Angiosarcoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Synonyms and Keywords: Hemangiosarcoma; Pulmonary angiosarcoma; Vascular sarcoma

Overview

Angiosarcoma is a rare malignant vascular neoplasm of endothelial-type cells that line vessel walls. The peak age of incidence appears to be the 7th decade, and men are affected more than women. Angiosarcoma was first described by Dr. Juan Rosai, in 1976. The pathogenesis of angiosarcoma is characterized by a rapid and extensively infiltrating overgrowth of vascular epithelial cells. Angiosarcoma may arise in any part of the body, but is more common in soft tissue than in bone. Common angiosarcoma locations include the head and neck area, kidney, liver, lung, and and the most common site of radiation-induced angiosarcoma development is the breast. The PTPRB/PLCG1 genes are associated with the development of angiosarcoma; mutation of these genes result in aberrant angiogenesis. The imaging modality of choice for diagnosing angiosarcoma will depend on the location. For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan. For other types angiosarcoma, the imaging modality of choice is MRI. On CT scan, findings suggestive of angiosarcoma may include vascular invasion, nodular enhancement (common), and a hypoattenuating mass. The mainstay adjuvant therapy for angiosarcoma is a doxorubicin-based regimen. The response rate for chemotherapy in patients with angiosarcoma is poor.

Historical Perspective

Angiosarcoma was first discovered by Dr. Juan Rosai, M.D. and colleagues in 1976.[1]

Classification

Angiosarcoma may be classified according to the clinical heterogeneity into two main groups, and every group can be subdivided into subtypes according to the anatomical location and etiology:[2] [3][4]

Angiosarcoma
Primary Secondary
Cutaneous Post Radiation Angiosarcoma
Breast Lymphedema-associated Angiosarcoma
Soft tissue and Bone Angiosarcoma due to exposure to mutatgens
Visceral

Staging

According to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and by Enneking classification, soft tissue sarcomas are classified to different stages based on the primary tumor characteristics, histological grading and the local or distant tumor involvement. Table below provides summarized information regarding staging of angiosarcoma:[5][6]

Stage Grade Site Metastasis
Ia Low grade (G1) Intracompartmental (T1) No metastasis (M0)
Ib Low grade (G1) Extracompartmental (T2) No metastasis (M0)
IIa High grade (G2) Intracompartmental (T1) No metastasis (M0)
IIb High grade (G2) Extracompartmental (T2) No metastasis (M0)
IIIa Low or High grade (G1-G2) Intracompartmental (T1) Metastasis (M1)
IIIb Low or High grade (G1-G2) Extracompartmental (T2) Metastasis (M1)

Pathophysiology

Pathogenesis

The pathogenesis of angiosarcoma is characterized by a rapid and extensive infiltrating overgrowth of vascular epithelial cells.[7] Angiosarcoma is a locally aggressive tumor with a high rate of lymph node infiltration and metastases.

Genetics

  • Angiosarcomas demonstrate obvious unregulated vascular-specific receptor tyrosine kinases containing TIE1, KDR, TEK and FLT.The up-regulation of these genes and over-expression of vascular endothelial growth factor receptors can cause endothelial cell expansion, angiogenesis, and also vascular leaks in the structure of vessels. [8][9][10][11]
    • KDR mutations are seen in primary breast angiosarcoma regardless of exposure to radiation.
    • High level MYC amplification is seen is seen in radiation- induced and lymphedema-associated angiosarcoma.
    • FLT4 amplification has been detected in 25% of secondary angiosarcomas.

Gross Pathology

On gross pathology, characteristic findings of angiosarcoma may include:[7]

  • Red/dark tan papules or noduls
  • Typically poorly circumscribed
  • Central earas of necrosis and hemoorrhage are common
File:AngiosarcomaGross.jpg
Source:Wikimedia commons

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of angiosarcoma may include:

  • Irregular anastomosing vascular spaces lined by endothelial cells[12]
  • Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots[13]
  • The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies[14]
    • Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.[15]

Causes

The most common cause of angiosarcoma appears to be therapeutic radiation, which was a well-recognized cause of hepatic angiosarcoma in the era when the thorium containing contrast agent Thorotrast was employed. Presently, the breast is the most common anatomic site affected by radiation-induced angiosarcoma. Angiosarcomas may arise after exposure to vinyl chloride, although they remain rare tumors even in an exposed population. Angiosarcomas are also observed after lymphedema from any cause, be it surgical, filarial, or congenital, and defined as Stewart-Treves syndrome. Common causes of angiosarcoma include:[7]

Differentiating Angiosarcoma from Other Diseases

Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass or non-healing cutaneous ulcerations such as:

Differentials for Cutaneous Angiosarcoma

Cutaneous angiosarcoma must be differentiated from other diseases with non-healing cutaneous ulcerations such as:[16][17][18]

Differentials for Non-cutaneous Angiosarcoma

Angiosarcoma must be differentiated from other diseases that cause a highly vascular mass such as:[19]

Epidemiology and Demographics

Incidence

  • In general 2% of soft tissue sarcomas are angiosarcomas, and the incidence of soft tissue sarcoma is about 6 per 100,000 person; on the other words,the incidence of angiosarcomas can be calculated approximately 1.2 per 1,000.000 person.[20][21]

Age

  • Angiosarcoma is more commonly observed among patients aged between 40 to 75 years old.The peak age of incidence appears is the 7th decade,[22]

Gender

  • Males are more commonly affected with angiosarcoma than females.[22]
  • The male to female ratio is 2:1.[22]

Race

  • There is no racial predilection for angiosarcoma. however, African-Americans in the U.S are rarely affected.[23]

Risk Factors

Common risk factors in the development of angiosarcoma include:[7]

