AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

An angiosarcoma (AS) is an uncommon malignant neoplasms 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.

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.

Frequency

United States

• 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.¹
• Based on analyses of Surveillance, Epidemiology, and End Results program, 4.1% of angiosarcomas were diagnosed in the 26,758 cases of soft tissue sarcoma available for analysis from 1978-2001. This is in contrast with the classic report of 1%.² The age-adjusted incidence rate for soft tissue sarcoma was 3.1 per 100,000 men and women per year in the 2000-2004 period.³

International

Worldwide incidence is also low.

Mortality/Morbidity

All angiosarcomas tend to be aggressive and are often multicentric. These tumors have a high local recurrence rate 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%.^{4, 5} Advanced stage at presentation and lack of extensive excision are associated with higher recurrence, higher distant metastasis rates, and worsened survival.

The 5-year survival for soft tissue sarcomas is 67%.⁶ The mortality for soft tissue sarcomas was around 1.6 cases per 100,000 population in 2000.

Race

African Americans in the United States are rarely affected by cutaneous angiosarcoma.¹

Sex

• Cutaneous angiosarcoma is more frequent in males than in females, with a male-to-female ratio of 2:1.
• Bone and soft tissue angiosarcoma are also  reported to be more frequent in males.⁷

Age

• Soft tissue angiosarcoma has a peak incidence in the seventh decade of life, although a wide age range of patients (5-97 y) can be affected.⁷
• Bone angiosarcoma appears most often in adults (second to seventh decades of life).
• Cutaneous angiosarcoma of the head and neck tends to occur in the elderly population.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Angiosarcomas are insidious, and they may not produce symptoms until the disease is well advanced. History should focus on identifying risk factors; however, most patients do not have these factors.

• Risk factors  
• • Toxic exposure or radiation therapy
  • Other carcinogens (eg, bone wax, Dacron, metal bodies)
  • Lymphedema
• Angiosarcomas arising at different sites and in different organs have some distinct features, but they cause symptoms associated with the amount of organ tissue replaced.  
• • Pathologic fractures, anemia, or hepatic dysfunction
  • Other intrinsic characteristics of a malignant vascular proliferation (eg, bleeding, thrombocytopenia, or intravascular disseminated coagulation)
  • Compression of adjacent neurovascular structures that causes pain

Physical

Physical examination findings often are unremarkable; however, subtle findings may provide clues to early detection.

