Practice Essentials
An angiosarcoma (AS) is an uncommon malignant neoplasm characterized by rapidly proliferating, extensively infiltrating anaplastic cells derived from blood vessels and lining irregular blood-filled spaces. Specialists apply the term angiosarcoma to a wide range of malignant endothelial vascular neoplasms that affect a variety of sites. Angiosarcomas are aggressive and tend to recur locally, spread widely, and have a high rate of lymph node and systemic metastases. The rate of tumor-related death is high. See the images below.
This is a gross specimen from a proximal humerus bone angiosarcoma. These tumors generally are red and hemorrhagic. Although the tumor has not extended into the adjacent soft tissues, cortical erosion is evident. The patient was treated with wide excision and reconstruction with a humeral spacer. The patient's next oncologic recheck showed multiple lesions, including a large destructive lesion in the right ilium extending to the sacroiliac joint and the right sacral ala. Also noted was an upper thoracic vertebral lesion, multiple indeterminate pulmonary nodules, extensive hepatic metastases most marked in the left lobe, and an indeterminate left adnexal mass.
Pathophysiology
Angiosarcomas arising at different sites and in different organs have some distinct features. Angiosarcomas may occur in any region of the body but are more frequent in skin and soft tissue. Angiosarcomas also can originate in the liver, breast, spleen, bone, or heart. [1, 2, 3, 4, 5]
The Angiosarcoma Project performed whole-exome sequencing of 47 tumors and found recurrent mutations of genes including KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, while angiosarcoma of the head, neck, face, and scalp was associated with a high tumor mutation burden and a dominant ultraviolet damage mutational signature, suggesting that ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. [6]
Etiology
The etiology of most cases of angiosarcoma is unknown. The tumors may develop as a complication of a preexisting condition. The following factors may be associated with tumor development [7, 8] :
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Radical mastectomy
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Radiotherapy
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Foreign materials
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Environmental carcinogens
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Preexisting benign lesions (eg, bone infarct, pagetoid bone, chronic osteomyelitis)
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Genetic disorders
Radical mastectomy
Chronic lymphedema is the most widely recognized risk factor, especially in angiosarcomas of the skin and soft tissue. Typically, lymphedema-associated angiosarcomas occur in women who have undergone radical mastectomy for breast carcinoma and have had chronic lymphedema for many years (Stewart-Treves syndrome) or in the leg of patients as a consequence of radical inguinal lymphadenectomy for metastases from malignant melanoma (Kettles syndrome). [9]
Chronic lymphedema occurring on a congenital, idiopathic, traumatic, or infectious basis also predisposes to angiosarcoma. The rationale for this association is the immunologic privilege of a lymphedematous region.
Radiotherapy
Radiation-induced angiosarcomas occur in the absence of chronic lymphedema after radiotherapy for carcinoma of the cervix, ovary, endometrium, or breast and Hodgkin lymphoma.
The lesion arises in the area of previous radiation, with a median interval between irradiation and the development of the new tumor of approximately 10 years. The risk of postradiotherapy sarcomas appears to augment with increasing dosage.
The diagnosis mandates that the lesion must have proven histologic differences from the primary neoplasm (carcinomas, lymphomas). Angiosarcomas of bone arising in a previously radiated bone are third in frequency after osteosarcoma and fibrosarcoma. Angiosarcoma of soft tissue is the first diagnosis in soft tissue sarcomas arising within the field of radiation, followed by malignant fibrous histiocytoma (MFH).
The Finnish Cancer registry [10] suggests that although an increased risk of angiosarcoma in cancer patients is evident, especially with breast [11] and gynecologic cancer, the excess does not appear to be strongly related to radiotherapy. Contrary to this finding, other researchers suggest that adjuvant radiotherapy increases the risk of breast angiosarcoma 9-fold. Regardless, radiation-associated angiosarcoma of the breast is rare, occurring in approximately 0.9 of 1000 cases. Reported onset is as late as 23 years following radiotherapy. [12]
In a study of breast angiosarcoma from the Swedish Cancer Registry from 1992 to 2018, 41 of the 49 cases identified were in patients who had received radiation therapy for breast cancer. The shortest latency of secondary angiosarcoma after breast cancer diagnosis was 4 years, and the cumulative incidence of angiosarcoma after breast radiation therapy increased continuously, reaching 1.4% after 20 years. [13]
Foreign materials
Some angiosarcomas are associated with foreign material introduced in the body, either iatrogenically or accidentally. This association is described with the following materials:
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Dacron
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Shrapnel
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Steel
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Plastic graft material
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Surgical sponges
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Bone wax
Environmental carcinogens
Vintners who spray vines against mildew and patients with psoriasis given prolonged treatment with Fowler solution (1% potassium arsenite) are at risk. Exposure to arsenic may increase the risk of angiosarcoma of the liver.
