Angiosarcoma

Angiosarcomas arising at different sites and in different organs have some distinct features. Angiosarcomas may occur in any region of the body but are more frequent in skin and soft tissue. Angiosarcomas also can originate in the liver, breast, spleen, bone, or heart.[1, 2, 3, 4]

The Angiosarcoma Project performed whole-exome sequencing of 47 tumors and found recurrent mutations of genes including KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, while angiosarcoma of the head, neck, face, and scalp was associated with a high tumor mutation burden and a dominant ultraviolet damage mutational signature, suggesting that ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial.[5]

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[6, 7] :

• Radical mastectomy
• Radiotherapy
• Foreign materials
• Environmental carcinogens
• AIDS
• Preexisting benign lesions (eg, bone infarct, pagetoid bone, chronic osteomyelitis)
• Genetic disorders

Radical mastectomy

Chronic lymphedema is the most widely recognized risk factor, especially in angiosarcomas of the skin and soft tissue. Typically, lymphedema-associated angiosarcomas occur in women who have undergone radical mastectomy for breast carcinoma and have had chronic lymphedema for many years (Stewart-Treves syndrome) or in the leg of patients as a consequence of radical inguinal lymphadenectomy for metastases from malignant melanoma (Kettles syndrome).[2]

Chronic lymphedema occurring on a congenital, idiopathic, traumatic, or infectious basis also predisposes to angiosarcoma. The rationale for this association is the immunologic privilege of a lymphedematous region.

Radiotherapy

Radiation-induced angiosarcomas occur in the absence of chronic lymphedema after radiotherapy for carcinoma of the cervix, ovary, endometrium, or breast and Hodgkin lymphoma.

The lesion arises in the area of previous radiation, with 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 lesion must have proven histologic differences from the primary neoplasm (carcinomas, lymphomas). Angiosarcomas of bone arising in a previously radiated bone are third in frequency after osteosarcoma and fibrosarcoma. Angiosarcoma of soft tissue is the first diagnosis in soft tissue sarcomas arising within the field of radiation, followed by malignant fibrous histiocytoma (MFH).

The Finnish Cancer registry[8]  suggests that although an increased risk of angiosarcoma in cancer patients is evident, especially with breast[9]  and gynecologic cancer, the excess does not appear to be strongly related to radiotherapy. Contrary to this finding, other researchers suggest that adjuvant radiotherapy increases the risk of breast angiosarcoma 9-fold. Regardless, radiation-associated angiosarcoma of the breast is rare, occurring in approximately 0.9 of 1,000 cases. Reported onset is as late as 23 years following radiotherapy.[10]

Foreign materials

Some angiosarcomas are associated with foreign material introduced in the body, either iatrogenically or accidentally. This association is described with the following materials:

• Dacron
• Shrapnel
• Steel
• Plastic graft material
• Surgical sponges
• Bone wax

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.

Genetic disorders

Approximately 3% of primary angiosarcomas are associated with hereditary diseases, such as the following[11] :

• Congenital retinoblastoma
• Neurofibromatosis type 1
• Ollier disease
• Maffuci disease
• Xeroderma pigmentosum

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.[12]

Around 2% of soft tissue sarcomas in general and 5.4% of cutaneous soft tissue sarcomas are angiosarcomas[1] . This is in contrast with the classic report of 1%.[13] The incidence of soft tissue sarcomas from 1973 to 2006 was 5.9 per 100,000 persons.[14]

Worldwide incidence is also low; in the United Kingdom, for example, the National Cancer Intelligence  Network (NCIN) reported that angiosarcomas represent 3.3% of all soft tissue sarcomas, with an incidence rate of 1.5 per million.[15]

Demographic variation includes the following:

• African Americans in the United States are rarely affected by cutaneous angiosarcoma. ^[12]
• Cutaneous angiosarcoma is more frequent in males than in females, with a male-to-female ratio of 2:1.
• Bone and soft tissue angiosarcoma have a similar sex distribution. ^{[1, 16, 17]}
• 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. ^[12]

All angiosarcomas tend to be aggressive and are often multicentric. These tumors have high rates of local recurrence and metastasis because of their intrinsic biologic properties and because they are often misdiagnosed, leading to a poor prognosis and a high mortality rate. Malignant vascular tumors are clinically aggressive, difficult to treat, and have a reported 5-year survival rate around 20-35%.[3, 18, 16]  Advanced stage at presentation and lack of radical or wide excision are associated with higher recurrence rates, higher distant metastasis rates, and worsened survival. This is in contrast to the 5-year survival for all types of soft tissue sarcomas, which is around 65%.[7]  