• Angiosarcoma of soft tissue (extremities, retroperitoneum, abdominal wall)^{2, 7}  
• • Patients with these angiosarcomas usually present with a moderately paced growing mass in the extremities. The rapid progression of the disease is sometimes the clue to the correct diagnosis.
  • Retroperitoneal angiosarcomas usually present as asymptomatic masses and generally grow to large sizes because the abdomen can accommodate tumors. Patients may present with neurologic symptoms from compression of lumbar or pelvic nerves.
  • Approximately 33% of patients have evidence of recent hemorrhage or coagulopathy, including anemia, persistent hematoma, hemothorax, hemorrhagic ascites, and gastrointestinal bleeding.
  • Frequently, the adjacent nodes are enlarged because the incidence rate of node metastasis is as high as 45% compared to other soft tissue sarcomas.
• Angiosarcoma of bone⁸
• • This type of tumor can affect any portion of the skeleton, although 33% of these tumors occur in the axial skeleton, 33% in long tubular bones, and the rest in the small bones of the hands and feet.
  • These tumors can be multifocal, affecting the same bone with multiple lesions, or multicentric, involving multiple bones of the same extremity. The patients do not present specific symptoms, although pain is common and the area is frequently tender.
  • Sometimes, swelling and increased size of the affected limb due to affectation of a superficial bone or to soft tissue extension characterize the presentation. Pathologic fractures occur in 10% of patients.
• Cutaneous angiosarcoma:^{9, 10} Four variants of cutaneous angiosarcoma are currently recognized, including angiosarcoma of the scalp and face, angiosarcoma in the context of lymphedema (Stewart-Treves syndrome), radiation-induced angiosarcoma, and epithelioid angiosarcoma.  
• • Cutaneous angiosarcoma of the scalp and face: This is the most common form of angiosarcoma. The disease is primarily located on the head and neck of elderly persons and is also known as Wilson-Jones angiosarcoma, senile angiosarcoma or malignant angioendothelioma. Most patients present with an enlarging bruise, a blue-black nodule, or an unhealed ulceration. Initially, these lesions can be confused with cellulitis, edema, bruising, or infection, leading to a delay in diagnosis. Bleeding and pain may be present. The clinical pattern of the lesions may be nodular, diffuse, or ulcerated.
  • Cutaneous angiosarcoma associated with lymphedema: Lymphedema-associated angiosarcoma (LAS) was first reported by Stewart and in 6 patients with postmastectomy lymphedema. In each case, angiosarcoma developed in the ipsilateral arm and occurred several years after mastectomy. Subsequently, LAS was reported after axillary node dissection for melanoma and in the context of congenital lymphedema, filarial lymphedema, and chronic idiopathic lymphedema. The risk for developing LAS 5 years after mastectomy is approximately 5%. The most common site is the medial aspect of the upper arm. LAS presents as a violaceous plaque or nodule superimposed on brawny, nonpitting edema. Ulceration may develop rapidly.
  • Radiation induced angiosarcoma: Lesions occur in the radiation field 4-40 years after irradiation. Exposure to thorotrast may lead many years later to liver angiosarcoma.
  • Epithelioid angiosarcoma is a rare, recently described variant with an aggressive course. Death occurs 2-3 years after presentation.

Causes

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:^{10, 6}

• Radical mastectomy  
• • Chronic lymphedema is the most widely recognized, 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).
  • Chronic lymphedema occurring on a congenital, idiopathic, traumatic, or infectious basis also predisposes to angiosarcoma. The rationale for this association is the status of 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 disease.
  • The lesion arises in the area of previous radiation, with an 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 patient 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 registry¹¹ suggests that although an increased risk of angiosarcoma among cancer patients is evident, especially with breast¹² and gynecological cancer, the excess does not appear to be strongly related to radiotherapy. Contrary to this finding, based on 135 soft tissue sarcomas identified in 194,798 women in the SEER database, Huang and Mackillop¹³ reported a 16-fold increased risk (95% CI, 6.6-38.0) of angiosarcoma (based on 27 cases) and a 2-fold increased risk (95% CI, 1.4-3.3) of other sarcomas in breast cancer patients who had received radiation therapy, compared to those who had not.¹⁴ 
• Foreign materials  
• • Some angiosarcomas are associated with foreign material introduced in the body, either iatrogenically or accidentally.
  • This association is described with Dacron, shrapnel, steel, plastic graft material, surgical sponges, and bone wax.
• Angiosarcoma associated with environmental carcinogens  
• • Vintners who spray vines against mildew and patients with psoriases 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.
• Angiosarcoma occurs with increased frequency in those with AIDS.
• Preexisting benign lesions: Angiosarcoma of bone may arise on a previous lesion as a bone infarct, a pagetoid bone, or chronic osteomyelitis.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Amelanotic melanoma
Spindle-cell malignant melanoma
Pyogenic granuloma
Leiomyosarcoma
Fibrosarcoma
Liposarcoma

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

Similar to most cancers of mesenchymal origin, little or nothing is demonstrated by blood work, although the sudden development of profound thrombocytopenia in patients with angiosarcoma may either suggest rapid growth of the primary tumor or herald the development of metastatic disease.

