Angiosarcoma: Symptoms, Types, Causes and Treatment

Angiosarcoma is a rare, aggressive cancer originating from the cells lining blood vessels or lymphatic vessels. While uncommon, it is notorious for its rapid progression, challenging diagnosis, and poor prognosis. Despite medical advances, managing angiosarcoma remains complex, requiring a nuanced understanding of its symptoms, types, causes, and treatment options. This article provides a comprehensive, evidence-based overview, synthesizing insights from recent research.

Symptoms of Angiosarcoma

Angiosarcoma often masquerades as more benign conditions, making early recognition difficult. Its symptoms vary depending on tumor location, but certain signs tend to predominate. Being aware of these manifestations is crucial for timely diagnosis and intervention.

Symptom	Description	Frequency/Context	Source(s)
Pain	Localized or diffuse, often in affected organ	Common in spleen, liver, heart, skin	1 2 3 4 6
Swelling/Mass	Palpable lump or organ enlargement	Spleen, liver, breast, skin	1 3 4 6 10
Skin Changes	Violaceous/bluish plaques, nodules	Especially scalp/face in elderly	6 7 19
Systemic Symptoms	Fatigue, fever, weight loss, anemia	Advanced/metastatic disease	1 2 3 5
Bleeding	Hemoptysis, hemoperitoneum, hemorrhage	Lung, spleen, liver, heart involvement	1 2 3 4 5

Table 1: Key Symptoms

Pain and Swelling

Pain is a leading symptom, reflecting tumor growth or invasion. In splenic angiosarcoma, upper abdominal pain is prevalent and can be chronic or acute, sometimes due to splenic rupture 1 4. Cardiac angiosarcoma causes thoracoabdominal pain and dyspnea, while hepatic angiosarcoma often presents with abdominal pain and mass effect 2 3.

Swelling or a palpable mass is common, especially with tumors in superficial locations (skin, breast) or when visceral organs enlarge (splenomegaly, hepatomegaly) 1 3 4 10. In skin involvement, lesions may mimic benign vascular malformations.

Skin Manifestations

Cutaneous angiosarcoma, most often affecting the scalp and face of elderly people, typically presents as bluish or violaceous plaques and nodules. These lesions can be mistaken for bruises or infections, delaying diagnosis 6 7 19.

Systemic Symptoms

With advanced or metastatic disease, systemic symptoms like fatigue, unexplained fever, weight loss, and anemia are common. These reflect the tumor's aggressive nature and possible internal bleeding or bone marrow involvement 1 2 3 5.

Bleeding

Bleeding is a hallmark of angiosarcoma due to its vascular origin. This may manifest as hemoptysis (coughing up blood) in lung involvement, hemoperitoneum (blood in the abdominal cavity) with splenic or hepatic rupture, or even internal hemorrhage in cardiac angiosarcoma 1 2 3 4 5.

Types of Angiosarcoma

Angiosarcoma is not a single disease but a group of related cancers that can appear almost anywhere in the body. Understanding its subtypes is essential for accurate diagnosis and tailored management.

Type	Common Sites	Distinct Features	Source(s)
Cutaneous	Scalp, face, extremities	Elderly, UV-associated, multifocal	6 7 8 19
Visceral	Liver, spleen, heart	Aggressive, high metastasis, poor prognosis	1 2 3 4 5
Breast	Primary or post-radiation	Younger or older women, often after radiotherapy	9 10
Lymphedema-associated	Limbs	Chronic swelling, Stewart-Treves syndrome	7 9 14
Radiation-associated	Skin, breast, other	Latency years after exposure	7 9 10 14
Pyothorax-associated	Pleura	Linked to chronic infection/inflammation	11

Table 2: Major Angiosarcoma Types

Cutaneous Angiosarcoma

This is the most common form, especially in elderly white men. It predominantly affects the scalp and face, often presenting as ill-defined, bruised-like lesions that rapidly spread locally and metastasize 6 7 8 19.

Visceral Angiosarcoma

These tumors arise in internal organs—most notably the liver, spleen, and heart. They are extremely aggressive, with high rates of early metastasis and a grim prognosis 1 2 3 4 5. For example, primary hepatic and splenic angiosarcomas frequently present with pain, organ enlargement, and internal bleeding.

Breast Angiosarcoma

Breast angiosarcoma can be primary or secondary (usually developing after breast irradiation for cancer). Primary cases affect younger women, while secondary cases typically occur in older women years after radiotherapy. Both are aggressive and prone to recurrence 9 10.

Lymphedema-associated Angiosarcoma

This type, classically known as Stewart-Treves syndrome, develops in chronically swollen limbs, typically after lymph node removal or damage (e.g., post-mastectomy). The persistent lymphedema appears to foster tumor development 7 9 14.

Radiation-associated Angiosarcoma

Angiosarcoma can develop years after exposure to therapeutic radiation, most commonly in the skin or breast. The latency period can be as short as three years, with tumors arising within irradiated tissues 7 9 10 14.

Pyothorax-associated Angiosarcoma

Rarely, angiosarcoma arises in the pleura (lining of the lungs) following decades-long chronic infection or inflammation, such as tuberculous pyothorax. The risk is markedly higher in these patients than the general population 11.

Causes of Angiosarcoma

While angiosarcoma often arises without a clear cause, several risk factors and molecular mechanisms have been identified.

