Angiosarcoma: Causes, Symptoms, Diagnosis, and Treatment

Angiosarcoma is rare cancer that develops in the inner lining of blood and lymph vessels. it can occur anywhere in the body but most often in the skin, breast, liver, and spleen.

For every million people, one case will be diagnosed with angiosarcoma per year in the US. They make up about 1% to 2% of all sarcomas. They are most common in people over the age of 70 but can occur at any age. There is no gender bias, except in liver angiosarcoma where males are commonly affected with a ratio of 3-4:1.

Varying presentation - completely asymptomatic to non-specific symptoms like skin lesions, ulceration, shortness of breath, and abdominal pain. Multiple organ involvement is common at the time of diagnosis and makes it difficult to ascertain the origin and treatment. Angiosarcoma is an easily infiltrative tumor. It has a high rate of local recurrence and metastasis

The classification of angiosarcoma is based on its origin and the underlying risk factors that may have contributed.

• Primary cutaneous angiosarcoma – Angiosarcoma in the skin (usually the head or neck) with no underlying risk factors (lymphedema or radiation therapy).

• Lymphedema associated angiosarcoma / StewartTreves – Lymphangiosarcoma resulting from chronic lymphedema, swelling due to the build-up of lymphatic fluid. It typically happens in the breast following a mastectomy. However, it can happen anywhere.

• Parenchymal angiosarcoma – Angiosarcoma in parenchymal organs such as the liver, breast, or heart.

• Primary breast angiosarcoma – Angiosarcoma of the breast without underlying causes such as radiation therapy or lymphedema. It is rare and aggressive. The prognosis is poor.

• Secondary breast angiosarcoma – arises in the breast from underlying causes such as lymphedema or radiation, usually from radiation therapy for breast cancer. Secondary breast angiosarcoma tends to have a bad prognosis.

• Primary brain angiosarcoma – Arises in the brain. They are exceedingly rare with only a few cases reported. Imaging is nonspecific and the differential diagnosis includes most other brain tumors such as gliomas or cavernomas. Requires biopsy to confirm the diagnosis, usually after surgery. The prognosis is poor.

• Primary cardiac angiosarcoma – Arises in the heart. Despite being very rare they are the most common malignant primary heart tumor. Symptoms may include shortness of breath, chest pain(46%), hypotension, and syncope. Superior vena cava syndrome is a complication of cardiac angiosarcoma. It is often missed due to non-specific symptoms. Metastasis at the time of diagnosis is common.

• Primary liver angiosarcoma – Primary angiosarcoma of the liver is the third most common type of liver cancer. It only makes up 0.1–2.0% of all liver cancers. It is rapidly fatal. Men are more commonly affected in a ratio of 3–4:1 It often presents with non-specific symptoms such as abdominal pain, jaundice, fatigue, weight loss, and distension.

• Deep soft tissue angiosarcoma – Angiosarcoma in the deep soft tissue such as adipose tissue, ligaments, or muscles.

Angiosarcoma: Causes

• DNA damage of endothelial cells occurs, causing them to divide uncontrollably and preventing programmed death. Part of it breaks off and lodges elsewhere resulting in metastasis

• Several risk factors of DNA damage – Lymphedema, Radiation therapy, Immunosuppression, Ultraviolet radiation.

• Chemicals such as arsenic, thorotrast, and vinyl chloride.

• Genetic syndromes – About 3% of primary angiosarcomas are gene-induced, gene-associated diseases. Such as bilateral retinoblastoma, Recklinghausen neurofibromatosis, Ollier disease, Maffuci disease, Xeroderma pigmentosa, Klippel-tenancy syndrome, etc.

Angiosarcoma: Symptoms

Patients suffering from angiosarcoma present with the following symptoms −

• Cutaneous angiosarcoma – Presents as a bruise or a purplish-red papule. It may be misdiagnosed as a benign tumor, which can delay correct diagnosis and treatment. Fungation, ulceration, and bleeding can occur.

• Cardiac angiosarcoma – Shortness of breath, chest pain (46%), weight loss, anemia-like symptoms, low blood pressure, and syncope.

• Metastatic angiosarcomas – Pleural effusion, pneumothorax, or other pleural diseases (lung – most common site of metastasis). Other common sites of metastasis include the liver, bone, and lymph nodes.

Angiosarcoma: Risk Factors

• Chronic lymphedema of any origin, Stewart-Treves Syndrome.

