Angiosarcoma

Synonyms and related keywords: angiosarcoma, hemangioendothelioma, lymphangioendothelioma, hemangiosarcoma, hemangioblastoma, lymphangiosarcoma, angioendothelioma, malignant angioma, malignant endothelioma, malignant neoplasm, soft tissue sarcoma, soft tissue angiosarcoma, angiosarcoma of the soft tissue, cutaneous angiosarcoma, angiosarcoma of the liver, breast angiosarcoma, angiosarcoma of the breast, bone angiosarcoma, angiosarcoma of the bone, head and neck angiosarcoma, visceral angiosarcoma, hepatic angiosarcoma, lung angiosarcoma, pulmonary angiosarcoma, heart angiosarcoma, cardiac angiosarcoma


INTRODUCTION

Background: Angiosarcomas are 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:

• In the US: Angiosarcomas are rare neoplasms. They account for approximately 1% of all soft tissue sarcomas. Physicians diagnose approximately 60 new cases of soft tissue angiosarcoma each year. The annual incidence is approximately 2-3 cases per 1,000,000 population. Because of the ubiquity of connective tissue, angiosarcomas and the rest of the soft tissue sarcomas are located throughout the body, including the extremities, head and neck, abdominal wall, and retroperitoneum.
• Approximately 50% occur in the head and neck, but they account for less than 0.1% of head and neck malignancies. Angiosarcomas of the soft tissue of the lower extremities are the next most frequent type (2- to 3-times more frequent than the upper extremity). The numbers are even smaller for visceral angiosarcomas. The most frequent of the latter are hepatic angiosarcomas, with an occurrence of approximately 25 new cases per year; followed by breast angiosarcoma, with 300 cases; and renal angiosarcoma, with 8 published cases per year. These small numbers challenge the creation of adequate guidelines for clinical management.

• Internationally: Worldwide incidence also is low. Reports show angiosarcoma of the liver with an annual incidence of 2 cases per 10 million population, rising to 2.5 cases per 1000 population in workers exposed to vinyl chloride.

Mortality/Morbidity: All angiosarcomas tend to be aggressive and often are multicentric. These tumors have a high local recurrence rate and metastasis because of their intrinsic biologic properties and because they often are 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 of less than 20%. Advanced stage at presentation and lack of extensive excision are associated with higher recurrence, distant metastasis rates, and worsened survival.

Sex:

• Cutaneous angiosarcoma and angiosarcoma of the liver are more frequent in males than in females (8:1 and 3:1, respectively). Bone angiosarcoma also is reported with a preponderance of male patients.

• Breast angiosarcoma has an obvious female predilection. In a series from Memorial Sloan Kettering Cancer Center (MSKCC) of angiosarcoma in patients younger than 21 years, the female-to-male sex ratio was 5:1.

Age:

• Although angiosarcomas can appear at any age, bone angiosarcoma appears most often in adults (second to seventh decade).

• Cutaneous angiosarcoma of the head and neck tends to occur in the elderly population.

• Angiosarcoma of the breast occurs in premenopausal women (third to fourth decade).

CLINICAL

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

• Risk factors

• Toxic exposure or radiation therapy

• Other carcinogens (eg, bone wax, Dacron, metal bodies)

• Hormonal status (eg, pregnancy, menopause) in breast angiosarcoma

• Presence or absence of weight loss, fever, growing masses, or any newly appearing or changing mole

• In chronic lymphedema, the finding of ulceration, violaceous nodules or papules, or apparent traumatic ecchymoses

• Angiosarcomas arising at different sites and in different organs have some distinct features, but they cause symptoms associated with the amount of tissue organ 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 causing associated pain

Physical: The physical examination often is unremarkable; however, subtle findings may provide clues to early detection.

• Angiosarcoma of the soft tissue (extremities, retroperitoneum, abdominal wall)

• These patients usually present with a moderately paced growing mass in the extremities. The rapid progression of the disease sometimes is 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 the bone

• 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 frequently is 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

• 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.

• Head and neck angiosarcoma (cutaneous sarcoma in elderly individuals, Wilson-Jones angiosarcoma)

• Angiosarcomas of the face usually present as nodules with ulceration, plaques, or bruiselike maculae.

