Angiosarcoma after conservation treatment for breast carcinoma: Our experience and a review of the literature

CLINICAL

REVIEW

Angiosarcoma after conservation treatment for breast carcinoma: Our experience and a review of the literature Ja´nos Fodor, MD, PhD, DSc,a Zsolt Orosz, MD, PhD,b E´va Szabo´, MD,c Zolta´n Sulyok, MD,d Csaba Polga´r, MD, PhD,a Zolta´n Zaka, MD,a and Tibor Major, PhDa Budapest, Hungary The development of angiosarcoma of the breast is a recognized complication of breast conservation therapy (BCT), but the evolution, prevalence, and outcome have not been accurately established. We sought to evaluate and review the clinicopathologic, prognostic, and treatment attributes of angiosarcoma arising in the irradiated breast after BCT. We conducted a retrospective chart and slide review of 8 patients seen between 1996 and 2004 with a diagnosis of secondary angiosarcoma. All were treated with mastectomy. Clinical and histopathologic findings were studied and previously reported cases were reviewed. Primary surgery-related breast edema and cellulitis was observed in 7 and 5 patients of the 8 patients studied, respectively. Postirradiation breast edema and grade 2/3 fibrosis occurred in 5 and 8 patients, respectively. The mean age of the patients at onset of the breast cancer and angiosarcoma was 65 and 72 years, respectively. The mean latency period between the treatment of the breast cancer and the diagnosis of angiosarcoma was 75 months. The actuarial rate of 2-year survival for patients presented with single (n = 4) compared with multiple (n = 4) skin lesions was 50% and 0%, respectively (P = .0233). The estimated incidence of angiosarcoma after BCT was found to be 0.14 %. BCT-associated angiosarcoma arises after a relatively brief interval, and breast edema-fibrosis can possibly contribute to its development. Special attention should be paid to skin changes occurring after BCT. The extent of skin lesions is predictive of survival. As shown by a review of the literature, angiosarcomas are often resistant to surgery, chemotherapy, and radiotherapy, and targeted therapy against tumor biological properties may be a new approach to angiosarcoma treatment. ( J Am Acad Dermatol 2006;54:499-504.)

T

he incidence of secondary angiosarcoma arising in the irradiated breast after breast conservation therapy (BCT) has increased as more women are treated with partial mastectomy and radiotherapy.1-4 Lymphedema of the ipsilateral arm has been considered as a primary risk factor for post-mastectomy upper extremity angiosarcoma.5 In such cases the role of radiotherapy (RT) is indirect by promoting lymphatic stasis. Whether post-BCT angiosarcoma of the breast is induced by edema or radiation or has a multifactorial origin is still unknown. The reported incidence of post-RT breast edema is from 0% to 100% in patients with BCT-

From the Departments of Radiotherapy,a Human and Experimental Tumor Pathology,b Diagnostic Radiology,c General and Thoracic Surgery,d National Institute of Oncology. Funding sources: None. Conflict of interest: None identified. Reprint requests: Dr Ja´nos Fodor, Department of Radiotherapy, National Institute of Oncology, Ra´th Gyo¨rgy u. 7-9, Budapest H-1122, Hungary. E-mail: [email protected]. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.017

associated angiosarcoma.1,6-11 The incidence of breast edema may be underestimated since all patients treated with BCT have some degree of edema, perhaps subclinical.4,12 Classically defined radiationinduced sarcomas develop after a latency period of not less than 10 years.13,14 The delay between the treatment of breast cancer and the diagnosis of BCTassociated angiosarcoma is shorter, approximately 4 to 7 years.4,7,11,15-17 Angiosarcoma arising in a breast after partial mastectomy not followed by RT has been described.18 Radiation exposure alone is unlikely to complete the cause and effect equation.4,8,9 To gain better insight into this emerging entity, we studied 8 patients with BCT-associated angiosarcoma seen at the National Institute of Oncology Budapest and review the relevant literature.

