Approach Considerations
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:
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Paclitaxel
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Anthracycline-based regimens
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Gemcitabine-based regimens
Anthracycline-based regimens include the following:
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Doxorubicin
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Epirubicin
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Liposomal doxorubicin
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AD (doxorubicin, dacarbazine)
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AIM (doxorubicin, ifosfamide, mesna)
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Ifosfamide, epirubicin, mesna
Gemcitabine-based regimens include the following:
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Gemcitabine and docetaxel
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Gemcitabine and vinorelbine
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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:
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Optimization for surgery
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Smaller volume of external beam fields
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Less hypoxic tissue
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Potential to reduce the chance of intraoperative implantation
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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 Care
Surgical treatment of angiosarcoma of the soft tissue, retroperitoneum, and abdomen is as follows [13] :
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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.
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Resection of large lesions can be extremely difficult and sometimes requires amputation for local control; however, local control does not prevent distant relapse.
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Free surgical margins sometimes have anatomic constraints, especially in retroperitoneal tumors.
Surgical treatment of angiosarcoma of bone is as follows:
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Surgical resection and radiation therapy are the standard treatment for localized disease.
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Low-grade lesions lead to similar benefits with either technique.
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Treat high-grade lesions as malignant bone neoplasms, with a combination of radical en bloc excision followed by radiotherapy and/or chemotherapy.
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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] :
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Surgical treatment is contraindicated in tumors extending into vital structures, in those of massive size, or in those with multicentricity.
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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.
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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
Complications from radiotherapy include the following:
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Wound complications
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Fractures
Complications from chemotherapy include the following:
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Fever
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Dose-dependent myelosuppression
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Nausea and vomiting unresponsive to antiemetics
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Moderate-to-severe fatigue
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Alopecia or hemialopecia in intra-arterial chemotherapy
Complications from surgery are as follows:
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Anesthetic complications
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Blood loss
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Infection, sepsis
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Wound complications
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Iatrogenic neurovascular injury
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Deep vein thrombosis, pulmonary embolism
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Limited limb function
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 carcinogen metabolism, or alter end-organ effects of carcinogens. Prevention also includes the successful treatment of preneoplastic lesions.
Long-Term Monitoring
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:
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Residual or recurrent neoplasm
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Postsurgical/postradiation change
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Scarring
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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.
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This is a classic example of angiosarcoma associated with chronic lymphedema after lymphadenectomy and radiotherapy. The patient is a 33-year-old woman who presented with a recurrent grade 2 angiosarcoma of the soft tissue after an attempt at wide excision and skin graft. Two weeks following this procedure, she developed multiple subcutaneous erythematous nodules involving the back and overlying the right scapula region, the supraclavicular fossa, the right breast, and arm. The window shows a microphotograph of the tissue obtained from the biopsy (hematoxylin and eosin stain, original magnification X160). Histologic preparation reveals neoplastic endothelial cells showing a solid pattern with occasional mitotic figures and sporadic protruding growth into the vascular lumens.
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This is a gross specimen from a proximal humerus bone angiosarcoma. These tumors generally are red and hemorrhagic. Although the tumor has not extended into the adjacent soft tissues, cortical erosion is evident. The patient was treated with wide excision and reconstruction with a humeral spacer. The patient's next oncologic recheck showed multiple lesions, including a large destructive lesion in the right ilium extending to the sacroiliac joint and the right sacral ala. Also noted was an upper thoracic vertebral lesion, multiple indeterminate pulmonary nodules, extensive hepatic metastases most marked in the left lobe, and an indeterminate left adnexal mass.
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This radiograph is from a 27-year-old woman who had preexisting mild pain in her left clavicle for a couple of weeks. She woke up one morning with severe pain. Radiographs showed a pathological fracture through a lytic lesion. The permanent section of the needle biopsy is shown in the window and was read as a grade 1 angiosarcoma. The cell morphology varied from epithelioid to spindle-shaped with indistinct borders. Most nuclei were large and vesicular, containing irregular large eosinophilic nucleoli and frequent mitoses. Physicians also found anastomosing vascular channels lined by pleomorphic malignant cells.
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CT scan, MRI, and bone scan from a 27-year-old woman with grade 1 angiosarcoma who presented with a pathological fracture through a lytic lesion on her left clavicle. Note the expansile lytic lesion in the left clavicle accompanied by a soft tissue mass visible on the MRI. No other lesions are identifiable. Regional lymph nodes are visible by MRI, and they do not appear involved. Lungs are clear. She was treated with wide resection of the clavicle, leaving both bony ends. No further reconstruction was attempted. Eighteen months after surgery, she is free of disease and has a full range of motion in the left shoulder. The residual aesthetic deformity is minimal.
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This 71-year-old man presented with a dark lesion on his scalp. The lesion was first treated with an excisional biopsy performed by his local physician; the lesion recurred quickly. He was treated with wide excision and adjuvant radiation therapy. The specimen (hematoxylin and eosin, original magnification X12.5) shows a well-differentiated cutaneous angiosarcoma composed of irregular vascular channels.
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This young woman presented with multicentric angiosarcoma. The images show several bones of the right foot, the right distal femur, and the right patella affected with the process. The microphotograph of the specimen revealed a grade 2 angiosarcoma (hematoxylin and eosin, original magnification X100). Most bone tumors are solitary lesions with a very low incidence of multicentricity. Vascular tumors are an exception and may involve multiple bones. Angiosarcoma presents in this case as multiple lytic lesions in the same extremity.
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This is a soft tissue angiosarcoma presenting as a rapidly growing mass in the calf. This 69-year-old woman was treated with wide resection of the mass followed by external beam radiotherapy. The full-thickness graft obtained from the ipsilateral thigh at the moment of surgery aided in the closure and prevented further wound complications during the adjuvant radiotherapy. The rapid growth of soft tissue angiosarcomas explains why they are often misdiagnosed as abscesses and tentatively treated with drainage. The drainage is sanguinous, with blood clots, and hemostasis may be challenging. To avoid this problem, fine-needle aspiration should precede any attempt at incisional or excisional biopsy of a soft tissue mass.
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This 45-year-old man presented with progressive pain in his left hip. Activity-related at first, the pain turned constant. The patient described it as a dull ache and a boring sensation, with occasional stubbing episodes. The pelvic bone involvement was extensive. The patient was treated with an external hemipelvectomy. The patient survived for 1.5 years.
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Plain film of the tibia demonstrates small lucencies without internal matrix production in keeping with the diagnosis of a vascular lesion.
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Coronal T1 magnetic resonance imaging (MRI) study reveals a lesion of the diaphysis with cortical breakthrough.
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Coronal T2 magnetic resonance image shows a diaphyseal lesion with intense surrounding edema (high signal intensity).
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Axial T2 magnetic resonance image shows a heterogeneous signal lesion with cortical destruction.
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Grossly, angiosarcomas show a reddish-brown color and solid patterns.
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Foci of angiosarcomas can show well-formed vascular channels that aid in the diagnosis. These channels can be difficult to find in a large number of tumors.
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Atypical cells in solid sheets or nests are typical of this tumor and can make diagnosis on hematoxylin and eosin (H&E) sections difficult, necessitating the use of immunohistochemistry.
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CD34 immunohistochemistry highlights the vascular nature of angiosarcomas and aids in the diagnosis.