• Clinical features are variable. Occasionally, the tumors are characterized with chronic edema and so-called cellulites. Angioneurotic edema and scarring alopecia are described.

• Cutaneous angiosarcoma associated with lymphedema: Consider a biopsy for ulceration, violaceous nodules, or papules in a lymphedematous area.

• Breast angiosarcoma

• In the cases reported to date, the tumor manifests as a painless and rather quickly enlarging palpable mass without tenderness. In most cases, the tumor is larger than 4 cm in diameter.
• These rapidly growing lesions often arise deep within breast tissue, causing diffuse breast enlargement with associated bluish skin discoloration. They usually spread locally as ill-defined, hemorrhagic, spongy masses.
• Unlike breast carcinomas, skin retraction, nipple discharge, and axillary lymph node involvement are absent.

• Visceral angiosarcoma

• Hepatic angiosarcoma: Patients usually present with nonspecific symptoms, including fatigue, weight loss, and right upper quadrant pain. Further workup shows hepatomegaly and ascites, which can be blood stained. The liver can be enormous with multiple masses, and a bruit may be audible. Jaundice is present in 25% of patients.
• Lung angiosarcoma: The initial symptoms usually are chest pain, hemoptysis, weight loss, cough, and dyspnea. However, some patients are asymptomatic.
• Heart angiosarcoma: Patients can be asymptomatic for a long time or they can present with symptoms mimicking acute pericarditis, pulmonary embolism, or tricuspid stenosis.

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:

• 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.

• 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.

• Thorotrast, a colloid solution containing thorium dioxide that emits alpha and beta radiation, was used by radiologists from 1930-1953 for cerebral angiography. Thorotrast exposure can result in an angiosarcoma after a latent period of decades. Approximately 25% of hepatic angiosarcomas arise in patients who received Thorotrast.

• Likewise, exposure to vinyl chloride used in polymerization in the plastic industry can lead to an angiosarcoma; the risk ratio is approximately 400-fold higher than in the general population.

• Isolated reports exist of angiosarcoma developing after use of stilboestrol or anabolic androgenic hormone therapy.

• Preexisting benign lesions: Angiosarcoma of bone may arise on a previous lesion as a bone infarct, a pagetoid bone, or chronic osteomyelitis.

DIFFERENTIALS

Angiosarcoma
Cystosarcoma Phyllodes
Hemangioblastoma
Hemangiomas, Hepatic
Kaposi Sarcoma
Metastatic Cancer, Unknown Primary Site

Other Problems to be Considered:

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

WORKUP

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:

• Angiosarcoma of the soft tissue (extremities, retroperitoneum, abdominal wall)

• MRI: This provides more accurate delineation of the extent of local disease than CT. MRI provides sagittal and coronal views and better distinction between bone, vascular structures, and tumor than CT. 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: 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.

• Angiosarcoma of the bone

• 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.

• Breast angiosarcoma

• In the first interview with the patient, note any risk factor, including history of previous breast cancer or atypical breast lesions and a history of radiation as a child or adolescent.

• Self-examination and regular gynecologic checkups are key to an early diagnosis. Masses discovered this way tend to look benign and feel mobile, without apparent fixation to the skin or chest wall. Any vascular lesion associated with a breast mass is an angiosarcoma until proven otherwise. Mammography is a method of detection rather than diagnosis, and it often fails to identify the tumor as malignant.

• MRI: This is a good diagnostic and staging tool that further characterizes focused areas of abnormality detected by clinical examination. Performing breast imaging prior to any needle aspiration is very important because bleeding after the needle stick is extremely frequent and could delay the diagnosis. After performing the fine-needle aspiration (FNA), changes resolve in 3 weeks.

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 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 appropriately excise the biopsy cavity.

• 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.

• Fine-needle aspiration

• FNA helps gather sufficient findings and cytologic features that allow recognition of this unusual neoplasm.

• In the case of breast angiosarcoma, researchers report a high incidence of histologic misdiagnosis. The false-negative rate associated with biopsy is 37%.