Imaging Studies

• Soft tissue angiosarcoma (extremities, retroperitoneum, abdominal wall)  
• • MRI: This provides more accurate delineation of the extent of local disease than CT scan. MRI provides sagittal and coronal views and better distinction between bone, vascular structures, and tumor than CT scan. MRI or plain radiographs should address the possibility of bone invasion by the tumor. MRI is the imaging modality of choice to evaluate the tumor response to preoperative radiation or chemotherapy. It can detect changes in tumor size and in the relationship of the mass to adjacent vital structures and can identify areas of intratumoral necrosis or hemorrhage, especially with the use of static or dynamic gadolinium-enhanced imaging techniques.
  • Chest CT scan: This test is more sensitive, although less specific, than conventional tomography in the detection of lung, pleural, and mediastinal metastasis. Searches for bone and brain metastasis rarely are indicated unless symptoms of affectation of these organs are present.
• Bone angiosarcoma¹⁵  
• • Radiography: The radiographic presentation of bone angiosarcoma is not specific, but plain radiographic assessment is paramount to characterize lesions and confirm their multiplicity. A solitary lesion (60% of cases) presents as a destructive lytic mass with irregular borders or a mixed lytic-sclerotic pattern and occasional bony expansion. High-grade lesions exhibit features of complete cortical destruction and extension into soft tissue. The vascular nature of the neoplasm can be suggested if synchronous multicentric involvement of several bones of one extremity or anatomic region is present (40% of cases). Bone angiosarcoma can present a distinctive pattern of soap-bubble lesions because it frequently extends up and down the bone. When the spine is involved, the most common pattern is regional involvement in several contiguous vertebral bodies.
  • CT scan: This test confirms the permeative, invasive character of the radiographic lesions and their multiplicity.
  • MRI: The test findings show a nonspecific decreased or variable signal intensity in T1 and an increased signal in T2. The lesions enhance with gadolinium. MRI is especially helpful in the characterization of the soft tissue extension and involvement of neurovascular structures and joints.
  • Bone scan: Delayed whole-body bone scintigraphy shows marked radioisotope uptake, although findings can be negative in aggressive destructive lesions. Radionuclide-tagged RBC scanning is helpful in the differential diagnosis with other multifocal vascular processes of bone and multiple myeloma or Langerhans cell histiocytosis.
• Cutaneous sarcoma: Both CT scan of the head and neck and MRI help in the preoperative planning to evaluate the extent of bone and soft tissue involvement, respectively. These studies help in identifying cervical lymph node affectation.

 See related CME at Imaging in the Era of Molecular Medicine.

Procedures

• Biopsy  
• • Early detection by means of biopsy offers the only realistic chance of a cure. Diagnosis is based on the microscopic features of the biopsy or specimen and the ultrastructural and histochemical markers.
  • Appropriate biopsy of an extremity lesion requires avoiding several potential pitfalls. Core-needle biopsies and fine-needle aspiration (FNA) are accurate tools; however, larger samples of tissue may be necessary to obtain sections of viable tissue adequate for determination of grade and histologic type.
  • Orient the biopsy incision along the long axis of an extremity or parallel to the dominant underlying muscle group on the trunk. An improper biopsy incision may result in a significantly larger surgical defect than otherwise would be necessary to excise the biopsy cavity appropriately.
  • In turn, this may result in significantly larger postoperative radiotherapy fields to encompass all tissues at risk. A poorly oriented biopsy tract can even challenge the planned limb salvage procedure.
  • The need for adequate hemostasis after a biopsy cannot be overemphasized. Extravasation of blood allows dissemination of tumor cells and therefore increases the volume of tissue requiring treatment.

Histologic Findings

All angiosarcomas have similar microscopic findings, with vascular spaces more or less obvious and lined by tumor cells showing atypia. Low-grade lesions have vascular spaces lined by large plump endothelial cells that penetrate the stroma and papillary fronds of cells that project into the lumen. Higher-grade lesions are more cellular, with atypical cells and abnormal mitoses.