MATERIAL AND METHODS Eight women with post-BCT angiosarcoma were diagnosed at the National Institute of Oncology, Budapest between 1996 and 2004. Before 1996, no known cases of BCT-associated angiosarcoma had been treated in our institute. The medical records were reviewed for such features as primary surgery, 499

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Table I. Characteristics of the primary breast cancer Patient no.

Table II. Breast cancer treatment-related complications Breast cellulitis

Age (y)*

Tumory

1 2 3 4 5

75 63 57 73 66

Right/4, T1N0 Right/5, T2N0 Left/4, T1N0 Left/4, T2N0 Right/4, T2N1

6

67

7 8

65 54

Adjuvant therapy

50 Gy (breast) 1 TAM 50 Gy (breast) 1 TAM 46 Gy (breast) 1 TAM 48 Gy (breast) 50 Gy (breast 1 axilla) 1 TAM Right/4, T2N1 50 Gy (breast 1 axilla) 1 TAM Right/5, T1N0 50 Gy (breast) Left/4, T1N1 50 Gy (breast 1 axilla) 1 Ch

Ch, Chemotherapy; TAM, tamoxifen. *Median age: 66 years; mean age: 65 years. y Pathological T and N and subanatomical location.

pathology, adjuvant treatment, and treatment-related complications. Primary surgery for breast cancer consisted of wide tumor excision and axillary dissection (level I-II 6 III). Patients were mainly node negative, with T1 or small T2 (22-26 mm) ductal, and in one case ductolobular, cancer without an extended intraductal component. In each case, tumor excision was complete by histologic evaluation. One patient had metachronous bilateral breast cancer. One patient received adjuvant chemotherapy. Five patients took tamoxifen, 20 mg/d, for 5 years. The daily fraction of adjuvant irradiation was 2 Gy, using 6 to 9 MV photon or telecobalt gamma beam. Patient and treatment characteristics are summarized in Table I. Patients were seen in follow-up at 3- to 6month intervals until the end of the fifth year and annually thereafter. Chest x-rays, mammograms, breast and abdominal ultrasound examination, and blood tests were performed at least yearly. Supplemented magnetic resonance imaging was used occasionally. The radiation effects to the skin and subcutaneous tissues were scored by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme.19 Angiosarcoma was verified by incisional biopsy or surgical excision in every case, and patients were subjected to mastectomy. Factor VIIIerelated antigen, CD34, and CD31 were examined by means of paraffin-section immunohistochemistry. Postmastectomy chemotherapy or radiation therapy was not given. After local relapse, patients were treated with surgical excision or palliative irradiation, and chemotherapy was administered for 3 patients. Pertinent information from the published literature was retrieved and reviewed. MEDLINE searches

Patient no.

Pre-RT

Post-RT

Yes Yes Yes Yes Yes No No No

No No Yes No Yes No No No

1 2 3 4 5 6 7 8

Breast edema

Fibrosis (grade)

Pre-RT Post-RT

Post-RT

Yes Yes Yes Yes Yes Yes Yes No

Yes No Yes Yes Yesy Yes No No

3 2 2* 3* 3 Grade 2 Grade 2 Grade 2

RT, Radiotherapy. *Grade 2 telangiectasia and fat necrosis also present. y Arm edema also present.

were done. The content of this review is based on critical examination of all published articles with a minimum of 3 cases.