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:

• 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 nonimmunological 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 surgically treat the disease 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, 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 accurately determine 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

Medical Care:

• Neoadjuvant therapy in soft tissue angiosarcoma

• Multiple randomized studies using doxorubicin-based chemotherapy fail to show a survival benefit, 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.
• Neoadjuvant 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)

• Neoadjuvant 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, mercaptoethanol, and doxorubicin). If clinical or radiographic improvement is not observed, consider a second regimen with cyclophosphamide, etoposide, and cisplatin.

• Neoadjuvant therapy in cutaneous angiosarcoma
  • 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.
  • Further investigation is warranted to define the optimal treatment dose and schedule.
• Neoadjuvant therapy in breast angiosarcoma

• Although angiosarcoma of the breast is quite resistant to systemic treatment, doxorubicin-based neoadjuvant therapy is reserved for inoperable tumors and tumors larger than 5 cm in diameter involving the skin of the breast or attachment to the chest wall.
• Breast angiosarcoma is best treated with a combination of radiotherapy and chemotherapy to achieve local control. In some patients, mastectomy may be part of this treatment program. If adopting this multimodality approach, neoadjuvant chemotherapy and radiation may be attempted first in an effort to down-stage the tumor and/or render it resectable.
• Furthermore, if the tumor responds to the preoperative chemotherapy, one may consider using the same regimen as an adjuvant to improve marginal resection.

Surgical Care:

• Angiosarcoma of the soft tissue, retroperitoneum, and abdomen

• 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 the 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 angiosarcoma

• 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.

• Angiosarcoma of the breast

• The treatment of angiosarcoma of the breast is early and complete surgical excision of the mass with tumor-free margins because the neoplasm often extends microscopically beyond its gross limits. Simple excision is unacceptable secondary to its high rate of recurrence at the operative site in locally excised tumors.
• Radical mastectomy is not appropriate unless the tumor extends to the deep fascia, which necessitates the resection of the pectoral muscle. Axillary dissection is not indicated because nodal involvement is rare. The decision for mastectomy versus breast-conserving treatment depends on numerous factors, as follows:
  • The size and location of the tumor
  • The presence of multifocal (multiple sites in the same quadrant) or multicentric (multiple sites in different quadrants) disease
  • Ease in ability to follow the postoperative breast mammographically and by physical examination for evidence of recurrent cancer
  • Patient preference

• Hepatic angiosarcoma: Surgical resection is complicated by a high early recurrence rate, and, clearly, liver transplantation has no role for this endothelial cell tumor. In contrast, the results after liver transplantation in epithelioid hemangioendothelioma are acceptable.
• Pulmonary and cardiac angiosarcoma: The prognosis is very poor. Radical resection may improve survival, but the role of transplantation remains unclear.

MEDICATION

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

Drug Category: Antineoplastic agents -- Inhibit cell growth and proliferation.

Drug Name	Doxorubicin (Adriamycin) -- A cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. These drugs are structurally similar to tetracycline and interfere with DNA production by the cell. All cells can be affected, but rapidly producing cells are damaged. Active against many cancers and has been in use for decades. A clear orange-red powder or liquid only administered IV. Binds DNA and inhibits nucleic acid synthesis. Also a powerful iron chelator and iron-doxorubicin complex, induces production of free radicals that can destroy DNA and cancer cells. Functional properties of a drug can be substantially affected by liposomal encapsulation. Liposomes used in different drug products can vary in their chemical and physical properties. These differences can substantially affect functional properties among liposomal drug products. May continue treatment for as long as patient shows progress, shows no evidence of cardiotoxicity, and continues to tolerate treatment; PPE, stomatitis, or hematological toxicity may require doses to be delayed or reduced. Minimum of 4 courses recommended.
Adult Dose	Doxorubicin HCL injection (Adriamycin): 60-75 mg/m2 IV as a single dose, repeat q21d; alternatively, 20-30 mg/m2 IV qd for 3 d, repeat in 4 wk; or 20 mg/m2 qwk Doxorubicin HCl liposome injection (Doxil): 50 mg/m2 (doxorubicin HCL equivalent) IV 1 mg/min, if tolerated, increase rate of infusion to complete administration over 1 h; repeat q4wk
Pediatric Dose	35-75 mg/m2 IV as a single dose q21d; or 20 mg/m2 qwk
Contraindications	Documented hypersensitivity; in severe CHF, if LVEF is less than 40%, therapy should not be instituted; preexisting myelosuppression; previous treatment with complete cumulative doses of other anthracyclines or anthracenediones
Interactions	Decreases digoxin plasma levels and renal excretion; allopurinol may enhance antitumor activity; toxicity increases with cyclophosphamide, mercaptopurine, and streptozocin; verapamil increases cell toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Total dose should not exceed 400 mg/m2 in patients with previous or concomitant treatment (eg, cyclophosphamide, daunorubicin, radiation of cardiac region), otherwise do not exceed 550 mg/m2; irreversible cardiac toxicity may occur as total dosage approaches 550 mg/m2; extravasation results in severe local tissue necrosis

