantly manifests as dermal or subcutaneous lesions, frequently on the legs, head, neck, or areas susceptible to trauma and sun exposure, particularly in middle-aged or older animals with light-colored coats.^[117] These tumors are linked to chronic injury or ultraviolet radiation, appearing as red nodules or bruise-like areas.^[117] Surgical excision of localized lesions is often curative, with low rates of distant metastasis and higher likelihood of local recurrence rather than systemic spread, contrasting with the more aggressive metastatic behavior observed in dogs.^[117]^[118] Hepatic angiosarcoma has been documented in cattle, typically as part of broader hepatic neoplasia, though it remains exceedingly rare.^[119] In pigs, angiosarcoma is sporadically reported, with isolated case reports highlighting its rarity across various sites.^[120] Experimental models in mice, such as those involving p53 loss in endothelial cells or combined Pten/Trp53/Ptpn12 deletions, have been developed to study human angiosarcoma pathogenesis and test targeted therapies like mTOR/MEK inhibitors.^[121]^[122] Veterinary diagnosis of angiosarcoma across species relies on similar immunohistochemical markers, with CD31 positivity confirming endothelial origin in formalin-fixed tissues from dogs, cats, horses, and other animals.^[123] However, species-specific differences in metastatic potential exist; for instance, equine dermal forms exhibit slower and less frequent dissemination compared to the rapid, widespread metastasis typical in canine visceral cases.^[117]^[103]

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Seventy-one percent of euthanized cats were euthanized within 1 day of diagnosis. The median survival time of the remaining cats (n = 6) was 77 days (range, 23 ...
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Angiosarcomas can vary greatly in appearance. Most commonly, they appear as 1 or more red lumps in the skin or underlying soft tissues. Less frequently ...
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Conclusions: Complete surgical excision may be associated with resolution of periocular and ocular hemangiosarcoma in horses. Etiopathogenesis may include ...Missing: angiosarcoma | Show results with:angiosarcoma<|separator|>
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Epithelioid Variant of Hemangioma and Hemangiosarcoma in the ...
We describe 12 epithelioid endothelial vascular tumors in 8 dogs, 3 horses, and 1 cow that share microscopic features with these tumors in humans.
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Primary Meningeal Hemangiosarcoma in a Grower Pig
Abstract. A juvenile female pig found dead was submitted for necropsy. A focal meningeal red mass measuring 3.5 cm in diameter was located over the left ...
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Development of mouse models of angiosarcoma driven by p53
Jul 9, 2019 · Here, we describe the development of an autochthonous mouse model of angiosarcoma driven by loss of p53 in VE-cadherin-expressing endothelial cells.
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Combined mTOR and MEK inhibition is an effective therapy in a ...
May 15, 2018 · We have developed a novel mouse model for angiosarcoma that encompasses deletion of Pten, Trp53, and Ptpn12 in vascular endothelial cells.
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The use of novel lymphatic endothelial cell-specific ... - PubMed
The use of novel lymphatic endothelial cell-specific immunohistochemical markers to differentiate cutaneous angiosarcomas in dogs. Vet Comp Oncol. 2016 Sep ...Missing: species | Show results with:species