Angiosarcoma. A rare secondary malignancy after breast cancer treatment

ARTICLE

Angiosarcoma of the skin is a highly malignant vascular tumor which has both a vascular and a lymphatic endothelial origin. The most common variety of the disease affects the face and the scalp of the elderly without a sex predominance [1]. Less frequent is Stewart-Treves syndrome, a special form of angiosarcoma which develops secondary to a chronic persistent lymphedema [2]. The edema develops in the arm after radical mastectomy and removal of axillary lymph nodes, but may also be congenital or due to infection. This form of angiosarcoma occurs almost exclusively in females, developing up to 20 years after mastectomy and has no obvious etiological connection with breast cancer. The frequency is about 0.45% in women who have survived after mastectomy for more than 5 years [3]. The rarest type of angiosarcoma occurs on breast skin after radiotherapy given as a treatment for breast cancer [4].

The different types of angiosarcomas are clinically and histologically similar. The lesions are erythematous or violaceus infiltrations, which may ulcerate and form haemorrhagic blisters [3]. In the early stage of the disease there are proliferating capillaries with atypical endothelial cells, which later form a sarcomatous mass [5].

We describe four patients with angiosarcoma: two of the tumors developed on the irradiated breast skin after mastectomy and radiation therapy, two Stewart-Treves-type angiosarcomas developed on an edematous arm after mastectomy and radiation therapy.

Patients

Case 1

A 43-year-old female had been treated for T1N0M0 breast cancer with a saving mastectomy and post-operative radiotherapy (total dose 6,000 cGy) in May 1989. In November 1992, skeletal metastases were noticed and ophorectomy was performed: she received additional chemotherapy. In 1992, blue-red patches were noticed on the breast skin on the opposite side to the operation scar. The first biopsy was taken in 1993 and the histopathological changes were regarded as vasculitis. The patches slowly became larger and more infiltrated.

A new biopsy was taken in November 1994. It revealed a network of irregular capillaries in the upper dermis. The endothelial cells were large and atypical with enlarged nucleoli. They demonstrated positivity for factor VIII-related antigen, CD 31 and CD 34 and were cytokeratin negative. The histopathological changes were typical of angiosarcoma. The patient first refused total mastectomy but agreed to the operation in May 1995. The post-operative histological diagnosis was angiosarcoma but adenocarcinoma cells were also found. The treatment was thereafter palliative and the patient died 9 months later. Autopsy was not performed.

Case 2

A 75-year-old female had been treated for T1N0M0 ductal breast cancer with a mastectomy in November 1992. She received post-operative radiotherapy (total dose 6,000 cGy) for four months. In 1993, erythema appeared on the irradiated breast. It was first regarded as an irradiation reaction and later treated as an infection with antibiotics. In April 1997, the patient was sent to a dermatologist, since the erythema had developed into infiltrated, dark-red patches (Fig. 1). The clinical picture was typical of angiosarcoma. A skin biopsy obtained from a patch revealed normal epidermis. In the dermis atypical capillaries with prominent endothelial cells were seen between the collagen bundles. The cells had abundant nucleoli and some mitoses (Fig. 2a). The atypical endothelial cells were clearly positive for CD 31 and slightly positive for factor VIII-related antigen (Fig. 2b). The histopathological findings indicated angiosarcoma.

In June 1997, total resection of the irradiated breast was performed. The post-operative histopathological diagnosis was grade IV angiosarcoma and the operation seemed to be radical. Thereafter the patient has been well. No relapses have been noticed until December 1997.

Case 3

A 64-year-old female, suffering from coronary disease and hypertonia, had been treated for bilateral T2N1M0 breast carcinoma in 1980 with radical mastectomy, axillary removal and post-operative radiotherapy. Massive lymphedema developed soon after surgery on the left upper extremity and was treated with manual lymphatherapy. The follow-up was performed until April 1990 and thereafter the patient was regarded as cured.

In December 1990, a blue haematoma-like patch developed on the edematous arm. The patch gradually enlarged, edema increased and haemorrhagic blisters appeared on the area. The infiltration was painful.

At dermatological consultation in January 1991, the clinical picture suggested lymphangiosarcoma of Stewart-Treves. Computer tomography revealed massive lymphedema and an expansive net-like tumor, but no bone destruction.

The biopsy of the tumor revealed atypical capillaries which invaded from the dermis into the subcutis. The prominent atypical endothelial cells were irregularly shaped, had large nucleoli and mitotic activity could be seen. The cells stained positively for factor VIII-related antigen and were negative for S-100 and cytokeratin antibodies. The histopathological picture was typical of angiosarcoma.

The left upper extremity was amputated 2 weeks after the histopathological diagnosis. The operation was considered to be radical and no additional therapy was given. The patient was followed until January 1996 and was free from recurrence. The patient died of a myocardial infarction in April 1996, autopsy was not done.