Dioxin, a contaminant of industrial processes, is a controversial risk factor associated with the development of soft tissue sarcomas. Likewise, exposure to vinyl chloride used in polymerization in the plastic industry can lead to angiosarcomas of liver and soft tissue.
Genetic disorders
Approximately 3% of primary angiosarcomas are associated with hereditary diseases, such as the following [14] :
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Congenital retinoblastoma
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Neurofibromatosis type 1
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Ollier disease
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Maffuci disease
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Xeroderma pigmentosum
Epidemiology
Angiosarcomas are rare neoplasms. Approximately 50% of angiosarcomas occur in the head and neck, but they account for less than 0.1% of head and neck malignancies. [15]
Around 2% of soft tissue sarcomas in general and 4% of cutaneous soft tissue sarcomas are angiosarcomas. [5] This is in contrast with the classic report of 1%. [16] A study of the Surveillance, Epidemiology, and End Results database found that the incidence of all soft tissue sarcomas from 1973 to 2006 was 5.9 per 100,000 persons. [17] This would yield an incidence of approximately 1.2 per million for angiosarcomas.
Worldwide incidence is also low; in the United Kingdom, for example, the National Cancer Intelligence Network (NCIN) reported that angiosarcomas represent 3.3% of all soft tissue sarcomas, with an incidence rate of 1.5 per million. [18]
Demographic variation includes the following:
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African Americans in the United States are rarely affected by cutaneous angiosarcoma. [15]
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Cutaneous angiosarcoma is more frequent in males than in females, with a male-to-female ratio of 2:1.
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Bone angiosarcoma appears most often in adults (second to seventh decades of life).
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Cutaneous angiosarcoma of the head and neck tends to occur in the elderly population. [15]
Prognosis
All angiosarcomas tend to be aggressive and are often multicentric. These tumors have high rates of local recurrence and metastasis because of their intrinsic biologic properties and because they are often misdiagnosed, leading to a poor prognosis and a high mortality rate. Malignant vascular tumors are clinically aggressive, difficult to treat, and have a reported 5-year survival rate around 20-35%. [22, 23, 20] Advanced stage at presentation and lack of radical or wide excision are associated with higher recurrence rates, higher distant metastasis rates, and worsened survival. This is in contrast to the 5-year survival for all types of soft tissue sarcomas, which is around 65%. [8]
Angiosarcoma of the viscera (particularly liver and heart) and retroperitoneal disease are especially associated with poor outcome. [19] In a study of 346 primary hepatic angiosarcoma (PHA) patients, the median survival was 1.9 months. Those who underwent surgical resection had a higher median survival rate of 7.7 months. Chemotherapy treatment also increased median survival to 5.1 months. [24]
More than 50% of patients develop metastatic disease, with the lung the primary organ involved. [23, 20]
Soft tissue angiosarcoma
Angiosarcoma of the soft tissue is a high-grade sarcoma with a high rate of death and short survival time. A large number of patients, 50% in some series, also had metastasis, and a significant number (20%) had local recurrences. [22, 23, 20]
Older patient age, retroperitoneum location, and larger tumor size are unfavorable prognostic factors. Approximately 66% of retroperitoneal angiosarcomas recur locally in the tumor bed and can recur diffusely throughout the peritoneal cavity (angiosarcomatosis).
Bone angiosarcoma
High-grade angiosarcomas exhibit extremely aggressive behavior with rapid local growth and early disseminated metastasis. Prognosis depends on the histologic grade, with the disease-free survival rate reported as 95% in grade 1 tumors, 62% in grade 2, and 20% in grade 3. Multicentricity does not affect prognosis.
Cutaneous angiosarcoma
Despite aggressive treatment, prognosis is poor. The median survival ranges from 15-24 months, with a 5-year survival rate of 12-33%. Local failure and metastases to local cervical lymph nodes are common. The lung is the most common site of distant metastasis, followed by the liver and bone, although these tend to occur late.
Unlike other sarcomas, grade is not useful in predicting survival. No correlation exists between appearance (eg, ulcerated, nodular, diffuse) and survival or local recurrence.
Findings of significantly favorable prognostic importance appear to be smaller tumor size (< 5 cm), complete surgical resection, and a moderate or marked lymphoid infiltrate in and around the tumor.
Unresectable lesions and metastatic disease at diagnosis suggest a dismal prognosis. Death can occur either from local extension or metastasis. Delayed diagnosis and treatment explain, in part, the poor prognosis of cutaneous angiosarcomas.
