March 2007

Fig.2

Fig.3

Fig.4

Diagnosis: Angiosarcoma (Stewart-Treves Syndrome)

Histopathology: Punch biopsies of the left upper arm on H&E (Figure 2 ,3) showed a deeply infiltrative, high grade neoplasm composed of solid nests of atypical epithelioid cells with slit-like vascular channels, intermixed with lymphocytes and scattered red blood cells. There are easily identifiable mitoses with some atypical forms and apoptotic bodies. The immunohistochemical stains (Fig.4) show tumor cells that are diffusely and strongly positive for CD31 and Vimentin. This immunophenotype confirms the histologic impression of an angiosarcoma.

Discussion: Stewart-Treves Syndrome (STS), which was first reported in 19481, describes the rare occurrence of a cutaneous angiosarcoma which develops in chronic lymphedematous regions following the treatment of breast carcinoma. At first there was debate over whether the disease process was caused by lymphedema or radiation. It is currently felt that lymphedema is the most likely culprit in producing the disease because one-third of patients have not received radiation, the lesions most commonly occur outside of the radiation field, and angiosarcoma may occur in other forms of lymphedema such as filarial, congenital, posttraumatic, or Milroy disease3. Current thought is that the angiosarcoma is not directly related to breast cancer or radiation treatment but represents a new primary neoplasm arising in chronic lymphedema of the extremity2. This new tumor arises from vascular endotheliocytes and develops multicentrically in the lymphedematous arm and subsequently rapidly spreads from these sites7.

STS occurs almost exclusively in women with the highest incidence occurring between the 5th and 7th decades6. There has been only one case of a man with STS reported4.

The median interval between the diagnosis of breast cancer and the development of STS was found to be 11 years with a range of 2-44 years8. The survival after diagnosis can range from 5 to 20 months (mean of 20 months) with untreated patients ranging from 5 to 8 months2,5,6,10. There have been a few cases of long-term survivors (6 and 9.3 years) after surgical treatment9. Unfortunately, local recurrence often occurs in STS. Most patients die from metastasis (usually to the lungs) within 2 years. Areas affected by STS in descending frequency are upper arm, forearm, elbow, and anterior chest wall. The skin lesions may appear as raised red bumps with surrounding discoloration resembling ecchymosis. The appearance of the lesions can range from ecchymosis to purplish, reddish, or bluish macules or papules to nodules or sclerotic plaques. These lesions can occasionally present as blisters, ulcerations, or cellulitis. In breast cancer patients who develop arm lymphedema following cancer treatment, the appearance of these lesions should prompt a skin biopsy in which specimens are sent for permanent sections and immunohistochemistry markers for CD31 and vimentin2.

Treatments for STS include surgical resection, radiation therapy, and chemotherapy. Because the tumor spreads along the subcutaneous plane, radical resection (shoulder disarticulation or forequarter amputation) rather than wide excision is considered first line therapy to surgically control the tumor. Moreover, early amputation may give the best chance for prolonging survival and cure2. However some believe that there is no significant difference in survival between those initially treated with wide excision and those treated with amputation5. Furthermore, even with surgical treatment, there is still a high rate of local recurrence and metastasis. Other treatments such as radiation therapy, chemotherapy, and immunotherapy have not been that promising and may be considered more as adjuvant therapeutic options2.

A metastatic work up for STS should be done because the presence of metastatic disease can preclude the use of surgical treatment except in instances where it may be used for symptomatic improvement. The work up includes an MRI to evaluate the local extent of disease even though there have been poor results in determining the tumor margins and a chest CT/chest radiograph to rule out pulmonary metastasis5.

Due to the poor prognosis following diagnosis and the role of lymphedema in the disease process, all breast cancer patients who develop lymphedema should be encouraged to wear pressure garments and undergo pressure gradient therapy. Delayed diagnosis is mostly due to unfamiliarity with the disease and the harmless appearance of the lesions. It is recommended that patients at high risk for STS be evaluated regularly and have suspicious lesions biopsied2.

The patient's work up in this case included a MRI of the left upper extremity which revealed an infiltrating lesion involving the medial skin of the left upper arm that infiltrated into the subcutaneous fat, extending 19 cm above the elbow joint. It also showed a single 1 cm lymph node in the subcutaneous region of the left upper arm, centered 12 cm below the top of the humeral head, at the inferior most attachment point of the deltoid on the humerus. She also had a chest CT that revealed no evidence of metastatic disease. Her ECG, BMP, and CBC were within normal limits. The patient decided to receive chemotherapy instead of surgery but was unresponsive to her chemotherapeutic regimen, which included six cycles of infusional Adriamycin and Taxol. She underwent left four quarter amputation with negative surgical margins. Approximately eight to nine months later, the patient developed biopsy proven angiosarcoma of the left anterior chest wall with several sites of possible angiosarcoma in that region. She initially responded partially to several cycles of Taxol but eventually developed progression of her local regional disease despite six cycles of Taxol. She then failed treatment with three cycles of Epirubicin, Neulasta, and Zinecard with disease progression and extension into the left upper extremity resection bed toward the back and down into the left abdominal wall and the development of a new FDG avid right axillary/chest wall lymph node. She currently is being treated with Gemzar with marked improvement in her disease.

References:
1. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer. 1948;1:64­81.

2. Chung KC, Kim HE, Jeffers LL. Lymphangiosarcoma (Stewart-Treves Syndrome) in Postmastectomy Patients. The Journal of Hand Surgery. 2000 Nov;25A(6):1163-1168.

3. Billings S, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous Angiosarcoma Following Breast-conserving Surgery and Radiation An Analysis of 27 Cases. Am J Surg Pathol. 2004 June;28(6):781-788.

4. Oettle´ AG, van Blerk PJP. Postmastectomy lymphostatic endothelioma of Stewart and Treves in a male. Br J Surg. 1963;50:736 ­743.

5. Grobmyer SR, Daly JM, Glotzbach RE, Grobmyer III AJ. Role of Surgery in the Management of Postmastectomy Extremity Angiosarcoma (Stewart-Treves Syndrome).
Journal of Surgical Oncology. 2000;73:182­188.

6. Kirova YM, Feuilhade F, Calitchi E, Otmezguine Y, Le Bourgeois JP. Stewart­Treves syndrome after treatment for breast cancer. The Breast. 1999;8:282­284.

7. Tomita K, Yokogawa A, Oda Y, Terahata S. Lymphangiosarcoma in postmastectomy lymphedema (Stewart-Treves syndrome): ultrastructural and immunohistologic characteristics. J Surg Oncol. 1988 Aug;38(4):275-82.

8. Brady MS, Garfein CF, Petrek JA, Brennan MF. Post-treatment sarcoma in breast cancer patients. Ann Surg Oncol. 1994 Jan;1(1):66-72.

9. Stewart NJ, Pritchard DJ, Nascimento AG, Kang YK. Lymphangiosarcoma following mastectomy. Clin Orthop. 1995 Nov;(320):135-41.

10. Hultberg BM: Angiosarcomas in chronically lymphedematous extremities. Two cases of Stewart-Treves syndrome. Am J Dermatopathol 1987 Oct;9(5):406-12.

Presented by Pooja Swamy MD, Margaret Mann MD, Beverly Faulkner-Jones MD, and Michael P. Heffernan MD.