Cutaneous breast angiosarcoma after conserving treatment of breast cancer

ARTICLE

Cutaneous angiosarcoma is a rare, highly malignant soft tissue sarcoma that sometimes occurs in the breast as a late sequela of conserving therapy of breast cancer. Currently, there are about 60 cases reported in the literature [1-7]. We report on a 79-year-old female who developed well-differentiated angiosarcoma of the left breast 5.5 years after breast conservation surgery and adjuvant radiotherapy.

Case report

In May 1993, the patient was diagnosed with bilateral invasive ductal breast cancer (age at diagnosis: 73.5 years). She underwent a modified radical mastectomy of the right breast, breast conservation therapy of the left breast, and bilateral dissection of the axillary lymph nodes. Histopathological tumor stage was pT2 pN0 (0/8) on the right, and pT1 pN0 (0/8) on the left with clear surgical margins. Immunohistochemically, the tumor was positive for estrogen and weakly positive for progesterone receptors. Therefore, Tamoxifen was given for 4 years at a daily oral dose of 30 mg.

Eight weeks after surgery, she received a course of adjuvant radiation therapy to the left breast and axillary lymph nodes with a total dose of 50.4 Gy (single dose: 1.8 Gy, 5 fractions per week, overall treatment time: 40 days) using 9 MV photons of a linear accelerator via tangential opposed fields (gantry 320°/140°, field size: 20 cm x 11 cm). Lymphedema of the left breast was noted shortly after operation and progressed further to chronic hard, taut edema after completion of the radiation treatment course.

Follow-up investigations were initially performed every 3 months for one year, and afterwards every 6 months. Chronic lymphedema especially of the medial aspect of the left breast was always present. Regularly performed mammography controls demonstrated a progredient thickening of the skin in this area up to three times normal thickness but no sign of locally recurrent breast cancer.

Four years after cessation of the initial treatment, in the chronic lymphedematous irradiated left breast, additional discoloration of the skin was observed by the dermatologist, interpreted as inflammatory dermatitis, and therefore locally treated with corticosteroids. Due to persistent cutaneous symptoms, the patient underwent a first punch biopsy of the suspicious area 6 months later. Histologically, the specimen demonstrated epidermal atrophy and a three times thickening of the corial connective tissue. Furthermore, ectatic capillary vessels were found in the superficial dermis, and perivascular lymphocytic infiltrates were observed. The specimen was diagnosed as scar tissue with atypical vascular lesion. However, the discoloration of the irradiated skin progressed further, accompanied by characteristic, rapidly growing, purple nodules, clinically suspicious for angiosarcoma (Fig. 1A).

Thus, a second deep excisional biopsy was taken. Histologically, the specimens showed the presence of small capillary-sized vessels forming anastomosing networks and dissecting between the collagen bundles of the dermal stroma, with focal invasion into subcutis (Fig. 1B). The nuclear atypia of the endothelial cells was mild to moderate. Focally mitotic figures could be detected. Furthermore, inflammatory infiltrates of lymphocytes, plasma cells as well as granulocytes were observed. Immunohistochemical studies revealed positive expression of CD 34 (human hematoprogenitor cell antigen) in the cytoplasm of tumour cells (Fig. 1B). The proliferation fraction as measured with Ki67 was focally different, but partially reached >= 50% of the neoplastic endothelial cells. Taken together, these findings were diagnostic for cutaneous well-differentiated angiosarcoma.

Preoperative staging including chest X-ray, computed tomography of the chest (Fig. 1C) and the abdomen, and abdominal ultrasound failed to reveal extra-cutaneous involvement. Therefore, a complete mastectomy was performed with cutaneous surgical safety margins of 5 cm. The 20 cm x 19 cm large surgical specimen demonstrated a 10 cm x 11 cm large cutaneous area of vascular tumour. Histologically, a well-differentiated angiosarcoma diffusely located in the up-to-1 cm thick dermis with only focal invasion of the superficial part of subcutaneous fat but without extension into mammary parenchyma and clear peripheral and deep surgical margins was diagnosed.

Four months after the operation purplish skin nodules were noted around the first mastectomy incision, suspicious for local recurrence. The malignant lesion along the scar on the left anterior chest wall skin was excised (specimen: 9 x 4 x 2 cm) and primarily closed. Histologically, the surgical specimen was diagnosed as papillary proliferations of a recurrent well-differentiated cutaneous angiosarcoma with clear deep and peripheral surgical margins. In addition, a typical vascular lesion of capillary type in the skin was found, which focally reached one lateral margin. This was preferentially related to the primary radiation treatment. However, a relation to well-differentiated angiosarcoma could not be entirely excluded. Retrospectively, this is very likely. Furthermore, subcutaneous lymphangiectases were described.

Three months after the second operation, again a 2 x 1 cm purplish nodule involving skin and subcutaneous tissue close to the chest wall scar became evident. The involved area was widely excised (specimen: 5 x 3 x 1 cm) and the defect was skin grafted. Examination of the surgical specimen once more confirmed the recurrence of well-differentiated cutaneous angiosarcoma. Histologically, the peripheral margins were clear but the deep surgical margin was focally reached. Three months later, the third local recurrence was diagnosed and treated by wide local excision with clear peripheral and deep surgical margins. The defect was plastically grafted.

