WORKUP	Section 5 of 11
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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%.

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	Section 6 of 11
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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	Section 7 of 11
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The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the cancer.

	MISCELLANEOUS	Section 9 of 11
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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.