Angiosarcoma
Synonyms and keywords:  Hemangiosarcoma; Pulmonary angiosarcoma; Vascular sarcoma

# Overview
Angiosarcoma is a rare malignant vascular neoplasm of endothelial-type cells that line vessel walls. The peak age of incidence appears to be the 7th decade, and men are affected more commonly than women.  Angiosarcoma was first described by Dr. Juan Rosai, in 1976. The pathogenesis of angiosarcoma is characterized by a rapid and extensively infiltrating overgrowth of vascular endothelial cells. Angiosarcoma may arise in any part of the body, but is more common in soft tissues than in bones. Common angiosarcoma locations include the  head and neck area, kidney, liver, lung, and and the most common site of radiation-induced angiosarcoma development is the breast.  The PTPRB/PLCG1 genes are associated with the development of angiosarcoma; mutation of these genes result in aberrant angiogenesis. The imaging modality of choice for diagnosing angiosarcoma will depend on the location. For pulmonary angiosarcoma, the imaging modality of choice is CT scan with intravenous contrast. For other types angiosarcoma, the imaging modality of choice is MRI. On CT scan, findings suggestive of angiosarcoma may include vascular invasion, nodular enhancement (common), and a hypoattenuating mass. The mainstay adjuvant therapy for angiosarcoma is a doxorubicin-based regimen. The response rate for chemotherapy in patients with angiosarcoma is poor.

# Historical Perspective
- Angiosarcoma was first discovered by Dr. Juan Rosai, M.D. and colleagues in 1976.

# Classification
- Angiosarcoma may be classified according to the clinical heterogeneity into two main groups, and every group can be subdivided into subtypes according to the anatomical location and etiology:

# Pathophysiology
- The pathogenesis of angiosarcoma is characterized by a rapid and extensive infiltrating overgrowth of vascular endothelial cells.
- Angiosarcoma is a  locally aggressive tumor with a high rate of lymph node infiltration and metastases.
- Angiosarcomas demonstrate obvious unregulated vascular-specific receptor tyrosine kinases containing TIE1, KDR, TEK and FLT.
- The up-regulation of these genes and over-expression of vascular endothelial growth factor receptors can cause endothelial cell expansion, angiogenesis, and also vascular leaks in the structure of vessels.
KDR mutations are seen in primary breast angiosarcoma regardless of exposure to radiation.
High level MYC amplification is seen is seen in radiation-induced and lymphedema-associated angiosarcoma.
FLT4 amplification  has been detected in 25% of secondary angiosarcomas.
- KDR mutations are seen in primary breast angiosarcoma regardless of exposure to radiation.
- High level MYC amplification is seen is seen in radiation-induced and lymphedema-associated angiosarcoma.
- FLT4 amplification  has been detected in 25% of secondary angiosarcomas.
- On gross pathology, characteristic findings of angiosarcoma may include red/dark tan papules or noduls, which are ytpically poorly circumscribed with central earas of necrosis and hemoorrhage.
- On microscopic histopathological analysis, characteristic findings of angiosarcoma may include irregular anastomosing vascular spaces lined by  cells.
- Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots.
- The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies.
- Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of the tumor cells.

# Causes
- Common causes of angiosarcoma include exposure to vinyl chloride monomer (VCM) for prolonged periods, polyvinyl chloride (PVC) polymerisation plants, arsenic-containing insecticides, and thorium dioxide irradiation.

# Differentiating Angiosarcoma from Other Diseases
- Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass or non-healing cutaneous ulcerations.
- Cutaneous angiosarcoma must be differentiated from other diseases with non-healing cutaneous ulcerations such as basal cell carcinoma, keratoacanthoma, nodular melanoma, mycosis fungoides, kaposi sarcoma, kaposi-like hemangioendothelioma, and angiolymphoid hyperplasia.
- Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass such as atypical vascular lesions, hemangioma, glomangiosarcoma, carotid body tumor, and malignant fibrous histiocytoma of soft tissue.

# Epidemiology and Demographics
- The incidence of angiosarcomas can be calculated approximately 1.2 per 1,000.000 person.
- Angiosarcoma is more commonly observed among patients aged between 40 to 75 years old.The peak age of incidence appears is the 7th decade,
- Males are more commonly affected with angiosarcoma than females.
- The male to female ratio is 2:1.
- There is no racial predilection for angiosarcoma. however, African-Americans in the U.S are rarely affected.

# Risk Factors
Common risk factors in the development of angiosarcoma include chronic lymphedema, chronic exposure to polyvinyl chloride (PVC), radiation exposure, and exposure to Thorotrast.

# Natural History, Complications and Prognosis
- The majority of patients with angiosarcoma remain asymptomatic for years.
- Early clinical features may include nonspecific symptoms, such as pain, fatigue, malaise, and nausea.
- If left untreated, the majority of patients with angiosarcoma may rapidly progress to develop metastases.
- Common complications of angiosarcoma include Pathologic fractures, anemia, and hepatic dysfunction.
- Prognosis is generally poor; the 5-year survival rate of patients with angiosarcoma is approximately 12-33%.
- Poor prognostic factors include patient age (> 65 years), retroperitoneal location, and large tumor size.