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This is a classic example of angiosarcoma associated with chronic lymphedema after lymphadenectomy and radiotherapy. The patient is a 33-year-old woman who presented with a recurrent grade 2 angiosarcoma of the soft tissue after an attempt at wide excision and skin graft. Two weeks following this procedure, she developed multiple subcutaneous erythematous nodules involving the back and overlying the right scapula region, the supraclavicular fossa, the right breast, and arm. The window shows a microphotograph of the tissue obtained from the biopsy (hematoxylin and eosin stain, original magnification X160). Histologic preparation reveals neoplastic endothelial cells showing a solid pattern with occasional mitotic figures and sporadic protruding growth into the vascular lumens.
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This is a gross specimen from a proximal humerus bone angiosarcoma. These tumors generally are red and hemorrhagic. Although the tumor has not extended into the adjacent soft tissues, cortical erosion is evident. The patient was treated with wide excision and reconstruction with a humeral spacer. The patient's next oncologic recheck showed multiple lesions, including a large destructive lesion in the right ilium extending to the sacroiliac joint and the right sacral ala. Also noted was an upper thoracic vertebral lesion, multiple indeterminate pulmonary nodules, extensive hepatic metastases most marked in the left lobe, and an indeterminate left adnexal mass.
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This radiograph is from a 27-year-old woman who had preexisting mild pain in her left clavicle for a couple of weeks. She woke up one morning with severe pain. Radiographs showed a pathological fracture through a lytic lesion. The permanent section of the needle biopsy is shown in the window and was read as a grade 1 angiosarcoma. The cell morphology varied from epithelioid to spindle-shaped with indistinct borders. Most nuclei were large and vesicular, containing irregular large eosinophilic nucleoli and frequent mitoses. Physicians also found anastomosing vascular channels lined by pleomorphic malignant cells.
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CT scan, MRI, and bone scan from a 27-year-old woman with grade 1 angiosarcoma who presented with a pathological fracture through a lytic lesion on her left clavicle. Note the expansile lytic lesion in the left clavicle accompanied by a soft tissue mass visible on the MRI. No other lesions are identifiable. Regional lymph nodes are visible by MRI, and they do not appear involved. Lungs are clear. She was treated with wide resection of the clavicle, leaving both bony ends. No further reconstruction was attempted. Eighteen months after surgery, she is free of disease and has a full range of motion in the left shoulder. The residual aesthetic deformity is minimal.
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This 71-year-old man presented with a dark lesion on his scalp. The lesion was first treated with an excisional biopsy performed by his local physician; the lesion recurred quickly. He was treated with wide excision and adjuvant radiation therapy. The specimen (hematoxylin and eosin, original magnification X12.5) shows a well-differentiated cutaneous angiosarcoma composed of irregular vascular channels.
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This young woman presented with multicentric angiosarcoma. The images show several bones of the right foot, the right distal femur, and the right patella affected with the process. The microphotograph of the specimen revealed a grade 2 angiosarcoma (hematoxylin and eosin, original magnification X100). Most bone tumors are solitary lesions with a very low incidence of multicentricity. Vascular tumors are an exception and may involve multiple bones. Angiosarcoma presents in this case as multiple lytic lesions in the same extremity.
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This is a soft tissue angiosarcoma presenting as a rapidly growing mass in the calf. This 69-year-old woman was treated with wide resection of the mass followed by external beam radiotherapy. The full-thickness graft obtained from the ipsilateral thigh at the moment of surgery aided in the closure and prevented further wound complications during the adjuvant radiotherapy. The rapid growth of soft tissue angiosarcomas explains why they are often misdiagnosed as abscesses and tentatively treated with drainage. The drainage is sanguinous, with blood clots, and hemostasis may be challenging. To avoid this problem, fine-needle aspiration should precede any attempt at incisional or excisional biopsy of a soft tissue mass.
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This 45-year-old man presented with progressive pain in his left hip. Activity-related at first, the pain turned constant. The patient described it as a dull ache and a boring sensation, with occasional stubbing episodes. The pelvic bone involvement was extensive. The patient was treated with an external hemipelvectomy. The patient survived for 1.5 years.
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Plain film of the tibia demonstrates small lucencies without internal matrix production in keeping with the diagnosis of a vascular lesion.
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Coronal T1 magnetic resonance imaging (MRI) study reveals a lesion of the diaphysis with cortical breakthrough.
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Coronal T2 magnetic resonance image shows a diaphyseal lesion with intense surrounding edema (high signal intensity).
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Axial T2 magnetic resonance image shows a heterogeneous signal lesion with cortical destruction.
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Grossly, angiosarcomas show a reddish-brown color and solid patterns.
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Foci of angiosarcomas can show well-formed vascular channels that aid in the diagnosis. These channels can be difficult to find in a large number of tumors.
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Atypical cells in solid sheets or nests are typical of this tumor and can make diagnosis on hematoxylin and eosin (H&E) sections difficult, necessitating the use of immunohistochemistry.
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CD34 immunohistochemistry highlights the vascular nature of angiosarcomas and aids in the diagnosis.
