Continuing Education Activity

Angiosarcoma is a tumor of endothelial cell-origin that comprises 1% of all soft tissue sarcomas. It is an aggressive malignancy that carries a poor prognosis, if not detected and treated in early stages. This activity describes the evaluation, diagnosis, and management of angiosarcoma and highlights the role of team-based interprofessional care for affected patients.

Objectives:

• Review the etioloigy, epidemiology, pathophysiology and pathology of angiosarcoma.
• Review the presentation of angiosarcoma including patient history, physical exam and imaging findings.
• Review the treatment options available for management of angiosarcoma
• Outline the importance of collaboration and coordination among the interprofessional team can enhance patient care when managing a patient with angiosarcoma to improve patient outcomes.

Introduction

Angiosarcoma (AS) comprises 1% of all soft-tissue sarcoma (STS), which are themselves a rare malignancy. They arise from lymphatic or vascular endothelial cells and are 'high-grade' by definition, which demonstrates their aggressive behavior.[1] Although AS can occur in any part of the body, it most commonly presents as a cutaneous disease in elderly white men or on the chest wall after receiving radiation therapy (RT) for breast cancer.[2] The treatment is very challenging, and the prognosis is poor, especially if AS is diagnosed in the metastatic stage. The best approach to patients with AS is offered in a multidisciplinary tumor board setting. Like any other STS, surgical resection with a negative margin affords the best outcomes in terms of overall survival. [3][4] Combining radiation therapy (RT) with weekly paclitaxel has been demonstrated to bear durable responses for cutaneous angiosarcoma.[4] Doxorubicin and paclitaxel are recommended regimens for advanced or metastatic disease.[5] Due to the increased vascularity of AS, targeted therapy against vascular endothelial growth factor (VEGF) has gained traction, however, yet remains to be proven in a prospective study.[2]

Etiology

AS is mostly a spontaneous tumor; however, a transformation from a benign vascular lesion has been reported previously. Radiation-induced AS is commonly seen in breast cancer survivors who receive RT to the chest wall. However, it can occur in any part of the body that has been irradiated previously. Stewart-Treves syndrome is defined as AS occurring in the setting of chronic lymphedema. Chronic lymphedema can occur with cancer and its treatment, infection like filariasis (Milroy's disease).

A few case reports suggest an association of AS with mutation in the DNA repair genes BRCA1 and BRCA2. Familial syndromes like neurofibromatosis, Maffuci syndrome, Klippel-Trenaunay syndrome are also associated with AS. chemicals like vinyl chloride, thorium dioxide, arsenic, radium, anabolic steroids are also associated with AS.[1]

Epidemiology

Overall STS comprises 1% of all malignancies. AS comprises up to 2% of all STS and 5-4% of all cutaneous STS.[6][7] AS has a similar distribution between sexes; however, is more common in elderly white men.[7] It can develop in any body organ, but cutaneous AS occurs more commonly in the head and neck region, particularly in the scalp.[7] Being a more of endothelial origin, AS can also occur rarely in major blood vessels and the heart.[5][1]

Histopathology

Histologic diagnosis of AS is challenging. Morphologic differences are very subtle and it is hard to distinguish between a benign proliferation of vessels versus AS. AS is infiltration and is devoid of a capsule, hence it is hard to distinguish normal from abnormal tissue. Abnormal, pleomorphic, malignant endothelial cells are the hallmark of AS. These cells can be rounded, polygonal, or fusiform and can have an epithelioid appearance.[1]

In the well-differentiated areas, abnormal endothelial cells form functioning vascular sinusoid continuous with normal vascular channels. As the aggressiveness of the tumor increases, the architecture gets more distorted and the abnormal cells stack in multiple layers and form papillary like projections into the vascular lumen. In poorly differentiated areas, the malignant epithelial cells form an epithelioid morphology with areas of hemorrhage and necrosis, which make it difficult to distinguish from anaplastic carcinoma or melanoma.[1]

Immunohistochemistry plays a critical role in identifying AS. As typically express endothelial markers including von Willebrand factor, CD34, CD31, Ulex europaeus agglutinin 1, and VEGF. Von Willebrand factor, U europaeus agglutinin 1, and CD31 are the most useful markers in poorly differentiated cases. It is imperative to check for melanocytic markers (S-100, human melanoma black-45, and melanoma antigen) to rule out melanoma.[8] 

History and Physical

A thorough history and physical exam are mandatory for any patient presenting with a mass suspicious for malignancy. History of receiving RT to a body part, especially if it was received a decade ago, should raise the suspicion for STS, including AS. Family history of AS is extremely rare, but must be covered in each patient. A history of exposure to chemicals (listed above) must be obtained. A history of surgical removal of lymph nodes, chronic lymphedema, and parasitic infections can provide a clue towards diagnosis. 

