Cancer, Angiosarcoma


Article Author:
Alison Spiker


Article Editor:
Michael Ramsey


Editors In Chief:
Amanda Oakley
Jules Lipoff
Shyam Verma


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/24/2019 2:17:31 PM

Introduction

Cutaneous angiosarcoma is an uncommon malignant tumor of vascular endothelial cells that most often affects the elderly and has a very poor prognosis. Although it may affect any area of the body, the most common areas of involvement are the face and scalp. Surgical excision, often followed by high-dose radiotherapy, represents the current standard of care, but recurrence remains frequent, and many patients develop the systemic disease. The cytotoxic chemotherapy effects partial response in metastatic disease, but is far from optimal. Targeted therapy with inhibitors of vascular epithelial growth factor (VEGF) and its receptor (VEGFR), or with tyrosine kinase inhibitors, has shown some efficacy and agents of this type may represent some promise for the future in treating this condition.[1][2][3][4]

Etiology

The etiology of cutaneous angiosarcoma remains unknown, but the vast majority of cases arise in sun-exposed skin, mainly the scalp and face, in elderly patients. Chronic or congenital lymphedema, chronic radiodermatitis, and immunosuppression can predispose patients to the development of angiosarcoma in other locations. Most radiation-induced angiosarcoma occurs in the breast. Angiosarcoma may also arise in areas of chronic lymphedema, and in this setting is called Stewart-Treves syndrome. The association between angiosarcoma and chronic lymphedema is clear, but the mechanism of this association remains uncertain. Radiation therapy is an independent risk factor for the development of angiosarcoma and pathogenesis has been linked to amplification of MYC and FLT4 genes.

Epidemiology

Angiosarcomas account for less than one percent of all sarcomas and have a predilection for the skin and superficial soft tissue, whereas most sarcomas are found in deeper tissues. Adults, especially elderly patients, are most often affected by cutaneous angiosarcoma with a male to female ratio of 3 to 1, and Caucasians are affected more frequently than individuals of African or Asian descent.

Pathophysiology

The pathogenesis of angiosarcomas is largely unknown. Tumor histology varies widely and ranges from well-differentiated variants, appearing very similar to benign vascular neoplasms, to poorly differentiated neoplasms that are difficult to discern from other malignant neoplasms. More banal tumors are comprised of clonal proliferations of endothelial cells that line blood vessels and lymphatics. Angiosarcomas typically do not have a capsule or well-defined histologic margins, in contrast to benign vascular growths. Less-differentiated lesions may require immunohistochemical studies for diagnosis. Most tumors stain with endothelial markers such as CD31, CD34, von Willebrand factor, agglutinin 1 and vascular epithelial growth factor. The best marker with high sensitivity and specificity is CD31.

History and Physical

The typical presentation is an ill-defined, expanding erythematous to a violaceous plaque on the scalp and face of an elderly patient. Lesions can resemble a bruise and are often subtle and asymptomatic, which can lead to a delay in medical treatment. As these lesions progress, they may assume a more thickened, nodular surface and ulceration or bleeding. Left untreated, angiosarcomas may assume significant diameter. Satellite lesions are also common. Less commonly, angiosarcoma can occur in areas of chronic lymphedema or areas treated with radiation therapy.

Angiosarcoma has a very aggressive course, with the lymphatic or vascular spread. Metastases most commonly occur in the lungs, followed in incidence by the liver, bone, soft tissue, and lymph nodes. Metastases may occur years after initial treatment, and most patients succumb to the effects of the systemic disease.

Evaluation

Skin biopsy should be performed for diagnosis. Well-differentiated cutaneous angiosarcoma will demonstrate numerous irregular vascular channels lined by endothelial cells. Poorly differentiated cutaneous angiosarcoma will demonstrate sheets of spindle cells or epithelioid shaped cells with increased mitotic activity and poorly formed vascular spaces. Immunohistochemistry is positive for CD31 especially, and CD34 in the majority of cases. MRI can greatly aid particularly in angiosarcoma of the scalp in delineating the extent of the primary neoplasm. Involvement often extends significantly beyond clinical margins. CT with contrast is helpful in identifying nodal involvement and lung metastases.[5][6][7]

Treatment / Management

Patients diagnosed with cutaneous angiosarcoma benefit from a multidisciplinary approach to treatment. These tumors are difficult to treat, and recurrences are common. Historically, wide surgical excision is the treatment of choice, yet local recurrence rates of 72% to 84% have been reported. Wide excision is often difficult due to the size of many of these lesions and their common occurrence in areas where the extensive surgery will result in substantial functional impairment and wounds that are extremely difficult to reconstruct. Mohs micrographic surgery has been considered as the treatment for cutaneous angiosarcoma as it is a tissue-sparing procedure that provides complete margin evaluation; however, its efficacy depends on the contiguous growth of tumors. Unfortunately, angiosarcomas are believed to demonstrate a noncontiguous growth pattern commonly, and for this reason, most dermatologic surgeons do not attempt to treat angiosarcomas with the Mohs technique.

Adjuvant radiotherapy is often employed primarily in an attempt to decrease chances of recurrence, and it has been shown to moderately improve prognosis. High doses of radiation are administered over a large field, often irradiating the entire scalp for cases of angiosarcoma in that location.