The main problem in the diagnosis of angiosarcoma is histopathologic recognition. Angiosarcoma may be confused with vascular tumors of intermediate malignancy (eg, epithelioid and spindle cell hemangioendotheliomas, histioid hemangioma, and malignant endovascular papillary angioendothelioma). In its more benign form, angiosarcoma may be confused with hemangiomas. In its more aggressive form, irregular sheets of anaplastic cells may have only poorly defined vascular channels and may be difficult to differentiate from anaplastic melanomas and carcinomas.

These tumors also are distinct from other malignant vasoformative tumors, including Kaposi sarcoma and malignant hemangiopericytoma. The diagnosis of angiosarcoma can be confirmed by immunohistochemical staining, described as follows:⁷

• The ultrastructure of tumor cells includes intercellular and intracellular lumina with or without red cells.
• In their cytoplasm, tumor cells contain intermediate filaments (vimentin, occasional tonofilaments [keratin]) and pinocytotic vesicles.
• Weibel-Palade bodies, a marker of endothelial differentiation, may be seen in some cases.
• The vast majority of lesions express vimentin and focally factor VIII–related antigen. Also expressed are CD34 (74%), BNH9 (an endothelial marker, 72%), and cytokeratins (35%).
• Some of the tumors show actin expression, demonstrating a prominent pericytic component. Epithelial membrane antigen is not expressed, which helps to rule out a carcinoma.
• S100 protein and gp100 (HMB-45 antigen, both melanocytic markers) also are not expressed; this helps to rule out melanoma.
• Researchers have shown that anti-CD31 antibodies are one of the most specific endothelial cell markers. However, several other immunohistochemical markers (against factor VIII–associated antigen or the nonimmunologic binding to Ulex Europeans) should be used to avoid misdiagnosis.

Staging

The characteristics of the primary tumor (T), spread to regional lymph nodes (N), and the involvement by the tumor of distant lymph nodes and other distant organs and tissues (metastasis, ie, M), form the basis of the American Joint Committee on Cancer (AJCC) staging of cancer and are used widely in the United States. The T, N, and M are further divided into Tx, T0, T1, T2, T3, T4; Nx, N0, N1, N2, N3; and Mx, M0, and M1. Tx indicates that the primary tumor cannot be assessed. This indicates carcinoma in situ, and stage IV indicates metastasis.

• Stage I: Localized and resectable tumor is found in 1 location of the liver and could be treated surgically.
• Stage II: Localized and possibly resectable primary tumor is found in 1 or more locations in the organ and may be treated surgically. The decision to treat the disease surgically depends on the experience of the physician.
• Stage III: Advanced cancer has spread to more than 1 location in the organ and/or to other parts of the body. Frequently these tumors require multiple treatment modalities for maximum benefit. Often, surgical resection does not provide benefit to the patient.
• Stage IV: Disseminated cancer involves multiple sites throughout the body. Frequently, surgery is not indicated, and chemotherapy is the best option.
• For bone and soft tissue sarcomas in adults,² the 2 most commonly used staging systems are those developed by the AJCC and by Enneking. In children, the Intergroup Rhabdomyosarcoma Study and the International Union Against Cancer describe the systems used most commonly. These systems for soft tissue sarcomas rely on an ability to determine accurately both the local and distant extent of disease.  
• • Ia - Low grade, intracompartmental G1/T1/M0
  • Ib - Low grade, extracompartmental G1/T2/M0
  • IIa - High grade, intracompartmental G2/T1/M0
  • IIb - High grade, extracompartmental G2/T2/M0
  • IIIa - Low or high grade, intracompartmental G1-G2/T1/M1 with metastases
  • IIIb - Low or high grade, extracompartmental G1-2/T2/M1 with metastases

