Stewart-Treves Syndrome

Etiology

Sarcomas of soft tissue are uncommon malignancies and account for less than 1% of all cancers. Angiosarcomas are a subtype of soft-tissue sarcoma and are aggressive, malignant endothelial-cell tumors of vascular or lymphatic origin with a dismal prognosis. Most angiosarcomas present as intermediate or high-grade lesions. Unfortunately, delays in diagnosis are common as angiosarcomas can present as relatively benign-appearing lesions.[5][6][7]

Epidemiology

Angiosarcomas occur in every region of the body. However, approximately 60% arise in the skin or superficial soft tissues. Cutaneous angiosarcomas usually occur in 3 clinical settings: 

• The majority are idiopathic and develop on the head and neck of the elderly, classically the scalp of men
• As a result of previous exposure to ionizing radiation
• In association with chronic lymphedema either from postsurgical complications or seen with congenital abnormalities

A reported 90% of cases of angiosarcoma associated with lymphedema occur following a mastectomy. This is known as Stewart-Treves syndrome.

Pathophysiology

Stewart-Treves syndrome is a rare and fatal disease arising from complications of chronic lymphedema. The first report of these findings came in 1948 when Stewart and Treves reported a case series describing 6 patients with lymphangiosarcoma in the setting of chronic lymphedema status post mastectomy. The reported incidence of developing angiosarcoma in patients surviving at least 5 years post radical mastectomy is 0.07% to 0.45%. Although the majority of Stewart-Treves syndrome-related angiosarcomas are a result of post-mastectomy lymphedema, the development of angiosarcoma has been associated with chronic lymphedema of any origin. The specific mechanism between chronic lymphedema and angiosarcoma is unknown. Stewart and Treves postulated the role of a systemic carcinogenic factor responsible for this process. It has also been suggested that a neoplastic transformation occurs in lymphedematous areas during development of collateral circulation. Other theories consist of a malignant transformation due to blockage of lymphatic drainage and impaired antigen presentation, resulting in malignancy avoiding immune surveillance in an “immunologically privileged site.”

Histopathology

Histologically, Stewart-Treves syndrome displays networks of small lymphatics and proliferating vascular channels that dissect dermal collagen and may obliterate appendages. The tumor endothelial cells lining these channels are commonly seen undergoing mitotic changes and display hyperchromatism and pleomorphism. The appearance of the epidermis can vary from atrophic to hyperkeratotic and acanthotic. Angiosarcomas typically can express CD31, CD34, D2-40, Ki67, and Ulex europaeus-1 lectin upon immunohistochemistry staining. Immunohistochemical detection of factor VIII-related antigen, although very specific for endothelial cells, is often negative in well-differentiated angiosarcomas.

History and Physical

Cutaneous angiosarcoma can initially appear as a “spreading bruise,” or a raised purple-red papule, eventually developing tissue infiltration, edema, tumor fungation, ulceration, and even hemorrhage due to increasing tumor size. The second most common location is in a lymphedematous upper extremity secondary to radical mastectomy, known as the Stewart Treves tumor. Median size lesions range from 3 to 6 cm, while untreated angiosarcomas can grow to 20 cm or larger. Although originally described in patients after a radical mastectomy, this syndrome can occur in the following:

• The setting of congenital or hereditary lymphatic malformations, for example, Turner syndrome, Noonan syndrome, Milroy disease, lymphedema praecox, and lymphedema tarda
• Chronic infections
• Chronic venous stasis
• Morbid obesity
• Malignant obstruction
• Surgical procedures that disrupt the lymphatic flow

Patients most commonly present complaining of pain or discomfort. The range of time for the progression of chronic lymphedema to develop angiosarcoma is between 4 to more than 50 years.

Evaluation

CT or MRI of the head and neck will help to establish the extent of bone and soft tissue involvement as well as aid in lymph node evaluation. Patients with angiosarcoma require referral to medical and surgical oncology. Radiation is also often given.[8][9][10]

Treatment / Management

Surgical treatment with wide margins is indicated. Even when margins are found to be negative by histologic studies, the recurrence rate and risk of metastatic disease remain increased. For this reason, a multispecialty approached is often warranted.

Differential Diagnosis

The differential diagnosis of cutaneous angiosarcoma includes both benign and malignant lesions such as hemangioma, hemangioblastoma, squamous cell carcinoma, Kaposi sarcoma, and anaplastic melanoma. Cutaneous telangiectatic metastatic breast disease should often be considered as well. There have been case reports of angiosarcoma mimicking rosacea and eczema as well as rare reports of mimicking eyelid edema and solid, non-pitting facial edema.

Surgical Oncology

There are not many treatment options due to lack of randomized trials. Initial surgical resection with wide margins has been shown to offer patients the best chance of survival. All efforts should be made to achieve negative margins even if it calls for repeat resections. The main problem with obtaining wide margins is that most lesions are relatively extensive at the time of diagnosis.

Radiation Oncology

Due to high risk of local recurrence, adjuvant radiotherapy with large doses and wide treatment fields is most-often recommended, except in cases where angiosarcomas are radiation-induced. Radiotherapy may be palliative, but unfortunately, does not improve survival.

Medical Oncology

Chemotherapy with single-agent doxorubicin or paclitaxel is the treatment of choice for advanced regional or metastatic disease. Promising studies have shown that bevacizumab acts as a tumor stabilizer and may aid in decreasing the progression rate of the disease. Isolated reports have shown successful outcomes with thalidomide therapy. Even in cases of early surgical intervention, prognosis remains poor, with a high rate of local recurrence and metastasis.

Staging

Staging is based on the International Union Against Cancer and American Joint Committee on Cancer system using the TNM system. Angiosarcoma tends to metastasize by lymphatic or hematogenous pathways, and 20% to 45% of patients have metastatic disease at presentation. The lungs are the most common site of metastasis and can present as pleural disease, hemorrhagic pleural effusion, or pneumothorax. Other common sites include the liver, bone, soft-tissue, and lymph nodes.

Prognosis

In a recent institutional review, patients were found to have a 3-year and 5-year survival of 55% and 35%, respectively. Median survival has been noted at just 7 months. Good prognostic factors have been found to be age (younger than 50 years), localized tumor stage, and anatomical site (trunk). The reason for increased survival in patients with angiosarcomas of the trunk is unclear.