Physical exam should evaluate for lymphedema, nail changes, or hair changes (a sign of exposure to harmful chemicals), radiation burns, previous scars from surgery and RT. Cutaneous AS can resemble a bruise or a raised purple-red papule. As the tumor size increases, it becomes ulcerated, fungating, bleeds easily, and is associated with tissue infiltration. Typically it is a multifocal disease.[9] Visceral AS usually presents with a mass effect where the enlarging tumor compresses the nearby structure and causes obstructive symptoms. They spread via hematogenous route, with lung, bone, and other soft-tissue structures.[10] 

Evaluation

Laboratory studies are usually unremarkable unless mass effect causes compression of critical organs and causes laboratory abnormalities (For e.g. compression of the ureter can lead to renal failure), or the disease is fairly advanced to cause subtle lab abnormalities (anemia of chronic disease, elevated sedimentation rate, etc.). However, no lab abnormality can specifically point towards a diagnosis of AS. 

Advanced imaging like CT scan, MRI, or PET scan is required to define the anatomy of the tumor and the extent of spread.[11] In the case of special locations, like heart, a 3-dimensional echocardiogram may also be needed.[5] The final diagnosis is established via biopsy and histopathology. This has been discussed earlier in the article.

Treatment / Management

Any patient diagnosed with any kind of STS benefits from a multidisciplinary approach. The same applies to AS. The treatment for AS can be divided based on the stage of presentation (metastatic versus non-metastatic).

• Non-metastatic disease:
  • Local surgery with R0 resection is the treatment of choice.[2] R1 and R2 resection confer a worse prognosis.[9][12][9] Due to the infiltrative nature of AS, wide margins are advised.
  • AS is a high-grade malignancy, hence peri-operative RT is always recommended. Small retrospective studies have demonstrated a survival benefit with local control.[9]
  • No study has shown a clear benefit to adjuvant chemotherapy. However, neoadjuvant chemotherapy can be considered in patients where the tumor size is large, and achieving negative margins may be a challenge.[1]
• Metastatic disease: Metastatic disease is treated with chemotherapy. Cytotoxic agents, targeted therapy, and Immune checkpoint inhibitors are being explored in treating metastatic disease. 
  • Cytotoxic chemotherapy- Anthracycline based regimens are usually the first line of treatment in a patient with any STS. However, in patients with AS, paclitaxel is an effective drug.
    • Anthracyclines- In patients with STS, the response rate is between 16-36%. A combination with another drug, ifosfamide in most cases, certainly increases toxicity but may not benefit outcome.[13] Liposomal doxorubicin has also shown therapeutic responses in patients with AS.[14]
    • Taxanes: The antiangiogenic properties of taxanes make them useful in patients with AS. After numerous retrospective studies reporting benefits in AS, a small phase II prospective study (ANGIOTAX study) was conducted that showed an ORR of 17%. However, two of the five patients with responses underwent surgery and achieved a complete pathological response.[15] Since then, multiple studies have confirmed the activity of weekly paclitaxel in patients with AS.[16]
    • Other cytotoxic drugs like Ifosfamdie, Gemcitabine, Cisplatin are also active in patients with AS; however, they are usually not deployed as the first line of treatment.
  • Targeted therapy
    • Anti-VEGF molecule- Since AS is a malignancy arising from vascular endothelium, anti-VEGF therapy, particularly bevacizumab, gained a lot of attention for metastatic AS. However, a prospective phase II study failed to show any benefit.[2]
    • Tyrosine Kinase inhibitors (TKI)- Several TKI (Sorafenib, Pazopanib, Axitinib, and regorafenib) have been tested in patients with AS. The drugs mainly target either VEGF or PDGFRA, which are critical to the growth of AS. Unfortunately, none of these drugs showed a beneficial response, despite clinical activity in patients with AS.
  • Immune checkpoint inhibitors (ICI). 
    • Recent data suggest that ICI may be active in patients with AS.[17] This is yet to be tested in a prospective trial.

