Stewart-Treves Syndrome 

Updated: Apr 06, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD 

Overview

Background

Stewart-Treves syndrome is a rare, deadly cutaneous angiosarcoma that develops in long-standing chronic lymphedema.[1, 2, 3, 4] See the image below.

Classic example of angiosarcoma associated with ch Classic example of angiosarcoma associated with chronic lymphedema after lymphadenectomy and radiation therapy.

Most commonly, this tumor is a result of lymphedema induced by radical mastectomy to treat breast cancer.[5] Unfortunately, although the breast cancer may be cured with such radical surgery, this second primary cancer may be responsible for the patient's worsening course. The term Stewart-Treves syndrome is broadly applied to an angiosarcoma that arises in a chronically lymphedematous region due to any cause, including congenital lymphedema and other causes of secondary lymphedema unassociated with mastectomy. As reported by Durr et al in 2004, this lymphangiosarcoma occurs as a rare complication.[6] Lymphangiosarcoma is a misnomer because this malignancy seems to arise from blood vessels instead of lymphatic vessels. A more appropriate name is hemangiosarcoma.

In 1906, Lowenstein first described angiosarcoma in a patient's arm that had been affected by severe posttraumatic lymphedema for 5 years.[7] In 1948, Stewart and Treves reported this rare secondary malignancy in 6 cases of angiosarcoma in postmastectomy lymphedema.[8] They recognized that an edematous arm after radical mastectomy for breast cancer may suggest recurrent breast cancer, but that long-standing chronic edema without recurrent cancer may occasionally produce "a heretofore unrecognized and unreported sequel ... long after the malignant breast neoplasm has apparently been arrested ... a new specific tumor." Stewart and Treves suggested that these angiosarcomas were probably not observed previously because they were mistaken for recurrent, inoperable, cutaneous manifestations of breast cancer.

Lymphangiosarcoma has been described in Milroy disease and in idiopathic, congenital, traumatic, or filarial lymphedema.[9, 10, 11]

Pathophysiology

The pathogenic mechanism by which lymphedema may induce angiosarcoma has been the subject of controversy. Stewart and Treves found a high incidence of third malignancies in patients with postmastectomy angiosarcoma. Thus, they speculated that a systemic carcinogenic factor was the main causative factor in the pathogenesis of lymphangiosarcomas.

In 1979, Schreiber and others postulated the concept of local immunodeficiency in the presence of lymphedema.[12] This theory is supported by experimental evidence. In 1960, Stark and associates demonstrated that homograft skin transplanted to lymphedematous arms survive much longer than those transplanted to healthy arms.[13] Therefore, lymphedema may cause some degree of local immunodeficiency and lead to oncogenesis.

The possibility that radiation therapy has an important role in the induction of lymphangiosarcoma is also postulated.[14] Sternby et al reported that in their study, the patient with the shortest interval between radical mastectomy and the onset of the tumor (8 mo) received both preoperative radiation therapy of the breast and involved axillary lymph nodes followed by fractionated radiation.[15] Others suggest that irradiation is not an essential factor in the pathogenesis of this tumor. Finally, irradiation may be an indirect cause of lymphangiosarcomas because it may cause axillary node sclerosis and thereby accelerate and aggravate the edema.

Clinical data from Swedish women with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 showed 31 angiosarcomas developed at a median age of 71 years.[16] The 14 women treated for breast cancer with radical mastectomy and radiotherapy from 1949-1988 developed angiosarcomas in edematous arms after a median 11 years, whereas 17 females treated by segmental resection, antihormonal treatment, and radiotherapy from 1980-2005 developed angiosarcomas in the irradiated field on the thoracic wall after a median 7.3 years.

A hemangiogenic and lymphangiogenic origin of this angiosarcoma has been documented.[17]

Etiology

The most important single causative agent in Stewart-Treves syndrome is prolonged chronic lymphedema. Although Stewart-Treves syndrome develops after radical mastectomy in most patients, lymphangiosarcoma also develops in other forms of acquired lymphedema and in congenital lymphedema. Causes for such secondary lymphedema may include trauma, surgical invasion of the groin for the treatment of penile or cervical cancer, filariasis, idiopathic acquired lymphedema, vascular stasis, and morbid obesity.

Edema secondary to cardiac or renal disease is not associated with this malignancy. Thus, edema alone is not sufficient to cause lymphangiosarcoma. Perhaps additional factors such as a genetic predisposition are required.