RESULTS The mean age of the patients at the time of breast cancer treatment was 65 years (range, 54-75 years). The characteristics of primary breast cancers are given in Table I. The pre- and post-RT complications are listed in Table II. A distinctive form of perioperative breast cellulitis (erythema, edema, and warmth without fever and malaise) was observed in 5 patients after seroma aspiration. In two patients post-RT relapsing cellulitis was also observed (in patient 3, two episodes; in patient 5, 3 episodes). The time from RT to the initial episode of cellulitis was 9 and 15 months for patient 3 and patient 5, respectively. In case 3 the first episode of post-RT cellulitis was clinically erysipelas, and the patient responded to penicillin. The characteristics of the subsequent angiosarcomas and survival times are given in Table III. The mean age of the patients at the time of diagnosis of angiosarcoma was 72 years (range, 61-80 years). All patients presented with striking skin changes (bluish black nodular lesions and/or reddish yellowish discoloration), which were single in 4 and multiple in 4 patients. The skin was swelling in 6 cases, and mammography revealed increased skin thickening. Breast magnetic resonance images showed suspect tissue mass in only two cases. The diagnosis of angiosarcoma was established by histologic examination in all cases. The tumor cells were reactive for factor VIIIerelated antigen and CD31/CD34 in each case. The high-grade (grade II or III) lesion was characteristic. The mean latency time between the histologic diagnosis of breast cancer and angiosarcoma was 75 months (range, 56-110 months). After

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Table III. Characteristics of angiosarcomas Patient no.

Age (y)*

Histology grade

1 2 3 4 5 6 7 8

80 70 67 80 71 72 71 61

2 2 3 2 2 3 1-2 2

Skin lesion

Delay BC/AS (mo)

Single 56 Multiple 84 Multiple 110 Multiple 80 Multiple 63 Single 58 Single 72 Single 76

LRF survival (mo)

Survival (mo)

14y 5y 2y 5y 1y 2y 90 10

22z 18z 21z 13z 10z 21 92 11

Delay BC/AS, Latency time between histologic diagnosis of breast cancer and angiosarcoma (median, 74 mo; mean, 75 mo); LRF survival, time from mastectomy to local (chest wall) relapse or to last follow-up (median, 5 mo; mean, 16 mo); Survival, survival after histologic diagnosis of angiosarcoma (median, 19.5 mo; mean, 26 mo). *Median age, 71 y; mean age, 72 y. y Local relapse. z Died of angiosarcoma.

radical mastectomy 6 of the 8 patients had local relapse. One of them is alive without disease after local excision and docetaxel (Taxotere) therapy. The mean local relapse-free survival after mastectomy was 16 months (range, 1-90 months), and the actuarial rate of 2-year local relapse-free survival was 19%. The local relapse-free time was brief, from 1 to 5 months, for patients presented with multifocal skin lesions (Fig 1). Five patients died of distant metastasis (site of first metastasis: pulmonary, 1; bony, 2; contralateral breast, 2). The mean survival time after the histologic diagnosis of angiosarcoma was 26 months (range, 10-92 months), and the actuarial rate of 2-year angiosarcoma-specific survival was 18%. The extent of skin involvement had a significant impact on survival. The actuarial rate of 2-year survival for patients who had presented with unifocal compared with multifocal skin lesions was 50% and 0%, respectively (P = .0233). The 8 patients underwent BCT between 1992 and 1999. The survey revealed that during this period in our institute the total number of women subjected to partial mastectomy and irradiation was 6729, resulting in an incidence of 1.19 angiosarcomas per thousand treated patients. On the assumption that 85% of the patients survive for 5 years, only 5720 were at risk for developing secondary angiosarcoma since the median latency period was 74 months. Therefore the incidence of angiosarcoma may be as high as 0.14 % in our patient population.

DISCUSSION The results in the current study regarding the delay between treatment of the breast cancer and diagnosis of the angiosarcoma, age of the patients at

Fig 1. A, Patient 5. Multiple skin lesions on right breast: swelling, discoloration, erythematous areas, and black nodule. Biopsy findings revealed angiosarcoma, and mastectomy was performed. B, Mastectomy scar and flap show multiple local relapse areas 4 weeks after surgery.