TREATMENT

Section 6 of 11  

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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Adjuvant therapy in soft tissue angiosarcoma^{7, 16}
• • Multiple randomized studies using doxorubicin-based chemotherapy fail to show a survival benefit from neoadjuvant chemotherapy, although metaanalysis suggests improved local control and disease-free survival with chemotherapy, but no survival advantage.
  • Because of the poor results (40-50% with the most active regimens) and the significant toxicity, specialists reserve preoperative chemotherapy for patients with high-grade lesions. Continue using the regimen for those patients who respond with tumor shrinkage after 2-3 courses of multiagent chemotherapy after tumor resection.
  • Offer patients with unresponsive tumors different treatment regimens. Response to neoadjuvant chemotherapy can be observed, but it does not always correlate with radiographic response.
  • Radiotherapy: The use of irradiation in conjunction with surgery continues to evolve and results in 80% of local control and excellent functional and cosmetic outcome. However, consider that 50% of angiosarcomas have distant metastasis, and irradiation does not improve survival. Better definition of the extent of the disease with the use of MRI helps to further delineate the radiotherapy fields and decrease long-term morbidity. Intraoperative radiation, brachytherapy, or more external beam therapy can complement preoperative external beam radiotherapy. The advantages and disadvantages are as follows:
  • • Advantages of preoperative radiation - Optimization for surgery, smaller volume of external beam fields, less hypoxic tissue, potential to reduce the chance of intraoperative implantation, and potential improvement in local control in advanced tumors
    • Disadvantages - Higher wound complication rate may delay surgery (1 wk of healing per 10 Gy of radiation delivered)
  • Surgery combined with radiotherapy appears to afford the best local control rates.⁵
• Adjuvant therapy in bone angiosarcoma
• • Evidence of multicentricity must be sought before making any decision regarding therapy. Some patients present with lesions affecting 45 different bones. In these cases, consider neoadjuvant chemotherapy.
  • A chemotherapeutic regimen common for sarcomatous tumors can be administered (ifosfamide and doxorubicin used together or sequentially). If clinical or radiographic improvement is not observed, consider a second regimen with cyclophosphamide, etoposide, and cisplatin. Gemcitabine may be effective as second line or third-line therapy.
• Adjuvant therapy in cutaneous angiosarcoma¹⁶
• • The role of chemotherapy in cutaneous angiosarcoma has not yet been established, although for patients with metastasis or tumors deemed unresectable, doxorubicin (intraarterial or systemic) is indicated.
  • Recent studies present paclitaxel as a single agent with substantial activity against angiosarcoma of the scalp or face, even in patients previously treated with chemotherapy or radiation therapy.¹⁷ Further investigation is warranted to define the optimal treatment dose and schedule.
  • The best outcomes are reported with surgery followed by radiotherapy.

Surgical Care

• Angiosarcoma of the soft tissue, retroperitoneum, and abdomen²
• • Target obtaining wide surgical margins, with at least 2 cm of unaffected tissue surrounding the tumor. The resection should include skin when applicable and the soft tissue around the angiosarcoma. Include biopsy sites, including the biopsy tract, en bloc with the specimen.
  • Resection of large lesions can be extremely difficult and sometimes requires amputation for local control; however, local control does not prevent distant relapse.
  • Free surgical margins sometimes have anatomic constraints, especially in retroperitoneal tumors.
• Angiosarcoma of  bone
• • Surgical resection and radiation therapy are the standard treatment for localized disease.
  • Low-grade lesions lead to similar benefits with either technique.
  • Treat high-grade lesions as malignant bone neoplasms, with a combination of radical en bloc excision followed by radiotherapy and/or chemotherapy.
  • The number of lesions in a limb may render limb salvage impossible, and amputation may be indicated.
• Cutaneous angiosarcoma¹⁰
• • Surgical treatment is contraindicated in tumors extending into vital structures, in those of massive size, or in those with multicentricity.
  • The lesion may be solitary or multicentric and frequently extends laterally throughout the dermis, making gross assessment of surgical margins difficult and necessitating multiple biopsies of the surrounding tissues.
  • In the primary treatment of angiosarcomas of the scalp, recognizing the horizontal and vertical extensions of the tumor is essential, which can only be discerned by microscopic examination of all the margins of the resected specimen. The primary excision of the scalp should be full-thickness, including the pericranium and, if indicated, the outer table of the cranial vault. The margins should be wide (at least 5 cm) on all sides.