Epidemiology

Frequency

Currently, approximately 400 cases of Stewart-Treves syndrome are reported in the world literature. In 1962, Schirger calculated that the incidence of this disease is 0.45% in patients who survive at least 5 years after radical mastectomy.[18] Another analysis calculated it as occurring in 0.03% of patients surviving 10 or more years after radical mastectomy.[19]

As a result of the increase in conservative treatment for breast carcinoma and improvement of operative and radiation therapy techniques, the prevalence of Stewart-Treves syndrome has decreased.[3]

Race

No racial predominance exists for Stewart-Treves syndrome.

Sex

Most patients with Stewart-Treves syndrome are women with a history of breast cancer that has been treated with radical mastectomy, which causes chronic lymphedema.

Age

Stewart-Treves syndrome usually occurs in middle-aged or elderly women, a few years or many years after mastectomy.

In 1981, Sordillo and associates reported a peak incidence in persons aged 65-70 years.[20] In 1972, Woodward et al described a series of 23 patients in a review of 163 cases of Stewart-Treves syndrome from the literature.[21] They recorded an average patient age of 68.8 years at the onset of lymphangiosarcoma; the youngest patient was aged 44 years and the oldest, 84 years.

Prognosis

The prognosis is dismal. Lymphangiosarcomas are extremely aggressive tumors with a high local recurrence rate and a tendency to metastasize early to many areas.[5]

Long-term survivors are the exceptions. The 5-year survival rate reported by Sordillo et al in 1981 was 13.6%,[20] In 1987, Hultberg found that patients with Stewart-Treves syndrome had a mean survival of 20 months after tumor onset.[22] Untreated patients have an average survival of 5-8 months. A more recent analysis showed the overall 5-year survival was 16%.[23]

Metastatic angiosarcoma to the lungs and chest wall are the most common cause of death in patients with Stewart-Treves syndrome. Metastases to the liver and bones can also occur. Lymphangiomas are associated with a high rate of local recurrence and metastasis, even after aggressive surgical treatment.

Early diagnosis and treatment by radical ablative surgery or possibly other approaches may afford an improved prognosis; patients at risk should be carefully monitored.[24, 25]

Patient Education

Patients should be informed about the significance of prolonged chronic lymphedema and about how to reduce and control it. Patients should be encouraged to seek early medical attention if they notice unexplained skin changes or unresolved lymphedema. Patients should be educated about complications, such as recurrent infections, deep venous thrombosis, and malignancies, that can occur with lymphedema.

For patient education resources, visit the Women's Health Center and Cancer Center. Also, see the patient education articles Mastectomy and Breast Cancer.

 

Presentation

History

Lymphangiosarcoma typically develops in patients many years after mastectomy, more commonly 5-15 years after surgery. In their original series, Stewart and Treves reported that the earliest angiosarcoma appeared 6 years after radical mastectomy, the longest interval being 24 years (average, 12.5 y).

In 1988, Tomita and associates demonstrated that the most common interval between radical mastectomy and the onset of lymphangiosarcoma was 5-14 years.[26] In 1981, Yap et al reported a series of 22 patients in whom the median interval from mastectomy to the onset of angiosarcoma was 11 years (range, 5-16 y).[27]

Clinical data from Sweden suggests 2 distinct groups: women who were treated for breast cancer with radical mastectomy and radiotherapy developed angiosarcomas in edematous arms (Stewart-Treves syndrome) after a median of 11 years, and those who were treated by segmental resection, anti-hormonal treatment and radiotherapy developed angiosarcomas in the irradiated field on the thoracic wall after a median of 7.3 years.[23]

It has also been described developing 15 years after a total hysterectomy and radiation therapy for cervical cancer.[28] Chronic lymphedema from other causes may also be associated with Stewart-Treves syndrome.[29, 30] It usually appears in atrophic, pachydermatous, hyperkeratotic skin in longstanding lymphedema.[24]

Physical Examination

As Stewart and Treves described, edema occurs first. Severe chronic edema of an upper extremity usually occurs in patients with Stewart-Treves syndrome. In patients who undergo radical mastectomy, edema first appears on the arm on the side operated on.[31]

The occurrence of edema is not associated with complications such as postoperative infection or thrombosis. The edematous area gradually extends from arm to forearm and dorsal aspect of the hand and fingers. Initially, pain is absent, although skin distention may produce local discomfort. In the areas of long-standing chronic edema, recurrent erysipelas may occur, just as they do in patients with congenital lymphedema.

The skin in patients with Stewart-Treves syndrome tends to become atrophic and eventually pachydermatous, with prominent wrinkle lines. At times, hyperkeratoses and telangiectasias can be observed.