onset of the angiosarcoma, time to local relapse and survival, concur with the majority of reported series with a minimum of 3 cases (Table IV).20-22 All the authors emphasize that post-BCT angiosarcoma must be suspected early and patients must be subjected to mastectomy, radical mastectomy, or chest wall resection to provide for wide-margin. In the study of Strobbe et al,1 microscopically complete surgical resection was predictive of survival. In our series survival was related to the extent of skin lesions, with a worse survival for patients presenting with multifocal spread. Even after radical surgery local failure is common, and despite several therapeutic attempts (multiple excision, chemotherapy, radiotherapy) to cure local relapse, the prognosis remains very poor.4,7,9,15 Discrepancies may be noted between results in the study by Feigenberg et al11 and those of other series. They reported the shortest time (mean, 1.3 months) to local relapse

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Table IV. Results from series with a minimum of 3 patients with breast angiosarcoma Authors

Billings et al17 Strobbe et al1 Marchal et al7 Lagrange et al16 Lamblin et al9 Sener et al10 Feigenberg et al11 Molitor, Spielmann, & Contesso15 Wijnmaalen et al20 Stokkel & Peterse21 Rao et al22 Present study

Age (y)

Patient no.

BC

AS

27 21 9 6 4 4 3 3

NS 60* 63 64 57 67 68 58

69 NS 69 69 64 75 73 63

3 3 3 8

55 57 58 65

61 62 67 72

Delay BC/AS (mo)

66 74* 74 60 89 90 66 60 74 64 102 75

Edema (%)

Fibrosis (%)

LFRS (mo)

LF (%)

26 (5/19) 33 (7/21) 11 (1/9) NS 100 (4/4) 50 (2/4) 0 (0/3) NS

NS 86 (18/21) NS NS 100 (4/4) NS NS NS

NS 3.5* 7.5* NS 18.5 2.8 1.3 10.3*

64 67 100 83 25 100 100 67

NS NS NS 63 (5/8)

100 (3/3) NS NS 100 (8/8)

17.7 15.3 17 16

33 67 33 75

Survival (mo)

Mortality rate (%)

(14/22) (14/21) (9/9) (5/6) (1/4) (4/4) (3/3) (2/3)

33.5* 28 15.5* 16.3 20 10.8 33 17

45 33 89 67 50 25 0 67

(10/22) (7/21) (8/9) (4/6) (2/4) (1/4) (0/3) (2/3)

(1/3) (2/3) (1/3) (6/8)

23.7 27 20 26

33 33 33 63

(1/3) (1/3) (1/3) (5/8)

AS, Angiosarcoma; BC, breast cancer; Delay BC/AS, delay between diagnosis of breast cancer and angiosarcoma; LF, local failure; LRFS, local relapse-free survival after mastectomy; NS, not stated. *Median values, all others mean values.

after mastectomy, and both local control and survival rate were 100% after hyperfractionated RT for local relapse. On the whole, 47 of 89 patients (53%) are reported to be alive at the time of publication of their report, and the mean-median survival time is from 10.8 to 33.5 months (Table IV). Studies have shown that angiosarcomas are often resistant to chemotherapy, radiotherapy, and surgery, and new treatment options are needed.4,7,9,15 Better understanding of the pathogenesis of angiosarcoma may lead to improved therapy.23,24 Vascular endothelial growth factor is a potent angiogenesis factor and has been demonstrated in angiosarcomas.25,26 Protein kinase inhibitors are potent against vascular endothelial growth factor receptor. Experimental and clinical evaluations of biological anticancer agents are promising research areas, and targeted therapy may be a new approach to the treatment of angiosarcoma.27-31 Observations indicate that patients treated with BCT have a statistically increased risk of developing subsequent angiosarcoma.3,32 The estimated incidence of post-BCT angiosarcoma was found to be 0.14% in our patient population. In other series the prevalence is from 0.05% to 0.16%.1,7,32 One of the first reported cases of angiosarcoma occurring after partial mastectomy was of a nonirradiated edematous breast.18 The chronic breast edema was induced by indolent and recurrent perioperative infection, and the adjuvant RT was omitted. Using data from the Surveillance, Epidemiology and End Results registries, Yap et al3 also found 5 secondary sarcomas out of 274,572 breast cancer patients, which developed in a nonirradiated breast. The role of RT, whether causative or promoting