Three months later the patient complained about cervico-brachyalgia, paraesthesia and incomplete paresis of the right arm. CT and MRI demonstrated osseous metastasis which involved vertebrae C5-Th1 with extra-osseous manifestations leading to compression of the spinal cord. Therefore, palliative radiation therapy of the cervico-thoracic spine (C4-Th2) with a total dose of 30 Gy (single dose: 3.0 Gy, 5 fractions per week, overall treatment time: 12 days) using 6 MV photons via anterior-posterior opposed fields was performed which completely removed neurological complaints. Three months after the palliative treatment control CT and MRI demonstrated almost complete regression of the extra-osseous metastatic manifestations as well as stabilization and no further progression of the osseous involvement. Clinically, the patient was free of neurological complaints.

Finally, 6 months after the third local recurrence again metastatic lesions on the left anterior chest wall were diagnosed (Fig. 1D). The patient was referred to the surgeon for local excision (specimen: 9 x 6 x 1.5 cm) and the defect was plastically grafted again. Histology once more confirmed the recurrence of well-differentiated cutaneous angiosarcoma with wide clear peripheral and deep surgical margins. At present, the patient is free of locally recurrent tumour for 7 months.

Discussion

Sarcomas of the soft tissue account for less than 1% of all the malignant tumors. Angiosarcomas comprise only 2% of all sarcomas, and sixty percent of angiosarcomas appear in the skin or superficial soft tissues [8]. They are therefore rare, but life-threatening, highly malignant vascular tumors.

Histologically, multiple biopsies may show different patterns of differentiation, and tumor tissue usually extends far beyond the clinically visible boundaries of the lesion. During the development of the angiosarcoma, at least three growth patterns can be observed, often within the same tumor. They include: (1) a well differentiated angio-matous pattern; (2) a metaplastic spindle cell pattern with moderately differentiated vascular spaces; and (3) an undifferentiated solid or sarcomatous pattern [9].

Clinically, cutaneous angiosarcomas most often show one of three patterns. First and most commonly, it appears in elderly persons as multifocal bruiselike lesions in the head and neck region [9]. Second in frequency, it is observed in areas of long-lasting chronic lymphedema, 90% after radical mastectomy with or without radiation therapy, which was primarily described in 1948 by Stewart and Treves [19]. Afterwards approximately 360 cases of the so-called Stewart-Treves syndrome have been reported in the literature [11]. In those cases the latent period averages 10 years with a range of 4 to 27 years [12]. Only 10% are due to lymphedema of other causes, such as trauma [13], congenital factors [14], postsurgical obstruction [15], filarial infestation [13] or idiopathic causes [8] including recurrent cellulitis [16].

Third and least common is angiosarcoma developing as a sequela of previous radiation therapy. Radiation induced angiosarcoma fulfils the following criteria: (1) there must be a history of irradiation, (2) the tumor must arise in the field of radiation or in the directly adjacent skin, (3) a latency period of several years must elapse, and (4) there must be histologic confirmation [1]. The most common site of radiation induced angiosarcoma is the skin or underlying soft tissue [7].

Radiation induced angiosarcoma has been documented after treatment for benign conditions such as eczema [17], sinusitis [18], and hemangioma [19]. Caldwell et al. [19] reviewed 11 cases of cutaneous angiosarcoma that developed in the field of radiation or in the directly adjacent skin subsequent to radiotherapy of hemangiomas (median age at initial therapy: 2.8 years, median radiation dose: 35 Gy). In those cases the latent period averages 21.8 years with a range of 14 to 33 years [19].

The main indication for radiotherapy, however, is the treatment of malignant diseases, and its efficacy in breast conservation therapy of breast cancer has been proven over time. Cutaneous breast angiosarcoma as a late sequela of conservative treatment for breast cancer was first described in 1987 [20].

Since that time, about 60 additional cases have been reported in the literature [1-7]. In those cases the latent period averages 6.2 years with a range of 4.8 to 9 years [3].

Etiology and pathogenesis of angiosarcoma are poorly understood. Cutaneous angiosarcoma can occur either independently or in association with chronic lymphedema, after irradiation or after persistent lymphedema promoted by radiation therapy [12]. The estimated risk of developing radiation-associated angiosarcoma after breast conserving therapy is 0.04% whereas primary breast angiosarcoma occurs at a rate of 0.05% of all malignant tumors of the breast [6].

A high proportion (67%) of the previously reported cases of radiation-associated angiosarcoma have a long period of breast lymphedema [21, 22]. As in our case, early temporary lymphedema occurs in most irradiated breasts, especially if a complete axillary dissection has been performed. Lymphedema that chronically persists is unusual, especially if proper noninvasive complex lymphedema therapy is performed. Some authors suggest that the presence of chronic lymphedema in the breast after radiation therapy indicates that the role of radiotherapy may rather be indirect by promoting lymphedema than by direct tumor induction [1]. However, angiosarcoma induction by treatment still remains controversial [3].