• Radiation – High doses, usually 50 Gy or more, for gynecologic and breast cancers, Hodgkin lymphoma.

• Foreign bodies – AV fistula in renal transplant patients, shrapnel, synthetic vascular grafts, gouty tophi, arthroplasty, surgical sponges, and bone wax, etc.

• Chemical carcinogens – Thorotrast, exposure to vinyl chloride, arsenic, androgenic anabolic steroids.

• Benign and malignant tumors – Port wine stains, hemangiomas, lymphangiomas, nerve sheath tumors, and leiomyomas

• Other conditions – Neurofibromatosis, bilateral retinoblastoma, chronic immunosuppression (HIV, renal transplantation), and stasis ulcers.

Angiosarcoma: Diagnosis

Angiosarcoma can be diagnosed in the following ways −

Clinical presentation

• Diagnosis of angiosarcoma remains a challenge due to the non-specific symptoms.

• Common symptoms include abdominal discomfort, nausea, vomiting, and altered bowel habits.

• Cutaneous angiosarcoma can present as single or multiple bluish/red nodules.

• Hepatic angiosarcoma- right upper quadrant abdominal pain, jaundice, and fatigue.

• Metastasis as pleural disease, pleural effusion, or dyspnea.

Diagnostic imaging – Ultrasound, CT, and MRI.

Various markers – CD31, Von-Willebrand factor, CD34, vascular endothelial growth factor.

Angiosarcoma: Treatment

Current treatment options include surgery, radiotherapy, and chemotherapy. The outcomes of treatment vary widely, depending on site, size, and tumor type. In addition, targeted medicines and immunotherapy have been studied as promising treatments for angiosarcoma.

Surgery

• Radical surgery remains the cornerstone of all treatments for angiosarcoma.

• Due to the extensive nature and the rapid progression of the disease, positive surgical margins are common in resection.

Radiotherapy

• Radiation therapy is effective for inoperable patients with angiosarcoma and reduces the risk of postoperative recurrence.

• Efficacy of radiotherapy depends on treatment volume, treatment dose, radiation modality, and treatment technique.

• In large series of retrospective studies, large doses (>50 Gy) with wide fields are given for controlling extensive angiosarcomas, and postoperative low-dose in treating local disease following resection of the tumor within 3 weeks

• Due to the risk of radiation – Induced angiosarcoma, further radiotherapy is cautiously used in the treatment of tumors.

Chemotherapy

Adjuvant chemotherapy can benefit patients after surgery or radiotherapy, and cytotoxic chemotherapy is the main treatment method for metastatic angiosarcoma. The primary chemotherapy agents include taxanes, doxorubicin, liposome doxorubicin, and ifosfamide. For example, Paclitaxel.

Anthracycline-based regimens include the following −

• Doxorubicin

• Epirubicin

• Liposomal doxorubicin

• AD (doxorubicin, dacarbazine)

• AIM (doxorubicin, ifosfamide, mesna)

• Ifosfamide, epirubicin, mesna

Gemcitabine-based regimens include the following −

• Gemcitabine and docetaxel

• Gemcitabine and vinorelbine

• Gemcitabine and dacarbazine

Targeted therapy

Vascular endothelial growth factor targeted therapy – Tyrosine kinase inhibitors (TKI) sorafenib and pazopanib have been implemented in targeted therapy as they inhibit the VEGF/VEGFR signaling pathway.

Adrenergic receptors – Beta-adrenergic receptors are expressed in high levels in malignant vascular tumors involving angiosarcomas. Non-selective beta-blockers such as Propranolol, improve the outcomes of patients with metastatic angiosarcoma.

Angiosarcoma: Prevention

Angiosarcoma can be prevented in the following ways −

• Sun protection

• Limit exposure to certain chemicals and carcinogens

• Adopting lifestyle or dietary factors that modify cancer-causing factors or genetic predispositions, alter carcinogen metabolism, or alter end-organ effects of carcinogens

• The successful treatment of preneoplastic lesions

Conclusion

Angiosarcoma is an aggressive malignancy of endothelial tumors and represents 1-2% of all soft tissue sarcomas in humans. The etiology of angiosarcoma is not clear but there are definite risk factors including chronic lymphoedema, a history of radiation, environmental carcinogens, and certain familial syndromes.

Ultrasound, CT, and MR are diagnostic tools, but the confirmatory diagnosis requires pathological and immunohistochemical examination. The conventional treatment options include surgery, radiotherapy, and chemotherapy.