MEDICATION

Section 7 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the cancer.

Drug Category: Antineoplastic agents

Inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Soft tissue angiosarcoma  
• • With larger higher-grade angiosarcomas, adjuvant radiotherapy is effective in reducing local recurrence.
  • Postoperative radiotherapy can be delivered intraoperatively, by brachytherapy, or by external beam. The brachytherapy technique results in rates of tumor control similar to those obtained with external beam, with a similar rate of wound complications. Moreover, it presents the advantage of requiring only 5 days, rather than the 5-6 weeks needed for external beam, and reduces radiation scatter.
  • Brachytherapy is often the technique of choice in angiosarcomas near joints or gonads.
• Bone angiosarcoma: Specialist use combinations of radiation therapy and chemotherapy as adjuvant methods of treatment, but significant data about their effectiveness are lacking.
• Cutaneous angiosarcoma  
• • Postoperative radiotherapy is warranted in cases with unsatisfactory margins, large tumor size, deep extension, and multicentricity.
  • Radical radiation therapy in the form of high-field electron beam therapy shows promise in prolonging survival of patients with localized lesions.

Further Outpatient Care

• Soft tissue angiosarcoma  
• • Recurrent neoplasms typically (80% of cases) develop within 2 years of the resection. Thus, the follow-up should be extremely stringent, ie, every 3 months in the first 2 years.
  • A chest radiograph every 6 months during this period is mandatory. If the chest radiograph reveals a suspicious nodule, obtain a CT scan of the chest for confirmation.
  • MRI is the most accurate technique for detecting locally recurrent or residual sarcoma. The baseline postoperative MRI examination serves a vital role in the evaluation.
  • After the first 2 years, schedule visits every 6 months for the next 3 years. After 5 years, see patients annually.
  • The following is a differential diagnosis for signal abnormality on a postoperative MRI:
  • • The residual or recurrent neoplasm usually is a discrete, ovoid, or rounded soft tissue mass. Nonspecific signal characteristics are present, with intermediate-to-low signal intensity in T1-weighted images and high signal on T2-weighted images. It enhances with gadolinium. Comparison with prior postoperative examinations is essential.
    • Postsurgical/postradiation change usually appears as a regional distribution of signal abnormality, with a linear, trabeculated, or latticelike morphology. This has low-to-intermediate signal on T1-weighted images and high signal on T2-weighted images.
    • Scars show a linear morphology. Scars correspond with skin thickening and the loss of adjacent subcutaneous fat. A scar has low signal on both T1-weighted images and T2-weighted images, although they can present a linear high-signal intensity on T2-weighted images and a variable enhancement with gadolinium.
    • Fluid collection develops as an abscess, seroma, or hematoma. Seromas are the most common. They represent a signal intensity lower than muscle on T1-weighted images and high signal on T2-weighted images and are differentiable from recurrence with gadolinium. Hematomas usually appear in the subacute stage at the time of the first postoperative MRI. Hematomas show a characteristic high signal on T1-weighted images and T2-weighted images from the methemoglobin. Abscesses present as low signal on T1-weighted images and high signal on T2-weighted images and may show some low-signal intensity depending on the presence of a fibrous capsule. Following gadolinium administration, they appear as a nonenhancing fluid collection with a thick, nodular, peripherally enhancing rim.
• Bone angiosarcoma: The follow-up is similar to that outlined for the soft tissue angiosarcomas.
• Cutaneous angiosarcoma  
• • Patients need clinical examination every 3 months to detect possible recurrences. Palpation of the cervical lymph nodes remains a major tool.
  • Imaging studies include CT scan and MRI of the head and neck and plain chest radiograph and CT chest scans every 3 months for 1 year, every 6 months for 2 more years, and then annually. Distant metastasis can occur in a late fashion.