Cause/Factor	Mechanism/Context	Risk Increase/Notes	Source(s)
Radiation	DNA damage, chronic inflammation	3+ years post-radiotherapy; breast, skin	7 9 10 14
Chronic Lymphedema	Stagnant lymph, immune dysfunction	Stewart-Treves syndrome	7 9 14
Environmental	Vinyl chloride, arsenic, thorium dioxide	Liver angiosarcoma	3 14 18
Chronic Infection	Long-term inflammation (e.g., pyothorax)	Pleural angiosarcoma	11
Genetic Changes	Fusion genes, MYC amplification, others	NUP160-SLC43A3, c-MYC, TP53, VEGFR	8 12 14
Idiopathic	No clear cause	Most cases	7 14 18

Table 3: Causes and Risk Factors

Radiation Exposure

Therapeutic radiation, especially for breast cancer, is a well-recognized cause of secondary angiosarcoma. Tumors arise within irradiated fields, often several years after treatment, but in some cases, as early as three years post-therapy 7 9 10 14.

Chronic Lymphedema

Prolonged lymphatic swelling, particularly after lymph node removal for cancer, significantly increases risk. The classic example is Stewart-Treves syndrome, seen in post-mastectomy arms 7 9 14.

Environmental Carcinogens

Occupational exposure to chemicals such as vinyl chloride, arsenic, and thorium dioxide has been linked to hepatic angiosarcoma. These agents induce mutations and chronic inflammation in vascular endothelial cells 3 14 18.

Chronic Infection and Inflammation

Chronic inflammatory conditions, notably long-standing pyothorax following tuberculosis, can lead to pleural angiosarcoma. The risk is exponentially higher in this population compared to the general public 11.

Genetic and Molecular Factors

Recent research has uncovered genetic drivers such as the NUP160-SLC43A3 fusion gene and c-MYC amplification. Mutations in TP53 and activation of angiogenic pathways (e.g., VEGFR) also play a role, especially in secondary types 8 12 14.

Idiopathic Cases

Despite these risk factors, most angiosarcomas occur sporadically without an identifiable cause 7 14 18.

Treatment of Angiosarcoma

Treating angiosarcoma is challenging due to its aggressiveness, heterogeneity, and frequent late-stage diagnosis. Management strategies depend on tumor location, stage, and patient fitness, with ongoing research into more effective therapies.

Treatment	Indication/Setting	Efficacy/Role	Source(s)
Surgery	Localized disease	Mainstay, especially for cutaneous/breast	6 7 14 17 18 19
Radiotherapy	Adjunct or primary (if inoperable)	Local control, especially cutaneous	6 14 17 18 19
Chemotherapy	Advanced/metastatic or high-risk	Anthracyclines, taxanes, vinblastine	14 15 16 17 18 19
Targeted therapies	Advanced/relapsed disease	Anti-angiogenics (pazopanib, bevacizumab)	7 13 14 15 17 19
Immunotherapy	Selected advanced cases	Checkpoint inhibitors, promising in some	8 13 14 16 19
Combination protocols	Advanced/metastatic	Propranolol + metronomic chemo	15

Table 4: Treatment Options

Surgery

Complete surgical excision is the gold standard for localized angiosarcoma, especially for superficial tumors (skin, breast). Clear margins are critical, but multifocality and ill-defined borders often complicate surgery 6 7 14 17 18 19.

Radiotherapy

Radiation is used postoperatively to reduce recurrence risk or as primary therapy for unresectable tumors. It is particularly beneficial for multicentric or ill-defined cutaneous lesions 6 14 17 18 19.

Chemotherapy

For advanced, metastatic, or high-risk localized angiosarcomas, systemic chemotherapy is standard. Anthracyclines (doxorubicin, ifosfamide) and taxanes (paclitaxel, docetaxel) are commonly used. Paclitaxel is especially effective for scalp and facial tumors 14 15 16 17 18 19. Vinblastine-based metronomic regimens, sometimes combined with propranolol, have shown promise in small studies 15.

Targeted Therapies

Given the tumor’s vascular nature, anti-angiogenic drugs like pazopanib (a multikinase inhibitor) and bevacizumab (an anti-VEGF antibody) have been explored. While some studies demonstrate efficacy, results remain mixed, and these agents are generally reserved for refractory or relapsed cases 7 13 14 15 17 19.

Immunotherapy

Recent research underscores the potential of immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, ipilimumab) in treating selected angiosarcomas, particularly those with high tumor mutation burden or immune cell infiltration 8 13 14 16 19. Response rates vary, but some patients have achieved durable remissions.

Combination Therapies and Future Directions

Combinations of chemotherapy with repurposed drugs like propranolol (a beta-blocker) have yielded encouraging results in small cohorts, suggesting new avenues for treatment, especially in resource-limited settings 15. Ongoing research focuses on molecularly targeted agents and immunotherapy, with the hope of improving outcomes in this challenging disease 8 13 14 19.

Conclusion

Angiosarcoma is a rare but formidable cancer that requires heightened clinical suspicion, multidisciplinary management, and continued research. Here’s a summary of the key points:

• Symptoms are diverse and depend on tumor location, but pain, swelling, skin changes, systemic symptoms, and bleeding are common.
• Types include cutaneous, visceral (liver, spleen, heart), breast, lymphedema-associated, radiation-associated, and rare forms linked to chronic infection.
• Causes range from radiation and chronic lymphedema to environmental carcinogens, chronic inflammation, and emerging genetic drivers; most cases remain idiopathic.
• Treatment relies on surgery for localized disease, with radiotherapy and systemic therapies (chemotherapy, targeted agents, immunotherapy) for advanced cases. New combination protocols and molecularly targeted approaches hold promise but require further validation.

Key Takeaways:

• Early recognition and accurate diagnosis are critical given angiosarcoma’s aggressiveness.
• Multimodal treatment strategies tailored to tumor type, location, and patient factors offer the best chance for improved outcomes.
• Ongoing clinical trials and molecular research are essential to advance care and understanding of angiosarcoma.

If you or a loved one are affected by angiosarcoma, seeking care at a specialized center with expertise in rare sarcomas is crucial for optimal management and access to emerging therapies.