Angiosarcoma of the viscera (particularly liver and heart) and retroperitoneal disease are especially associated with poor outcome.[1]  In a study of 346 primary hepatic angiosarcoma (PHA) patients, the median survival was 1.9 months.  Those who underwent surgical resection had a higher median survival rate of 7.7 months. Chemotherapy treatment also increased median survival to 5.1 months.[19]

More than 50% of patients develop metastatic disease, with the lung the primary organ involved.[18, 16]

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.[3, 18, 16]

Older patient age, retroperitoneum location, and larger tumor size are unfavorable prognostic factors. Approximately 66% of retroperitoneal angiosarcomas recur locally in the tumor bed and can recur diffusely throughout the peritoneal cavity (angiosarcomatosis).

Bone angiosarcoma

High-grade angiosarcomas exhibit extremely aggressive behavior with rapid local growth and early disseminated metastasis. Prognosis depends on the histologic grade, with the disease-free survival rate reported as 95% in grade 1 tumors, 62% in grade 2, and 20% in grade 3. Multicentricity does not affect prognosis.

Cutaneous angiosarcoma

Despite aggressive treatment, prognosis is poor. The median survival ranges from 15-24 months, with a 5-year survival rate of 12-33%. Local failure and metastases to local cervical lymph nodes are common. The lung is the most common site of distant metastasis, followed by the liver and bone, although these tend to occur late.

Unlike other sarcomas, grade is not useful in predicting survival. No correlation exists between appearance (eg, ulcerated, nodular, diffuse) and survival or local recurrence.

Findings of significantly favorable prognostic importance appear to be smaller tumor size (< 5 cm), complete surgical resection, and a moderate or marked lymphoid infiltrate in and around the tumor.

Unresectable lesions and metastatic disease at diagnosis suggest a dismal prognosis. Death can occur either from local extension or metastasis. Delayed diagnosis and treatment explain, in part, the poor prognosis of cutaneous angiosarcomas.

Angiosarcomas are insidious, and they may not produce symptoms until the disease is well advanced.[1, 18, 20] The history should focus on identifying risk factors; however, most patients do not have these factors.

Risk factors are as follows:

• 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 the clinical manifestations they cause are associated with the amount of organ tissue replaced, as follows:

• Pathologic fractures, anemia, or hepatic dysfunction
• Other intrinsic characteristics of a malignant vascular proliferation (eg, bleeding, thrombocytopenia, or disseminated intravascular coagulation)
• Compression of adjacent neurovascular structures that causes pain

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

Angiosarcoma of soft tissue

Patients with soft tissue angiosarcomas[13] usually present with a moderately paced growing mass in the extremities; the rapid progression of the disease is sometimes the clue to the diagnosis. Soft tissue angiosarcomas may also develop in the retroperitoneum or abdominal wall.

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; the incidence rate of node metastasis is as high as 45%

Angiosarcoma of bone

Angiosarcoma of bone[17, 21] 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. Patients do not present with specific symptoms, although pain is common and the area is frequently tender.

Sometimes, swelling and increased size of the affected limb due to involvement of a superficial bone or to soft tissue extension characterize the presentation. Pathologic fractures occur in 10% of patients.

Cutaneous angiosarcoma

Four variants of cutaneous angiosarcoma are currently recognized, as follows[22, 6] :

• Angiosarcoma of the scalp and face
• Angiosarcoma in the context of lymphedema (Stewart-Treves syndrome)
• Radiation-induced angiosarcoma
• Epithelioid angiosarcoma

Angiosarcoma of the scalp and face

This is the most common form of angiosarcoma. The disease is primarily located on the head and neck, and usually occurs in elderly persons; it 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 in six 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

These lesions occur in the radiation field 4-40 years after irradiation. Exposure to Thorotrast (a radioactive radiographic contrast agent used in the United States until the 1950s) may lead many years later to liver angiosarcoma.

Epithelioid angiosarcoma

This is a rare, recently described variant with an aggressive course. Death occurs 2-3 years after presentation.

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.

The choice of imaging studies for angiosarcoma varies somewhat, depending on whether the lesion is located in soft tissue, bone, or skin.