Natural History, Complications and Prognosis

Natural History

  • The majority of patients with angiosarcoma remain asymptomatic for years.[7]
  • Early clinical features may include nonspecific symptoms, such as pain, fatigue, malaise, and nausea.
  • If left untreated, the majority of patients with angiosarcoma may rapidly progress to develop metastases.[22]

Complications

Common complications of angiosarcoma include:[7]

Prognosis

  • Prognosis is generally poor; the 5-­year survival rate of patients with angiosarcoma is approximately 12-33%.
  • Poor prognostic factors include patient age (> 65 years), retroperitoneal location, and large tumor size.[22]

Diagnosis

Diagnostic Study of Choice

  • There is no single diagnostic study of choice for the diagnosis of angiosarcomas. The imaging modality of choice for angiosarcoma or use of punch biopsy of skin will depend on the anatomic location of lesions.
    • Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluating of suspicious lesions of the extremities, retroperitoneum, or abdominal wall.[24]
    • CT scan is useful in for evaluating of lung, pleural, and mediastinal involvement.
    • An x-ray may be helpful in the diagnosis of bone angiosarcoma. Findings on an x-ray suggestive of diagnostic include solitary lytic lesion, with irregular borders or a mixed lytic-sclerotic pattern.[25]
    • Punch biopsy of cutaneous lsions accompanied with immunohistochemical staining provide accurate findings for diagnosis of cutaneous angiosarcoma. Findings associated with angiosarcoma include irregular anastomosing vascular spaces lined by endothelial cells, and immunohistochemical staining of tumor cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.[26][27]

Symptoms

  • Angiosarcomas occur at different anatomic sites and grow insidiously, then they can present with various misleading symptoms.[28] The most common clinical manifestation is a gradually enlarging, painless mass. [29]Some patients complain of pain or symptoms due to compression of adjacent neurovascular structures that causes pain or edema in an extremity.
  • Primary cutaneous, head and neck and breast angiosarcoma may present with skin thickening, erythema, or skin discoloration.[30][31]
  • Secondary angiosarcomas include radiation-Induced and lymphedema-associated Angiosarcoma have a distinct feature, presenting as single or several ecchymotic maculopapular cutaneous lesions in the radiation field or in areas exposed to chronic lymphedema.[32]

Physical Examination

Patients with angiosarcoma may appear cachectic or normal. In cutaneous angiosarcoma, physical examination findings may include:

Laboratory Findings

There are no specific laboratory findings associated with angiosarcoma.

Imaging Findings

  • The imaging modality of choice for angiosarcoma will depend on the location.
  • For pulmonary angiosarcoma, the imaging modality of choice is enhanced CT scan.[22] For other types angiosarcoma, the imaging modality of choice is MRI.

CT

On CT, findings of angiosarcoma may include:[22]

  • Vascular invasion
  • Nodular enhancement (common)
  • Hypoattenuating mass
  • Multicentric lesions

MRI

On MRI, findings of angiosarcoma may include:[33]

  • T1/T2: heterogeneous areas of hyperintensity suggestive of a mixed tumour and hemorrhage
  • T1 C+ (Gd): heterogeneous enhancement

Biopsy

  • Lesion biopsy findings associated with angiosarcoma include:
    • Irregular anastomosing vascular spaces lined by endothelial cells[34]
    • Endothelial cells have hyperchromatic or vesicular nuclei with fast mitotic activity and necrotic spots[35]
    • The tumor cells in solid area are characterized by a spindled appearance and contain Weibel-Palade bodies[36]
    • Immunohistochemical staining of spindle cells highlights CD31, CD34 and von-Willebrand factor related antigens which define the vascular origin of tumor cells.[37]

Treatment

The mainstay of treatment for angiosarcoma is complete surgical resection with wide margins for local and locoregional disease in combination with preoperative or postoperative radiotherapy.[38][39] The role of adjuvant chemotherapy, is unclear. Adjuvant chemotherapy and/or radiotheray provide less mutilating surgery, and for patients with unresectable tumors or those who refuse surgery is an option.[40][41]

Medical Therapy

  • Since angiosarcomas are histologically anthracycline-sensitive, then initial systemic chemotherapy for unresectable and/or metastatic angiosarcomas include doxorubicin-based therapy with or without ifosfamide.[42]
  • However, taxane-based regimen may be preffered for initial therapy.Paclitaxel is effective for advanced angiosarcoma.[43]
  • Gemcitabine-based regimen is preferable to doxorubicin with or without ifosfamide for patients with significant clinical haert failure, due to heart-toxicity of doxorubicin.[44]
  • In addition, some vascular biologic molecules, with antiangiogenic characteristics including bevacizumab, sunitinib, and sorafenib, and with or without cytotoxic chemotherapy have shown dramatic responses in a small number of angiosarcoma patients.[45]

Surgery

  • Surgical resection in combination with radiation therapy is the treatment of choice for small angiosarcomas.[7]
  • Complete surgical resection with wide margins is preferred for local and locoregional angiosarcoma.[7] Owing to the tendency for local infiltration, surgical resection should be associated with preoperative or postoperative radiotherapy.[46]
  • Surgery is not recommended on patients with large sized angiosarcomas. The recurrence rate of angiosarcoma after surgery is 80%.It usually occures after a median of six months locally or distantly and the three-year disease-free and overall survival rates both are low.[47][48]

Prevention

Primary Prevention

There are no primary preventive measures available for angiosarcoma.

Secondary Prevention

Once diagnosed and successfully treated, patients with angiosarcoma are followed-up every 3, 6, or 12 months depending on the stage at diagnosis. Follow-up testing for angiosarcoma may include:[7]

References

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