The few cases of cutaneous breast angiosarcoma after conservative treatment for breast cancer reported in the literature, demonstrate that these lesions are difficult to diagnose due to their rarity and their highly variable and benign appearance, which sometimes may mimic radiation-induced cutaneous changes. Since chronic lymphedema in the irradiated breast possibly contributes to the development of angiosarcoma and thus may be an early warning sign, long-term clinical surveillance of these patients for this rare malignancy is recommended. Discoloration of the irradiated skin and the characteristic purple nodules are highly suspicious. Skin biopsies should be taken in patients who present with new skin lesions after conservative treatment for breast cancer.

Article accepted on 23/5/01

REFERENCES

1. Majeski J, Austin RM, Fitzgerald RH. Cutaneous angiosarcoma in an irradiated breast after breast conservation therapy for cancer: association with chronic breast lymphedema. J Surg Oncol 2000; 74: 208-12.

2. Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol 1999; 9: 118-21.

3. Marchal C, Weber B, de Lafontan B, Resbeut M, Mignotte H, du Chatelard PP, Cutuli B, Reme-Saumon M, Broussier-Leroux A, Chaplain G, Lesaunier F, Dilhuydy JM, Lagrange JL. Nine breast angiosarcomas after conservative treatment for breast carcinoma: a survey from French comprehensive Cancer Centers. Int J Radiat Oncol Biol Phys 1999; 44: 113-9.

4. Kim MK, Huh SJ, Kim DY, Yang JH, Han J, Ahn YC, Lim DH. Secondary angiosarcoma following irradiation - case report and review of the literature. Radiat Med 1998; 16: 55-60.

5. Zucali R, Merson M, Placucci M, Di Palma S, Veronesi U. Soft tissue sarcoma of the breast after conservative surgery and irradiation for early mammary cancer. Radiother Oncol 1994; 30: 271-3.

6.Wijnmaalen A, van Ooijen B, van Geel BN, Henzen-Logmans SC, Treurniet-Donker AD. Angiosarcoma of the breast following lumpectomy, axillary lymph node dissection, and radiotherapy for primary breast cancer: three case reports and a review of the literature. Int J Radiat Oncol Biol Phys 1993; 26: 135-9.

7. Edeiken S, Russo DP, Knecht J, Parry LA, Thompson RM. Angiosarcoma after tylectomy and radiation therapy for carcinoma of the breast. Cancer 1992; 70: 644-7.

8. Mark RJ, Poen JC, Tran LM, Fu YS, Juillard GF. Angiosarcoma - a report of 67 patients and a review of the literature. Cancer 1996; 77: 2400-6.

9. Haustein UF. Angiosarcoma of the face and scalp. Int J Dermatol 1991; 30: 851-6.

10. Stewart FW, Treves N. Lymphangiosarcoma in post mastectomy lymphedema. A report of six cases in elephantiasis chirurgica. Cancer 1948; 1: 64-81.

11. Bisceglia M, Attino V, D'Addetta C, Murgo R, Fletcher CD. Early stage Stewart-Treves syndrome: report of 2 cases and review of the literature. Pathologica 1996; 88: 483-90.

12. Enzinger F, Weiss S. Soft tissue tumors. 3rd ed. St. Louis: CV Mosby, 1995: 641-77.

13. Sordillo PP, Chapmann R, Hajdu SI, Magill GB, Golbey RB. Lymphangiosarcoma. Cancer 1981; 48: 1674-9.

14. Merrick TA, Erlandson RA, Hadju SI. Lymphangiosarcoma of congenitally lymphedmatous arm. Arch Pathol 1971; 91: 365-71.

15. Calnan J, Cowdell RH. Lymphangioendothelioma of the anterior abdominal wall. Br J Surg 1959; 46: 375-9.

16. Hallel-Halevy D, Yerushalmi J, Grunwald MH, Avinoach I, Halevy S. Stewart-Treves syndrome in a patient with elephantiasis. J Am Acad Dermatol 1999; 41: 349-50.

17. Mach K. Zur Frage des Lymphangioendothelioms. Arch Klin Exp Dermatol 1966; 226: 318-35.

18. Hodgkinson DJ, Soule EH, Woods JE. Cutaneous angiosarcoma of the head and neck. Cancer 1979; 44: 1106-13.

19. Caldwell JB, Ryan MT, Benson PM, James WD. Cutaneous angiosarcoma arising in the radiation site of a congenital hemangioma. J Am Acad Dermatol 1995; 33: 865-70.

20. Benda JA, Al-Jurf AS, Benson AB. Angiosarcoma of the breast following segmental mastectomy complicated by lymphedema. Am J Clin Pathol 1987; 87: 651-5.

21. Joshi MG, Crosson AW, Tahan SR. Paget's disease of the nipple and angiosarcoma of the breast following excision and radiation therapy for carcinoma of the breast. Mod Pathol 1995; 8: 1-4.

22. Del Mastro L, Garrone O, Guenzi M, Cafiero F, Nicolo G, Rosso R, Venturini M. Angiosarcoma of the residual breast after conservative surgery and radiotherapy for primary carcinoma. Annals of Oncology 1994; 5: 163-5.