FOLLOW-UP

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 often is 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.

• Breast angiosarcoma

• Angiosarcoma of the breast is a rare and highly malignant neoplasm with few long-term survivors. Little is known about the effects of chemotherapy for patients with disseminated disease or its role in the adjuvant setting.

• In general, radiotherapy is reserved after lumpectomy (4500-5000 cGy) and following total mastectomy if the tumor is larger than 5 cm, the margins are positive, or the regional nodes or skin are affected (6000-7000 cGy).

• Multifocal lesions, locally invasive lesions, and stromal sarcoma histology tend to occur more often than other sarcomas and tend to recur locally. Consider for adjuvant therapy.

• Adjuvant chemotherapy that includes doxorubicin for patients with poorly differentiated angiosarcoma of the breast results in a higher proportion of patients who are relapse-free compared to patients not receiving adjuvant chemotherapy.

• Patients with well-differentiated tumors do not appear to benefit from adjuvant chemotherapy. The hormonal dependency of angiosarcoma still is unresolved.

Further Outpatient Care:

• Soft tissue angiosarcoma

• Recurrent neoplasms typically (80%) 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 x-ray every 6 months during this period is mandatory. If the chest x-ray 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 x-ray 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.

• Breast angiosarcoma

• For patients who underwent breast conservation therapy, perform follow-up examination every 4 months for the first 2 years, every 6 months in the third through fifth years, and then annually thereafter.
• For patients who underwent mastectomy, obtain an annual contralateral mammogram. For patients who receive both chemotherapy and a chest radiograph, limit further evaluation to annual serum biochemical evaluation.
• Bone scans, CT scans, or skeletal surveys are indicated only in symptomatic patients.

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.

• A large number of patients, 50% in some series, also had metastasis, and a significant number (20%) had local recurrences.

• 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 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 (less than 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 by local extension or metastasis.
• Delayed diagnosis and treatment explains, in part, the poor prognosis of cutaneous angiosarcomas.

• Breast angiosarcoma
  • This neoplasm carries a very poor prognosis, with a 5-year survival rate of 8-50%. Up to 90% of the patients with primary breast angiosarcoma die within 2 years of diagnosis. However, more recently, survival (lower tumor grade, smaller lesion size, prompt mastectomy) has improved. Recurrence usually is local, although hematogenous dissemination may occur. Dissemination usually involves the lungs, skin, contralateral breast bone, liver, brain, and ovary, in decreasing frequency.
  • If primary surgery fails, survival is seriously compromised because adjuvant or palliative treatments are not effective. The odds for a significant response of metastatic disease to chemotherapy are approximately 35%, with rare complete responses. If metastases are amenable to surgical extirpation, first attempt surgery for cure and reserve chemotherapy and radiation for either the immediate postoperative period or for the next failure.

Patient Education:

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

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to obtain an adequate history and physical to identify risk factors (eg, toxic exposure, radiation therapy)

• Failure to consider obtaining and documenting informed consent in individuals requiring 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 any lump or mole arising in a radiation field as an angiosarcoma

• Failure to provide adequate follow-up care to cancer survivors

Special Concerns:

• Future and controversies

• 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.

• 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 prescribed out of clinical trials.
  • Antiangiogenic drugs (eg, combrestatin, angiogenesis inhibitors [2-methoxyestradiol, TNP-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.
  • 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.
  • 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.
  • Thalidomide has been associated with tumor necrosis in small intestine angiosarcoma.