edema, is not yet clear. Edema can be attributed to lymphatic obstruction caused by surgical interruption or fibrosis. RT-related fibrosis is also a potent factor for chronic edema.33 Essentially, all patients treated with BCT have at least subclinical breast edema.4 The incidence of the overt RT-related edema is from 0% to 100% in the aforementioned series (Table IV). The incidence of the primary surgery-related preeadjuvant RT breast edema has not been evaluated in patients with secondary breast angiosarcoma. In our series it was present in 7 of 8 patients. The frequency of BCT-related breast fibrosis has been inconsistently reported. The rate was 86% in one study, and 100% in our and two other series (Table IV). Ipsilateral breast cellulitis is a novel complication of BCT for breast cancer and is currently more common.34,35 Breast cellulitis can be a relapsing complication of BCT and can be seen before, during, or after breast RT. Lymphatic obstruction from axillary dissection, breast seroma aspiration, and postoperative edema seem to indicate a subset of patients at risk of early breast cellulitis. Late cellulitis may be caused by the modifications of vascular and skin integrity by surgery and irradiation. Patients with chronic edema are predisposed to recurrent cellulitis.35-38 The incidence of BCT-related breast cellulitis in patients with secondary angiosarcoma has not been studied. In the current study, perioperative cellulitis was observed in 5 of 8 breasts (63%), and two patients (25%) also experienced postirradiation relapsing cellulitis. Edematous-fibrotic breast is an immunologically vulnerable site which is predisposed to cellulitis and vascular tumors by continual angiogenetic stimulus.39 Olivotto, Weir, and Kim-Sing37

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emphasize that some women with substantial postoperative breast edema with erythema may be better served by a policy of observation. On the other hand, the small difference in risk of secondary angiosarcoma for breast cancer patients receiving RT does not supersede the benefit of radiotherapy.3,14 In the current study all patients presented with various skin changes (discoloration, erythematous areas, bluish black nodules, edema), and spread of the lesion (single vs multiple) had a significant impact on survival. Special attention should be paid to skin changes occurring after BCT. The early detection of skin lesions is emphasized because they develop very quickly and multiply.7,16 The skinthickening sign in combination with the skin lesions raise suspicion of angiosarcoma.1,9,20 The spectrum of postirradiation vascular lesions of the mammary skin ranges from lymphangiectasialike vascular proliferation to angiosarcoma. These lesions can be challenging to diagnose and their more precise classification is emphasized. The development of cytogenetic and molecular analysis may constitute an additional aid to the diagnosis and classification.10,24,40,41 In conclusion, BCT-associated angiosarcoma is a rare disease with a poor prognosis and arises after a relatively brief time. Results of the current study revealed that both breast cancer surgeryerelated and RT-related complications are common in patients with subsequent breast angiosarcoma. Because of the wide application of BCT, it is worthy to receive further information regarding the actual frequency of the pathologic correlation between primary treatmenterelated complications and angiosarcoma development. The diagnosis of angiosarcoma must be suspected early, when skin lesions occur after BCT. Angiosarcomas are often resistant to surgery, chemotherapy, and radiotherapy. Increased understanding of the pathogenesis of angiosarcoma may lead to improved therapy. REFERENCES 1. Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutgers EJT. Angiosarcoma of the breast after conservation therapy for invasive cancer, the incidence and outcome. An unforeseen sequela. Breast Cancer Res Treat 1998;47:101-9. 2. Huang J, Mackillop WJ. Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 2001;92:172-80. 3. Yap J, Chuba PJ, Thomas R, Aref A, Lucas D, Severson RK, et al. Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 2002;52:1231-7. 4. Monroe AT, Feigenberg SJ, Mendenhall NP. Angiosarcoma after breast-conserving therapy. Cancer 2003;97:1832-40. 5. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema. A report of six cases in elephantiasis chirurgica. Cancer 1948;1:64-81.

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