Deterrence/Prevention

• Prevention of angiosarcoma is included in cancer prevention guidelines. The reduction of cancer mortality is achieved via reduction in the incidence of cancer.
• Prevention strategies include avoiding carcinogens and adopting lifestyle or dietary factors that modify cancer-causing factors or genetic predispositions, alter of carcinogen metabolism, or alter end-organ effects of carcinogens. Prevention also includes the successful treatment of preneoplastic lesions.

Complications

• Neurovascular injury
• Range of motion and strength
• Complications from radiotherapy
• • Wound complications
  • Fractures
• Complications from chemotherapy
• • Fever
  • Dose-dependent myelosuppression
  • Nausea and vomiting unresponsive to antiemetics
  • Moderate-to-severe fatigue
  • Alopecia or hemialopecia in intraarterial chemotherapy
• Complications from surgery
• • Anesthetic complications
  • Blood loss
  • Infection, sepsis
  • Wound complications
  • Iatrogenic neurovascular injury
  • Deep vein thrombosis, pulmonary embolism
  • Limited limb function

Prognosis

• 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.⁷
  • 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^{1, 9}  
• • Despite aggressive treatment, prognosis is poor. The median time of 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 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.

Patient Education

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Mastectomy and Breast Cancer.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to obtain an adequate history and thorough enough physical examination to identify risk factors (eg, toxic exposure, radiation therapy)
• Failure to consider obtaining and documenting informed consent in individuals who require the use of materials previously related to the development of angiosarcoma (eg, Dacron grafts, bone wax, surgical sponges, metal foreign bodies)
• Failure to consider changes in signs or symptoms as a possible manifestation of local or distant relapse
• Failure to consider a diagnosis of angiosarcoma for any lump or mole arising in a radiation field
• Failure to provide adequate follow-up care to cancer survivors

Special Concerns

Future and controversies for angiosarcoma treatment

• Chemotherapy with doxorubicin may be promising for metastatic and/or unresectable tumors, although few studies compare intraarterial versus systemic chemotherapy and the role of preoperative versus postoperative radiotherapy.
• Liposomal encapsulation of doxorubicin may reduce cardiac effects and overcome multidrug resistance 1 (MDR-1). Positron emission tomography scanning measures metabolic activity of the tumor and may become an additional imaging technique to correlate with tumor grade.
• Paclitaxel as a single agent has substantial activity against angiosarcoma of the scalp or face, even in patients previously treated with chemotherapy or radiation therapy. Further investigation is warranted to define the optimal treatment dose and schedule.¹⁷
• Several recent approaches attack a proliferating endothelium. Close interactions between endothelial cells and the bloodstream appear to make the vasculature a practical target for tumor therapy. Most of these therapies use drugs that have not been approved for use by the US Food and Drug Administration or drugs approved for other uses. Caution should be used when these drugs are prescribed out of clinical trials.
• • Antiangiogenic drugs (eg, combrestatin, angiogenesis inhibitors [2-methoxyestradiol, CNTOT 95, NP-470]) cut off the blood supply to tumors. Interferon alfa-2a has shown antiangiogenesis activity through down-regulation of basic fibroblast growth factor, which is commonly overexpressed in angiosarcoma. Good responses to this treatment have been reported.^{18, 15}
  • After demonstrating that rapidly proliferating tumor endothelial cells are susceptible to immunotoxins in experimental models, specific antibodies conjugated with efficient cytotoxins (eg, ricin), virus (eg, parvovirus) or radioactive isotopes may be used to target the tumor vessels.¹⁹
  • Radiotherapy following treatment with radiosensitizers (eg, halogenated pyrimidines, platinum salts, gadolinium porphyrins) has been especially helpful in treating tumors when surgery is considered too risky or is contraindicated.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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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Media type:  Photo

Media file 2:  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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Media type:  MRI