Soft tissue angiosarcoma

For angiosarcoma of the extremities, retroperitoneum, or abdominal wall, magnetic resonance imaging (MRI) provides more accurate delineation of the extent of local disease than computed tomography (CT). MRI provides sagittal and coronal views and better distinction between bone, vascular structures, and tumor than CT scanning. 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 is useful in the detection of lung, pleural, and mediastinal metastasis. Searches for bone and brain metastasis rarely are indicated unless the patient has clinical manifestations suggesting involvement of these organs.

Bone angiosarcoma

Plain radiographic assessment is paramount to characterize lesions of bone angiosarcoma and confirm their multiplicity.[21]  However, the radiographic presentation of bone angiosarcoma is not specific. A solitary lesion (60% of cases) appears 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 confirms the permeative, invasive character of the radiographic lesions and their multiplicity.

MRI shows 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.

Delayed whole-body bone scintigraphy shows marked radioisotope uptake, although findings can be negative in aggressive destructive lesions. Radionuclide-tagged red blood cell 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 involvement.

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.

The gross appearance of angiosarcoma is that of soft, dark red tissue that may have a spongy consistency (see the image below).[23] Solid gray areas may be interspersed with embedded bone fragments if the cortex has been breached.

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.

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 challenge 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[20] :

• 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%).

• CD34 immunohistochemistry highlights the vascular nature of angiosarcomas and aids in the diagnosis.

• 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.

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.[24] 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. Stages are as follows:

• Stage I: Localized and resectable tumor is found at one site in the liver and could be treated surgically

• Stage II: Localized and possibly resectable primary tumor is found at one 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 one 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,[13] the two 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. The stages are as follows:

• 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 of soft-tissue angiosarcoma

For stage I angiosarcomas, the National Comprehensive Cancer Network (NCCN) recommends surgery to obtain adequate oncologic margins. For stage II and stage IIIA and IIIB disease that can be resected with acceptable functional outcomes, the NCCN also recommends preoperative radiation therapy (category 1). For stage IIIA-B disease, category 2B recommendations include preoperative chemoradiation or chemotherapy, and postoperative chemoradiation.[25] The NCCN lists the following as preferred for treatment of angiosarcoma:

• Paclitaxel
• Anthracycline-based regimens
• Gemcitabine-based regimens

Anthracycline-based regimens include the following:

• Doxorubicin
• Epirubicin
• Liposomal doxorubicin
• AD (doxorubicin, dacarbazine)
• AIM (doxorubicin, ifosfamide, mesna)
• Ifosfamide, epirubicin, mesna

Gemcitabine-based regimens include the following:

• Gemcitabine and docetaxel
• Gemcitabine and vinorelbine
• Gemcitabine and dacarbazine

Neoadjuvant chemotherapy can be considered in patients with large localized angiosarcomas, where achieving negative margins may be a challenge.[1]  However, response to preoperative chemotherapy is only 40-50% with the most active regimens, and toxicity is significant. European guidelines list neoadjuvant chemotherapy as an option in selected patients with high-risk local or locoregional disease.[26]

Angiosarcoma is highly sensitive to taxanes, and paclitaxel has proved well tolerated and active even in pretreated patients with locally advanced or metastatic angiosarcoma.[27, 26]  Paclitaxel is used as single-agent therapy and is administered weekly.[28]

Ravi et al report exceptional response to treatment with pazopanib in a patient with angiosarcoma that harbored amplification of vascular endothelial growth factor receptor (VEGFR) and that had not responded to sorafenib. These authors suggest that a subset of patients with angiosarcoma with genomic alterations in vascular signaling genes may respond well to pazopanib.[29]  In a retrospective study of treatment for advanced vascular sarcomas in patients previously treated with standard chemotherapy including anthracyclines, 8 of 40 patients with angiosarcoma responded to pazopanib, with median progression-free survival of 3 months and median overall survival of 9.9 months.[30]  

Pasquier et al reported effective treatment in seven patients with advanced angiosarcoma using the combination of twice-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m2) and methotrexate (35 mg/m2). All patients responded; one patient showed a complete response and three showed very good partial responses. Median progression-free and overall survival was 11 months (range 5–24) and 16 months (range 10–30), respectively.[31] In 2017, propranolol was granted orphan drug status in Europe for the treatment of soft tissue sarcoma.[32]

Similarly, Amaya et al reported increased progression-free and overall survival in patients with metastatic angiosarcoma who received treatment with nonselective beta-blockers. Eight of their patients were treated with propranolol (20 to 100 mg/day) and one patient was treated with carvedilol (6.25 mg/day).[33]

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

With larger higher-grade soft-tissue angiosarcomas, adjuvant radiotherapy is effective in reducing local recurrence.