After an interval of 1-30 years, a purplish patch appears that then develops into a plaque or nodule in the area of chronic lymphedema. Other initial lesions of Stewart-Treves syndrome may include a palpable subcutaneous mass or a poorly healing eschar with recurrent bleeding and oozing.

The lesions of Stewart-Treves syndrome typically appear as multiple reddish blue macules or nodules that may become polypoid. Around these nodules, small satellite areas can develop and become confluent, forming an enlarging lesion. Sometimes, a bullous component may be seen. Thus, the morphology may be heterogeneous, with hematomalike lesions, multiple bluish-reddish nodules, and asymptomatic nodules.[23]

As the angiosarcoma continues to grow and expand, the overlying atrophic epidermis may ulcerate, producing recurrent episodes of bleeding and infection.[32] Necrosis may be evident in advanced cutaneous tumors.

Ultimately, extensive cutaneous nodules and systemic metastases appear. These nodules most commonly occur in the lungs and cause the patient's death. Not every tumor in an area of lymphedema is an angiosarcoma.

Complications

Patients can present with recurrent episodes of erysipelas and deep venous thromboses in areas of chronic lymphedema. Other complications include recurrent infections and malignancies.

 

DDx

Diagnostic Considerations

Also consider the following:

  • Telangiectatic metastatic breast disease to the skin
  • Hemangioendotheliomas
  • Hemangiopericytomas
  • Anaplastic Kaposi sarcoma can mimic Stewart-Treves syndrome. [33, 34]
  • Some authors have suggested a distinction between Stewart-Treves syndrome and cutaneous postradiation angiosarcoma. [35]
  • Other lymphedema-related neoplasms [4]

Differential Diagnoses

 

Workup

Laboratory Studies

Although Stewart-Treves syndrome is also known as lymphangiosarcoma, ultrastructural and immunohistologic studies show that this malignancy arises from blood vessels rather than lymphatic vessels.

The following immunohistologic and ultrastructural findings can be used to confirm that the tumor originates from blood vessels:

  • Antibodies against factor VIII–related antigen are markers for endothelial cells. Although malignant endothelial cells may not always show positive staining with this marker, a more sensitive endothelial marker, lectin Ulex europaeus-I, is more likely to react with hemangiosarcoma tumor cells. However, the specificity of this marker is reduced in people with blood group O because normal epithelial cells and carcinomas also bind this lectin in these individuals.

  • CD34 antigen is a marker of vascular endothelial cells and does not react with the lymphatic endothelium.

  • Antikeratin antibodies show no evidence of keratin in this malignancy; this finding confirms that the tumor cells are nonepithelial in origin.

  • Positive staining for laminin, CD31, collagen IV, and vimentin can aid in diagnosing the tumors as angiosarcomas.

Imaging Studies

Magnetic resonance imaging (MRI) is recommended to evaluate the local extent of angiosarcomas. However, its true value is in question because of poor results in delineating the margin of the tumor. It may be low in signal intensity on T2-weighting and short-tau inversion recovery (STIR) imaging, reflecting the densely cellular, fibrous stroma and sparsely vascularized tumor histology.[36, 37] Additional administration of intravenous contrast medium may reveal significant enhancement of the tumorous lesions. However, in patients with chronic lymphedema, nodules detected by MRI within the lymphedema should be evaluated for Stewart-Treves syndrome.[38, 39]

Chest CT scanning should be performed to rule out metastatic disease to the lungs before the patient undergoes extensive surgery.

Chest radiography can help in identifying pulmonary metastases and pleural effusion. A positron-emission tomographic (PET) scan may document the extent of subcutaneous spread and aid in planning surgical management.[40] Fluorodeoxyglucose (FDG) PET/CT scanning may delineate tumor spread, including metastases, and detect the possible malignant transformation in patients with chronic lymphedema.[41]

Procedures

Analysis of a biopsy specimen is essential to the diagnosis of lymphangiosarcoma. Fine-needle aspiration is inadequate for diagnosis of Stewart-Treves syndrome.

Histologic Findings

Histologically, angiosarcomas in Stewart-Treves syndrome are indistinguishable from angiosarcomas in nonlymphedematous sites. Postlymphedema angiosarcomas are characterized by proliferating vascular channels, which dissect the dermal collagen and, often, the obliterate appendages. Tumor endothelial cells lining these channels show marked hyperchromatism and pleomorphism. Mitoses are commonly seen in these tumor cells. The vascular endothelial cells appear round or oval, and they are protuberant and often project into the lumen. Erythrocytes can be seen inside these vascular channels. The overlying epidermis may be hyperkeratotic and acanthotic, or it may be atrophic. Prominent proliferation of reticular fibers can be seen in association with this malignancy.