Case 4

A 76-year-old female had been treated for breast cancer with a radical mastectomy, axillary removal and post-operative radiation therapy in 1987. Persistant lymphedema of the right upper extremity developed after the operation, which was treated with manual lymphatherapy. In the follow-up no relapses were noticed. In January 1997, a large haematoma-like infiltration appeared on the edematous area of the right arm (Fig. 3).

In the skin biopsy, extensive capillary proliferation and infiltration of atypical endothelial cells with large nucleoli could be seen. The endothelial cells were positive for CD31. The histopathological picture corresponded to angiosarcoma.

Since the general condition of the patient was weak, she received only palliative 20 Gy radiation therapy without surgery in March 1997 and died a few weeks later. Autopsy was not performed.

Discussion

Angiosarcoma is a rare, highly malignant disease. Angiosarcomas appearing on edematous or irradiated skin areas are especially rare. To the best of our knowledge, 27 cases of angiosarcoma, including our cases 1 and 2, appearing on irradiated breast skin, have so far been reported [6-24] (Table I). Stewart-Treves-type angiosarcomas are more common since over 200 cases have so far been published [17].

The clinical picture of angiosarcoma with violaceous infiltrations is typical. It should be differentiated from skin metastases of breast cancer, especially from "carcinoma erysipeloides", a cancer growing in the lymphatic vessels of the breast. This form of breast cancer is, however, not as red-blue in colour as angiosarcoma. Histologically, these two malignancies are easy to differentiate because carcinoma cells stain with cytokeratin antibodies, whereas angiosarcoma cells stain with endothelial markers. Erysipelas of the breast is also easily differentiated from angiosarcoma as there is rapid onset, fever and increased serum C-reactive protein. However, vasculitis which was first suspected in our case 1 is not as localised as angiosarcoma.

Differential diagnosis of recurrent pyogenic granuloma, papular angioplasia, Masson's pseudo-angiosarcoma, Kaposi's sarcoma and angiolyphoid hyperplasia with eosinophilia must be based on the histopathological findings [5].

The pathomechanisms leading to angiosarcoma after radiation therapy or chronic persistent edema remain obscure. It has been suggested that radiation therapy might induce cellular edema and the consequent development of angiosarcoma. Hence, the pathomechanisms in radiation-induced and Stewart-Treves-type angiosarcoma could basically be the same [7].

Post-irradiation angiosarcomas appear in post-menopausal women on irradiated breast skin after a 3-5 year latent period, after radiation therapy of at least 25-80 Gy [6]. Both of our cases meet these criteria, even if it was difficult to determine exactly the first appearance of the first angiosarcoma lesions in case 2. Our case 1 is, so far, the youngest patient with post-irradiation angiosarcoma of the breast in the literature (Table I). She also had the longest survival time, although there was a two year delay from appearance of the first symptoms until the definitive diagnosis was made. This may have been due to the rarity of the disease; clinicians may not immediately recognize the typical clinical picture. In the early stage of the disease it may also be difficult to differentiate histologically neoplastic capillaries from benign capillary proliferation, because the endothelial cells are only slightly atypical and no mitoses are seen. The skin biopsy specimen should therefore always be taken from the most infiltrated and darkest area and not from the edge of the lesion.

In general, the prognosis for angiosarcomas seems to be poor due to its undifferentiated nature, frequently delayed diagnosis and haemato- or lymphogenic metastases to the lungs, liver and other organs [3, 5]. The mean survival time after diagnosis of post-irradiation angiosarcoma for all published patients is 17.5 months (Table I). Nine out of 27 patients died within 5-63 months after definitive diagnosis (Table I). The prognosis for Stewart-Treves-type angiosarcoma is roughly the same [3]. Due to the aggressive nature of angiosarcoma early surgical excision of the tumor or amputation of the extremity is crucial. Angiosarcoma is initially sensitive to radiotherapy but later becomes more resistant. Polychemotherapy may lead to prolonged survival time and hyperthermia and recombinant interleukin-2 injections have been reported to be favourable in treatment of individual cases [9].

The breast carcinomas of 22 out of the 25 patients with breast angiosarcoma, including our patients, had been treated by mastectomy and radiation therapy (Table I) [6, 7]. The occurrence of post-irradiation angiosarcomas in postmenopausal women raises the question as to whether mastectomy and additional radiotherapy is the most rational treatment of localized breast cancer in older patients. Veronesi, et al. have suggested that additional radiotherapy does not improve the prognosis for patients over 55-years-old treated with quadrantectomy [25]. Recent studies, however, show that these women also benefit from radiotherapy [26]. It is therefore obvious that dermatologists will be confronted with radiation-induced angiosarcomas more often in the future. Thus, a history of malignant disease treated with radiotherapy warrants early biopsy of any skin rash appearing on irradiated or edematous skin areas.

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