Media file 3:  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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Media type:  X-RAY

Media file 4:  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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Media type:  CT

Media file 5:  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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Media file 6:  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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Media type:  X-RAY

Media file 7:  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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Media file 8:  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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Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Sturgis EM, Potter BO. Sarcomas of the head and neck region. Curr Opin Oncol. May 2003;15(3):239-52. [Medline].
2. Soft Tissue Tumors. Enzinger FM, Weiss SW, eds. Soft Tissue Tumors. 3^rd ed. St. Louis, Mo: Mosby; 1995:648-77.
3. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases. Int J Cancer. Dec 15 2006;119(12):2922-30. [Medline].
4. Lezama-del Valle P, Gerald WL, Tsai J, et al. Malignant vascular tumors in young patients. Cancer. Oct 15 1998;83(8):1634-9. [Medline].
5. Mark RJ, Poen JC, Tran LM, Fu YS, Juillard GF. Angiosarcoma. A report of 67 patients and a review of the literature. Cancer. Jun 1 1996;77(11):2400-6. [Medline].
6. Schottenfeld D, Fraumeni J, eds. Cancer. Epidemiology and Prevention. 3^rd ed. New York: Oxford University Press; 2006:763-786/959-974.
7. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol. Jun 1998;22(6):683-97. [Medline].
8. Wenger DE, Wold LE. Malignant vascular lesions of bone: radiologic and pathologic features. Skeletal Radiol. Nov 2000;29(11):619-31. [Medline].
9. Morgan MB, Swann M, Somach S, et al. Cutaneous angiosarcoma: a case series with prognostic correlation. J Am Acad Dermatol. Jun 2004;50(6):867-74. [Medline].
10. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 8^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008.
11. Virtanen A, Pukkala E, Auvinen A. Angiosarcoma after radiotherapy: a cohort study of 332 163 Finnish cancer patients. The British Journal of Cancer. Jul 2007;97:115. [Medline].
12. Patton KT, Deyrup AT, Weiss SW. Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Am J Surg Pathol. Jun 2008;32(6):943-50. [Medline].
13. Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer. 2001;Jul 1;92(1):172-80. [Medline].
14. USA: National Cancer Institute (NCI); 2000-2004. The Surveillance, Epidemiology, and End Results (SEER) Program. Available at http://seer.cancer.gov/.
15. Mullamitha SA, Ton NC, Parker GJ, Jackson A, Julyan PJ, Roberts C, et al. Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res. Apr 2007;13(7):2128-35. [Medline].
16. Budd GT. Management of Angiosarcoma. Curr Oncol Rep. 2002;4(6):515-519. [Medline].
17. Skubitz KM, Haddad PA. Paclitaxel and pegylated-liposomal doxorubicin are both active in angiosarcoma. Cancer. Jul 15 2005;104(2):361-6. [Medline].
18. Vogt T, Hafner C, Bross K, et al. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamidein patients with advanced malignant vascular tumors. Cancer. Nov 15 2003;98(10):2251-6. [Medline].
19. Liekens S, Verbeken E, De Clercq E, Neyts J. Potent inhibition of hemangiosarcoma development in mice by cidofovir. Int J Cancer. Apr 15 2001;92(2):161-7. [Medline].
20. Espat NJ, Lewis JJ, Woodruff JM, Antonescu C, Xia J, Leung D, et al. Confirmed angiosarcoma: prognostic factors and outcome in 50 prospectively followed patients. Sarcoma. 2000;4(4):173-7. [Medline].
21. Kantarjian H, Wolff R, Koller C. MD Anderson Manual of Medical Oncology. New York, NY: McGraw Hill; 2006.
22. NCCN. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Available at http://www.nccn.org/professionals/physician_gls/default.asp.
23. Adami H, Hunter D, Trichopoulos D, eds. Textbook of Cancer Epidemiology. 2^nd ed. Oxford University Press; 2008.

Article Last Updated: Jun 25, 2008