At electron microscopic examination, lymphangiosarcoma cells are surrounded by a complete basal lamina. In some tumor cells, pinocytosis, intercellular junctions, and cytoplasmic intermediate filaments are observed. In addition, Weibel-Palade bodies and erythrophagocytosis are often present. These ultrastructural findings suggest a vascular endothelial origin rather than a lymphatic endothelial origin.

Staging

In 1959, McConnell and Haslam divided the course of development of lymphangiosarcoma into 3 stages.[42] This staging system lacks universal application.

Stage 1 (prolonged lymphedema) is as follows:

  • This stage is characterized by extensive edema that causes the degeneration of fat and collagen mainly in the deep part of the dermis.

  • Edema separates the collagen bands, creating a misperception of an increased amount of fibrous tissue in the area.

Stage 2 (premalignant angiomatosis) is as follows:

  • This stage involves multiple foci of small, proliferating channels in the dermis and subdermis. These vessels are lined by hyperplastic endothelial cells, as well as normal, flattened cells.

  • The areas of angiomatosis vary in size, ranging from 100 µm to a couple of centimeters in diameter.

  • Superficial areas can be seen as bruises or vesicles, whereas deeper areas are seen as areas of induration and hemorrhage.

  • Early lesions show little evidence of malignancy, but more advanced lesions reveal early malignant transformation with an increased number of mitotic figures and pleomorphic cells.

Stage 3 (frankly malignant angiosarcoma) is as follows:

  • These aggressive tumors develop from areas of premalignant angiomatosis.

  • The histologic features of this malignancy are described above in stage 2.

 

Treatment

Medical Care

Chemotherapy and irradiation continue to be evaluated as adjuvants to surgery for the treatment of Stewart-Treves syndrome. Currently, these treatment options offer little benefit.

Multimodal therapy including hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan, combined with radical resection of the affected skin and subcutaneous tissue including the fascia, with large safety margins, may provide enhanced survival.[43]

In 2000, Grobmyer and associates found no statistical significant difference in the survival rates of patients treated with chemotherapy compared with those treated with irradiation.[44] Although long-term survivors after either radiation therapy or systemic chemotherapy have been reported,[45, 46] the overall results have been discouraging. A questionable response to weekly paclitaxel has been described.[47] As a result of these findings, these treatment options are reserved for patients with inoperable, advanced disease or those who refuse surgery.

Intra-arterial mitoxantrone/paclitaxel was used for angiosarcoma of the lower limb associated with chronic lymphedema (Stewart-Treves syndrome) in a patient with cervical cancer.[48]

In 1994, Furue et al demonstrated that immunotherapy may be beneficial as palliative treatment for pleural effusions caused by metastatic angiosarcoma.[49]

Expression of VEGF-C makes this angiosarcoma a good potential candidate for targeted antilymphangiogenic therapy.[17]

Complications from metastatic disease, such as pleural effusions, may require hospitalization of the patient. A CT scan may identify bilateral pulmonary involvement. Stewart-Treves syndrome patients may need further inpatient care for pain control.

Stewart-Treves syndrome occurring in the abdominal wall was successfully treated with eribulin mesylate, a structurally modified analog of halichondrin B, originally isolated from the marine sponge Halichondria okadai.[50]

Surgical Care

Early amputation or wide local excision provides the best chance of long-term survival in patients with Stewart-Treves syndrome. Some authorities favor radical ablative surgery with an early diagnosis, in order to confer a reasonable prognosis with this rare but aggressive disease.[32, 51] A nihilistic approach is undesirable.

The most common approach in patients with lymphangiosarcoma is amputation of the limb or forequarter rather than wide local surgical excision. Even in cases with early surgical treatment, the prognosis is disappointing, with a high rate of local recurrence and metastasis. Metastatic disease should exclude surgical treatment unless surgery is useful for symptomatic improvement.

Chemotherapy, immunotherapy, and/or radiation therapy can be used as adjuvants to surgery (see Medical Care).

Prevention

The most efficient way to avoid Stewart-Treves syndrome, a highly lethal disease, is by preventing or treating long-standing lymphedema, which predisposes individuals to this lymphangiosarcoma years later.

Other complications commonly associated with chronic lymphedema, such as erysipelas and deep venous thromboses, must be prevented by regularly examining these areas and then treating them.

Early biopsy of any suggestive lesion should be performed because early diagnosis and surgical treatment offers the highest rate of long-term survival.

Prevention of tumor progression in Stewart-Treves syndrome with the use a low dose of pazopanib has been suggested.[52]