# Diagnosis

## Diagnostic Study of Choice
- There is no single diagnostic study of choice for the diagnosis of angiosarcomas.
- The imaging modality of choice for angiosarcoma or use of punch biopsy of skin will depend on the anatomic location of lesions.
Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluating of suspicious lesions of the extremities, retroperitoneum, or abdominal wall.
CT scan is useful for evaluating lung, pleural, and mediastinal involvement.
Punch biopsy of cutaneous lesions accompanied with immunohistochemical staining provide accurate findings for diagnosis of cutaneous angiosarcoma.
- Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluating of suspicious lesions of the extremities, retroperitoneum, or abdominal wall.
- CT scan is useful for evaluating lung, pleural, and mediastinal involvement.
- Punch biopsy of cutaneous lesions accompanied with immunohistochemical staining provide accurate findings for diagnosis of cutaneous angiosarcoma.

## Staging
- According to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and by Enneking classification, soft tissue sarcomas are classified to different stages based on the primary tumor characteristics, histological grading and the local or distant tumor involvement.
- Table below provides summarized information regarding staging of angiosarcoma:

## History and Symptoms
- Angiosarcomas occur at different anatomic sites and grow insidiously, then they can present with various misleading symptoms.
- The most common clinical manifestation is a gradually enlarging, painless mass.
- Some patients complain of pain or symptoms due to compression of adjacent neurovascular structures that causes pain or edema in an extremity.
- Secondary angiosarcomas include radiation-Induced and lymphedema-associated angiosarcoma have a distinct feature, presenting as single or several ecchymotic maculopapular cutaneous lesions in the radiation field or in areas exposed to chronic lymphedema.

## Physical Examination
- Patients with angiosarcoma may appear cachexic or normal. In cutaneous angiosarcoma, physical examination findings may include:
- Primary cutaneous, head and neck and breast angiosarcoma may present with skin thickening, erythema, or bruise or skin ulceration, and blushed purple-red papule.

## Laboratory Findings
- There are no specific laboratory findings associated with angiosarcoma.

## Electrocardiogram
- There are no ECG findings associated with angiosarcoma.

## Echocardiography or Ultrasound
- On ultrasound imaging, angiosarcoma may have variable features according to the location of the tumor. It may appear as an echogenic, nodular, or lobulated mass.

## X-ray
- An x-ray may be helpful in the diagnosis of bone angiosarcoma.
- Findings on an x-ray suggestive of diagnostic include solitary lytic lesion, with irregular borders or a mixed lytic-sclerotic pattern.

## Imaging Findings
- The imaging modality of choice for angiosarcoma will depend on the location.
- For pulmonary angiosarcoma, the imaging modality of choice is CT scan with intravenous contrast.
- For other types angiosarcoma, the imaging modality of choice is MRI.

## CT Scan
On CT, findings of angiosarcoma may include vascular invasion, nodular enhancement (common), and multicentric lesions.

## MRI
- On MRI, findings of angiosarcoma may include:
T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumor and hemorrhage
T1 C+ (Gd): heterogeneous enhancement
- T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumor and hemorrhage
- T1 C+ (Gd): heterogeneous enhancement

## Other Imaging Findings
- There are no other imaging findings associated with angiosarcoma.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with angiosarcoma.

# Treatment

## Medical Therapy
- The role of adjuvant chemotherapy, is unclear. Adjuvant chemotherapy and/or radiotheray provide less mutilating surgery, and for patients with unresectable tumors or those who refuse surgery is an option.
- Since angiosarcomas are histologically anthracycline-sensitive, then initial systemic chemotherapy for unresectable and/or metastatic angiosarcomas include doxorubicin-based therapy with or without ifosfamide.
- However, taxane-based regimen may be preferred for initial therapy.
- Paclitaxel is effective for advanced angiosarcoma.
- Gemcitabine-based regimen is preferable to doxorubicin with or without ifosfamide for patients with significant clinical heart failure, due to heart-toxicity of doxorubicin.
- In addition, some vascular biologic molecules, with antiangiogenic characteristics including bevacizumab, sunitinib, and sorafenib, and with or without cytotoxic chemotherapy have shown dramatic responses in a small number of angiosarcoma patients.

## Surgery
- The mainstay of treatment for angiosarcoma is complete surgical resection with wide margins for local and locoregional disease in combination with preoperative or postoperative radiotherapy.
- Surgical resection in combination with radiation therapy is the treatment of choice for small angiosarcomas.
- Complete surgical resection with wide margins is preferred for local and locoregional angiosarcoma.
- Owing to the tendency for local infiltration, surgical resection should be associated with preoperative or postoperative radiotherapy.
- Surgery is not recommended on patients with large sized angiosarcomas.
- It usually occurs after a median of six months locally or distantly and the three-year disease-free and overall survival rates both are low.

### Primary Prevention
- There are no primary preventive measures available for angiosarcoma.

### Secondary Prevention
- There are no secondary preventive measures available for angiosarcoma.