Continuous chemotherapy with docetaxel and/or paclitaxel has shown to improved disease-specific survival and event-free survival, but that improvement is limited, and side effects of these drugs in usual elderly patients often is not tolerable for long periods. Monotherapy with propranolol has been reported to reduce the proliferative index of cutaneous angiosarcoma. Combined treatment with propranolol, paclitaxel, and radiotherapy led to substantial regression of a facial angiosarcoma in one patient. Targeted biologic therapy with bevacizumab and imatinib have been reported to treat cutaneous angiosarcoma with variable success. In one study of the vascular epithelial growth factor-A monoclonal antibody, bevacizumab, eleven of 23 patients (57%) showed either partial response or stabilization of disease.[8][9][10][6][11]

Pearls and Other Issues

Cutaneous angiosarcomas are difficult to treat given their aggressive behavior and high recurrence rate, with almost half of cases having local or distant metastases at the time of diagnosis. Metastasis often occurs in the lung, liver, lymph nodes, soft tissues, brain, and bone. The majority of patients present with local disease, but 20% to 40% have distance disease when first seen. Five-year survival for angiosarcoma is approximately 30%. For patients presenting with systemic disease, median survival is seven months.

Surgical excision, followed by high-dose, wide-field radiotherapy, represents the current standard of care, but many patients progress to widespread disease. Cytotoxic chemotherapy with anthracyclines, taxanes, and ifosfamide are employed in disseminated disease, with partial effect. Ongoing studies with agents that target the vascular epithelial growth factor receptor hold promise for more effective treatment in the future.

Enhancing Healthcare Team Outcomes

The management of cutaneous angiosarcoma is multidisciplinary. These tumors are difficult to treat, and recurrences are common. Historically, wide surgical excision is the treatment of choice, yet local recurrence rates of 72% to 84% have been reported. Wide excision is often difficult due to the size of many of these lesions and their common occurrence in areas where the extensive surgery will result in substantial functional impairment and wounds that are extremely difficult to reconstruct. Mohs micrographic surgery has been considered as the treatment for cutaneous angiosarcoma as it is a tissue-sparing procedure that provides complete margin evaluation; however, its efficacy depends on the contiguous growth of tumors. Unfortunately, angiosarcomas are believed to demonstrate a noncontiguous growth pattern commonly, and for this reason, most dermatologic surgeons do not attempt to treat angiosarcomas with the Mohs technique.

Adjuvant radiotherapy is often employed primarily in an attempt to decrease chances of recurrence, and it has been shown to moderately improve prognosis. High doses of radiation are administered over a large field, often irradiating the entire scalp for cases of angiosarcoma in that location. Even though chemotherapy is used, it has not made a big impact on survival. The overall prognosis of patients with cutaneous angiosarcoma is poor. (level V)


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Cancer, Angiosarcoma - Questions

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What is the most common primary malignant tumor of the heart?



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Which of the following can result from long-standing chronic lymphedema?



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A large abdominal tumor is removed from a patient and is found to be very vascular. Two months after surgery, several metastases are found. The development of metastases after the removal of the large tumor is most likely to be a decrease in which of the following?



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Angiosarcomas are most common in what part of the bony skeleton?



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Exposure to vinyl chloride is associated with angiosarcoma of which of the following?



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A 66-year-old is found to have a very vascular abdominal tumor which is excised. Three months after surgery several metastasis are found. The development of metastasis after removal of the vascular mass tumor is most likely to be a decrease in which of the following?



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An elderly male presents with an ill-defined, bruise-like plaque on his scalp. It is asymptomatic. It is subsequently diagnosed as an angiosarcoma. With which of the following would this tumor most likely stain?



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An elderly female with a prior history of breast cancer status post mastectomy and radiation therapy presents with swelling of her right arm and an ill-defined, erythematous plaque. A biopsy is performed of the lesion. Histopathology reveals numerous irregular vascular channels lined by endothelial cells. Immunohistochemistry demonstrates CD31 and CD34 staining of the tumor cells. Which of the following is true regarding this tumor?



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Cancer, Angiosarcoma - References

References

Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version 2002;     [PubMed]
Tan YB,Yu XF,Fan JQ,Li JF, Angiosarcoma originating in the anterior mediastinum: A case report. Medicine. 2018 Dec;     [PubMed]
Chen JX,Kozin ED,O'Malley J,Chebib I,Hedley-Whyte ET,Faquin W,Nadol J Jr,Quesnel AM, Otopathology in Angiosarcoma of the Temporal Bone. The Laryngoscope. 2018 Dec 11;     [PubMed]
Childhood Vascular Tumors Treatment (PDQ®): Health Professional Version 2002;     [PubMed]
Fedeli U,Girardi P,Gardiman G,Zara D,Scoizzato L,Ballarin MN,Baccini M,Pirastu R,Comba P,Mastrangelo G, Mortality from liver angiosarcoma, hepatocellular carcinoma, and cirrhosis among vinyl chloride workers. American journal of industrial medicine. 2019 Jan;     [PubMed]
Bhatt MD,Nambudiri VE, Cutaneous Sarcomas. Hematology/oncology clinics of North America. 2019 Feb;     [PubMed]
Fujisawa Y,Funakoshi T,Nakamura Y,Ishii M,Asai J,Shimauchi T,Fujii K,Fujimoto M,Katoh N,Ihn H, Nation-wide survey of advanced non-melanoma skin cancers treated at dermatology departments in Japan. Journal of dermatological science. 2018 Dec;     [PubMed]
Milman T,Shields CL,Brooks JSJ,Lally SE,Shields JA,Tuluc M,Eagle RC Jr, Primary Cutaneous Angiosarcoma of the Eyelid: A Diagnostic and Therapeutic Challenge. Ocular oncology and pathology. 2018 Jun;     [PubMed]
Liu D,Li B,Shi W,Chen X,Zhao S, A case report of cutaneous angiosarcoma combined treated by photodynamic therapy with chemotherapy and surgery. Photodiagnosis and photodynamic therapy. 2018 Dec 28;     [PubMed]
Hata H, Can we manage refractory cutaneous angiosarcoma? The British journal of dermatology. 2018 Dec;     [PubMed]
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