Differential Diagnosis

AS is one of the over 70 different subtypes of STS.[3] It is also included in the broad category of the vascular tumors that make the bulk of differential diagnosis for AS. 

• Reactive and benign vascular tumors
  • Capillary haemangiomas
  • Juvenile haemangioma (strawberry naevus)
  • Cherry angioma (Campbell de Morgan spot)
  • Pyogenic granuloma
  • Cavernous haemangiomas
  • Epithelioid haemangioma
  • Vascular ectasis (naevus flammus, spider naevus)
  • Angiomatosis
  • Postradiation atypical vascular lesion
• Intermediate grade vascular tumors
  • Kaposi’s sarcoma
  • Epithelioid haemangioendothelioma
• Malignant vascular tumors
  • Angiosarcoma
• Tumors of perivascular cells
  • Haemangiopericytoma (solitary fibrous tumor)

Staging

The staging of AS is done like any other STS.[3] By definition, AS is a high-grade tumor that confirms its aggressive nature.

Prognosis

AS has a 5-year survival of nearly 35%.[12] Even with localized disease amenable to resection with negative margins, only 60% of patients are alive at 5 years (median survival of 7 months).[18] Old age, metastatic disease at presentation, and poor performance status have been consistently shown to be predictors of poor outcome. In addition to this, AS of atypical locations like liver and heart, and RT induced AS also have a very poor prognosis.[3][19] Tumor size of more than 5 cm has been associated with a worse outcome in some studies.[1]

Deterrence and Patient Education

The patients and physicians must understand the rarity and the aggressive nature of the disease, and the need for multidisciplinary discussions. Although no large randomized trials have been done specifically for AS, retrospective data clearly shows the survival benefit of local control which involves surgery with perioperative RT. Despite of good local control measures, recurrence rates are high, and a close follow up with frequent imaging is mandatory.

Pearls and Other Issues

Angiosarcoma is rare cancer and hence the data is scarce to drive evidence-based decision making. Despite that, certain approaches have shown clear benefits. 

• History of RT, chronic lymphedema, and exposure to chemicals like vinyl chloride have been linked with the development of AS.
• Multidisciplinary tumor board discussion is a must for any patient diagnosed with angiosarcoma.
• R0 resection with perioperative RT is the best approach for local control of the disease.
• A combination of paclitaxel with RT has been demonstrated to achieve durable responses in patients with cutaneous AS.
• Weekly paclitaxel as a first-line treatment for AS has comparative efficacy to anthracycline-based regimens in patients with AS.
• Targeted therapy with anti-VEGF and anti-PDGFRA drugs has not to be proven to be beneficial over conventional chemotherapy, although did add to the toxicity of the regimen.
• Immune checkpoint inhibitors are currently being explored as a potential option for the treatment of AS.

Enhancing Healthcare Team Outcomes

The rarity of angiosarcoma has prevented clinicians from conducting large randomized clinical trials. This is the precise reason for discussing all patients with AS in a multidisciplinary tumor board to offer them the best approach. An expert pathologist trained in sarcoma specialty must be present at these tumor boards to appropriately identify AS and differentiate it from other tumor types, especially melanoma. Since local control offers the best survival outcome, surgical oncologists must collaborate with radiation oncologists to offer surgery with perioperative RT. Medical oncologists can offer concurrent chemotherapy and RT to the patients to achieve durable responses. Treating physicians must collaborate with radiologists to determine the results of the follow-up imaging and to discuss the best imaging modality in order to appropriately diagnose a patient with AS. Lastly, nurses, chemotherapy suites, and social workers must come together to provide comprehensive care to the patient. [Level III to Level IV]

Due to the rarity of the pathology, no large randomized trials are possible, and the evidence of treatment comes from case series, retrospective studies of international registries, and few small prospective trials. [Level III to Level IV]