Radiotherapy can be delivered intraoperatively, by brachytherapy, or by external beam radiotherapy (EBRT). The brachytherapy technique results in rates of tumor control similar to those obtained with EBRT, 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 EBRT, and reduces radiation scatter. Brachytherapy is often the technique of choice in angiosarcomas near joints or gonads.

The use of irradiation in conjunction with surgery continues to evolve and results in 80% of local control and excellent functional and cosmetic outcome.[16] However, consider that 50% of angiosarcomas have distant metastases, 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 disadvantage of preoperative radiation is that a higher wound complication rate may delay surgery (1 wk of healing per 10 Gy of radiation delivered). The advantages of preoperative radiation are as follows:

• Optimization for surgery
• Smaller volume of external beam fields
• Less hypoxic tissue
• Potential to reduce the chance of intraoperative implantation
• Potential improvement in local control in advanced tumors

A novel treatment of cardiac angiosarcoma with concurrent proton beam therapy and paclitaxel followed by adjuvant chemotherapy with gemcitabine and docetaxel reported prolonged survival and improved quality of life in a 26-year-old patient.[34]

Bone angiosarcoma

In bone angiosarcoma, specialists use combinations of radiation therapy and chemotherapy for adjuvant treatment, but significant data about their effectiveness are lacking. Evidence of tumor multicentricity must be sought before making any decision regarding therapy. Patients have presented with lesions affecting as many as 45 different bones. In such 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.

Cutaneous angiosarcoma

The best outcomes are reported with surgery followed by radiotherapy. 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.

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.[35]

Paclitaxel as a single agent has shown substantial activity against cutaneous angiosarcoma, even in patients previously treated with chemotherapy or radiation therapy.[36]  Solid evidence supports first-line use of paclitaxel in advanced cutaneous angiosarcoma. Options for second-line treatment include pazopanib, eribulin, and trabectedin.[37]

Surgical treatment of angiosarcoma of the soft tissue, retroperitoneum, and abdomen is as follows[13] :

• 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. Resect 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.

Surgical treatment of angiosarcoma of bone is as follows:

• 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.

Surgical treatment of cutaneous angiosarcoma is as follows[6] :

• 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.

Complications from radiotherapy include the following:

• Wound complications
• Fractures

Complications from chemotherapy include the following:

• Fever
• Dose-dependent myelosuppression
• Nausea and vomiting unresponsive to antiemetics
• Moderate-to-severe fatigue
• Alopecia or hemialopecia in intra-arterial chemotherapy

Complications from surgery are as follows:

• Anesthetic complications
• Blood loss
• Infection, sepsis
• Wound complications
• Iatrogenic neurovascular injury
• Deep vein thrombosis, pulmonary embolism
• Limited limb function

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 carcinogen metabolism, or alter end-organ effects of carcinogens. Prevention also includes the successful treatment of preneoplastic lesions.

Soft-tissue and bone angiosarcomas

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 differential diagnosis for signal abnormality on a postoperative MRI includes the following:

• Residual or recurrent neoplasm
• Postsurgical/postradiation change
• Scarring
• Fluid collection

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. The lesion 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 can be differentiated from recurrence with gadolinium.

Hematomas usually appear in the subacute stage at the time of the first postoperative MRI. Because of the methemoglobin, hematomas show a characteristic high signal on T1-weighted images and T2-weighted images.

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.

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 late.

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

Class Summary

Inhibit cell growth and proliferation.

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.

Ifosfamide (Ifex)

An alkylating agent. Inhibits DNA and protein synthesis and, thus, cell-proliferation by causing DNA cross-linking and denaturation of double helix.

Gemcitabine (Gemzar)

Cytidine analog. Metabolized intracellularly to active nucleotide. Inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Cell-cycle specific for S phase. Indicated as first-line treatment for locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) pancreatic adenocarcinoma. Indicated for patients previously treated with 5-FU.

Paclitaxel (Taxol)

Natural taxane, prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition.