Sarcoma of the Breast: Outcome and Reconstructive Options

Original Study

Sarcoma of the Breast: Outcome and Reconstructive Options Antonio Toesca,1 Gianluca Spitaleri,2 Tommaso De Pas,2 Edoardo Botteri,3,4 Oreste Gentilini,1 Luca Bottiglieri,5 Nicole Rotmentsz,3 Claudia Sangalli,1 Emilia Marrazzo,1 Enrico Cassano,6 Paolo Veronesi,1 Mario Rietjens,7 Alberto Luini1 Abstract This retrospective study analyzes prognostic factors, outcome, and reconstructive options in 37 patients affected by primary and secondary sarcoma of the breast. A 5-year cumulative incidence of death and events was 43.4% and 70.8%, respectively. Secondary sarcomas were associated with a higher risk of events. Patients undergoing breast conservative surgery or reconstruction after mastectomy did not show a worse prognosis compared with patients undergoing mastectomy. Introduction: Surgery is the mainstay of treatment for all breast sarcomas. The role of adjuvant chemotherapy and radiation therapy has not been clearly defined. The aim of this single-center retrospective study was to analyze prognostic factors, outcome, and recent advances. Materials and Methods: Data from 203 patients with all breast sarcomas treated in a single center were collected from 1996 to 2010. Phyllodes tumors and metastatic disease at presentation were excluded from the population. Thirty-six women and 1 man were included in the analysis. Local recurrence, metastatic disease, survival, and reconstructive outcome were evaluated. Results: Thirty-four patients out of 37 (91.9%) had an angiosarcoma and 3 had a stromal sarcoma (8.1%). Twenty-one patients (56.8%) had previously undergone breast radiation therapy for breast carcinoma or lymphoma. Twenty-six patients (70.3%) underwent mastectomy, 14 of whom (53.8%) with breast reconstruction. Thirty-six patients (97.3%) had free margins, 1 (2.7%) had a microscopically focally involved margin after surgery. Five patients received adjuvant chemotherapy and 6 received adjuvant radiation therapy. Median follow-up was 58 months (range, 4-146 months). Twelve sarcoma-related deaths were observed with a 5-year cumulative incidence of 43.4%. Twentyfour sarcoma-related events were observed with a 5-year cumulative incidence of 70.8%. The same figure was 49.7% in patients affected by primary sarcoma and 85.7% in patients with secondary sarcoma (P ⫽ .06). Conclusion: Secondary sarcomas were associated with a higher risk of events. Patients undergoing breast conservative surgery or reconstruction after mastectomy did not show a worse prognosis compared with patients undergoing mastectomy. Clinical Breast Cancer, Vol. 12, No. 6, 438-44 © 2012 Elsevier Inc. All rights reserved. Keywords: Angiosarcoma, Breast reconstruction, Breast sarcoma, Primary sarcoma, Secondary sarcoma

Introduction Sarcomas of the breast (BS) represent ⬍ 1% of entire body sarcomas.1-4 Some authors estimate 45 new cases per 10 million women.5-8

1

Division of Senology Division of Medical Oncology 3 Division of Epidemiology and Biostatistics 4 Department of Occupational Health, University of Milan, Milan, Italy 5 Division of Pathology 6 Division of Radiology 7 Division of Plastic Surgery European Institute of Oncology, Milan, Italy 2

438

Clinical Breast Cancer December 2012

The multiplicity of cells present in mesenchymal tissue of the mammary gland such as endothelial cells, fat cells, and muscle cells explain the different histologic types described (angiosarcoma, lipo-

Submitted: Apr 18, 2012; Revised: Aug 31, 2012; Accepted: Sep 13, 2012; Epub Oct 11, 2012 Address for correspondence: Antonio Toesca, MD, European Institute of Oncology, Division of Breast Surgery, Via Ripamonti 435, 20141 Milan, Italy Fax: ⫹39-02-94379228; e-mail contact: [email protected]

1526-8209/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2012.09.008

sarcoma, leiomyosarcoma, and the more rare chondrosarcoma and osteosarcoma). Many authors describe sarcoma according to their etiopathogenesis distinguishing primary sarcoma (PS) from secondary sarcoma (SS). Secondary sarcoma might occur in patients treated previously with radiation therapy for antecedent primary breast carcinoma and non-Hodgkin’s lymphoma. It might also occur in patients with chronic lymphoedema (Stewart-Treves syndrome) arising from axillary dissection for previous breast cancer, from Milroy’s disease or from chronic infections such as filariasis.1,9-11 A work-related angiosarcoma is also described, developed after long-term exposure and contact with the carcinogenic agent vinyl-chloride.1,12 The cumulative incidence of PS is 2.3 per 1000. The cumulative incidence of SS is 3.2 per 1000 at 15 years after radiation therapy.13 Surgery is the mainstay of treatment for all BSs. The option for surgical therapy include total mastectomy and breast conservative surgery.1,14,15 The role of chemotherapy and radiation therapy has not been clearly defined even though a trend in improved survival seems to be present.7 Their indication after surgery is derived from an extrapolation of data from large trials including all the soft tissue sarcomas irrespective of their primary site. Radiation therapy should be given as an adjuvant to surgery only for primary intermediate- to high-grade BS and a size larger than 5 cm. Data about adjuvant chemotherapy are more conflicting and a final demonstration of efficacy is lacking. Therefore, adjuvant chemotherapy is not standard treatment in soft tissue sarcomas and can be proposed as an option to the high-risk individual patient (having a Grade 2-3, deep, ⬎ 5-cm tumor). The current regimen used consisted of 3 or 5 courses of ifosfamide and epidoxorubicin at adequate dosages. For the recurrences cases the choice of the drug is driven by the hystotype (eg, paclitaxel is considered the most active drug in angiosarcomas).16 The aim of this single-center retrospective study was to analyze prognostic factors, outcome, reconstructive options, and recent advances.

Materials and Methods The research received the Institutional Review Board approval. Data from 203 patients with all BSs treated at the European Institute of Oncology (IEO) in Milan from 1996 to 2010 were retrieved from 2 institutional databases: the Breast Cancer database, which contains detailed and comprehensive information on all the breast cancer patients who received surgery at IEO, and the Tumor Registry, which collects basic information for all individuals presenting at IEO, regardless of the place of surgery. All the selected patients received at least 1 treatment in IEO. Metastatic disease at presentation, sarcomatoid carcinoma, dermatofibrosarcoma of the breast, benign, borderline, and malignant phyllodes tumors were excluded from the analysis because of their different behaviors in terms of clinical management and prognosis. The final histology reports were systematically reviewed by the pathologist. Estrogen and progesterone receptor analysis of tumor tissue, normally performed for breast carcinoma, was not detected because of lack of the epithelial component.1,17,18 Local recurrence, metastatic disease, and survival were evaluated. Follow-up was conducted by internal database clinical collection and interviews. Thirty-seven patients were included in the final analysis.

Statistical Analysis Sarcoma-related events were any local, regional, or distant recurrence or deaths from BS, whichever occurred first. Crude cumulative incidence of sarcoma-related events were computed in a competing risk framework, with other breast and non-breast primary tumors and contralateral breast tumors treated as competing events. Deaths from causes other than BS were treated as competing events in the computation of cumulative incidence of sarcoma-related deaths. Cumulative incidences were compared across different subgroups by means of the Gray test. All analyses were carried out with the SAS software (SAS Institute, Cary, NC) and the R software (cran.r-project.org). All the reported P values were 2-sided.

Results Patient Characteristics Median follow-up was 58 months (range, 4-146 months). Patient characteristics are reported in Table 1. In 12 patients (32.4%) the tumor size was ⱕ 2 cm; in another 12 patients tumor size ranged from 2.1 to 5 cm. In 13 patients (35.0%) the size of sarcoma was bigger than 5.1 cm. There were 3 stromal sarcomas and 34 angiosarcomas (91.9%). Because angiosarcoma is a high grade tumor by definition9,10 and all stromal sarcomas in our series were high grade, histologic grading was not used in the univariate analysis. One patient had microscopically focally involved margins after surgery, 7 patients had a close margins defined as ⬍ 1 cm. Twentyeight women had negative margins defined as ⬎ 1.1 cm. Twenty-one patients had previously undergone radiation therapy for invasive breast cancer, 1 for ductal intraepithelial neoplasia, and 1 for lymphoma of the breast.

Treatments Surgery was performed in all patients. Breast conservative surgery was the choice for 11 patients. Twenty-five patients underwent total mastectomy without nipple-areola complex sparing, even though, in some cases, the tumor was located far from the areola. One patient received a nipple-sparing mastectomy and sentinel node biopsy. No other sentinel lymph node biopsies were carried out in the other cases. One patient underwent radical mastectomy. One patient had clinical lymph node involvement so complete axillary dissection was performed in the course of conservative surgery. We describe the timing of breast reconstruction as delayed or immediate and classify reconstruction as autologous tissue and implant-based. Autologous flaps include the latissimus dorsi musculocutaneous flap and transverse rectus abdominis musculocutaneous (TRAM) flap. No deep inferior epigastric artery perforator or superior gluteal artery perforator flap procedures were performed (Table 2). Fourteen patients underwent reconstruction, 12 were immediate and 2 were delayed. Eight patients received flap reconstructions and 6 patients underwent implant reconstruction alone. Patients with PS underwent breast reconstruction more often than patients with SS (Fisher exact test P ⫽ .08) (Table 2). The overall complication rate was evaluated considering flap loss, tissue expander, or permanent implant displacement, se-

Clinical Breast Cancer December 2012

439

Outcome and Reconstructive Options in Sarcoma of the Breast Table 1 Characteristics of Sarcomas, Sarcoma-Related Events, and Deaths Sarcoma-Related Events

Sarcoma-Related Deaths

n (%)

Events, n, 5-Year Cumulative Incidence (%)

37 (100)

24 (70.8)

12 (43.4)

⬍35

3 (8.1)

3 (100.0)

2 (66.7)

35-49

13 (35.1)

6 (52.8)

ⱖ 50

21 (56.8)

15 (75.9)

36 (97.3)

24 (73.1)

1 (2.7)

0 (0.0)

ⱕ 2 cm

12 (32.4)

8 (78.6)

2.1-5 cm

12 (32.4)

6 (53.1)

⬎ 5 cm

13 (35.1)

10 (77.0)

Total

P

Events, n, 5-Year Cumulative Incidence (%)

P

Age

.30

3 (27.8)

.53

7 (49.1)

Sex Female Male

.23

12 (45.1) 0 (0.0)

.41

Tumor Size 4 (54.2) .38

3 (31.4)

.65

5 (46.0)

Histology Stromal sarcoma

3 (8.1)

0 (0.0)

34 (91.9)

15 (75.9)

Negative

28 (77.8)

17 (67.7)

Close or positive

8 (22.2)

6 (75.0)

Angiosarcoma

.06

0 (0.0) 12 (47.1)

.24

Surgical Marginsa .95

9 (42.1) 3 (41.7)

.68

Surgery BCS

11 (29.7)

6 (62.3)

Mastectomy

26 (70.3)

18 (70.8)

12 (46.2)

6 (51.4)

.40

2 (25.9) 10 (51.1)

.19

Reconstruction After Mastectomy Immediate Delayed

2 (7.8)

2 (100.0)

12 (46.2)

10 (83.3)

Yes

5 (13.5)

3 (70.0)

No

32 (86.5)

21 (71.1)

No

3 (28.4) .21 .17b

1 (50.0)

.51 .25b

6 (66.7)

Adjuvant Chemotherapy .99

2 (62.5) 10 (41.3)

.23

Adjuvant Radiation Therapy Yes

6 (16.2)

4 (79.2)

No

31 (83.8)

20 (69.8)

14 (37.8)

6 (49.7)

23 (62.2)

18 (85.7)

.43

2 (66.7) 10 (41.3)

.19

Primary or Secondary Sarcoma Primary c

Secondary

.06

3 (25.0) 9 (64.1)

.16

Abbreviation: BCS ⫽ breast conservative surgery. a Information was missing for one patient. b Reconstruction versus no reconstruction. c Twenty-one patients had previously undergone radiation therapy for invasive breast cancer, 1 for ductal intraepithelial neoplasia, and 1 for lymphoma of the breast.

roma, necrosis of mastectomy flaps or autologous flap, and infections. One patient developed a partial necrosis of the mastectomy flap which required a long-term observation and medication without permanent implant removal. One patient had seroma in a latissimus dorsi flap with implant which required long-term fine needle aspiration.

440

Clinical Breast Cancer December 2012

The general guidance present in the literature regarding the treatment of soft tissue sarcoma at any location was used to manage adjuvant chemotherapy. We considered only chemotherapy administered after surgery to treat primary cancer. We did not analyze treatments for local recurrence or for metastatic disease. In this firstline therapy, 4 patients received epirubicin/isofosfamide combina-

Antonio Toesca et al Table 2 Reconstruction After Mastectomy. Patients with Primary Sarcomas Underwent Breast Reconstruction More Often Than Patients with a Secondary Sarcoma (Fisher Exact Test P ⴝ .08) All Sarcomas, n ⴝ 26

Primary Sarcomas, nⴝ7

Secondary Sarcomas, n ⴝ 19

Reconstruction

14 (53.8)

6 (85.7)

8 (42.1)

No Reconstruction

12 (46.2)

1 (14.3)

11 (57.9)

Immediate reconstruction

12

5

7

Delayed reconstruction

2

1

1

Flap only

3

0

3

Flap with implant

5

0

5

Tissue expander

1

1

0

Permanent implant

5

5

0

Necrosis

1

0

1

Seroma

1

0

1

Reconstructive Timing

Reconstructive Type

Complications

Table 3 Description of Sarcoma-Related Events and Deaths Description of Event

n (%)

First Event Ipsilateral Breast Recurrence

15 (39.5)

Skin Relapse

1 (2.6)

Distant Metastases

7 (18.4)

Other Primary Tumor

2 (5.3)

Death From Sarcoma as First Event Death From Sarcoma

1 (2.6) 12 (31.6)

tion chemotherapy and 1 patient received paclitaxel according to the histotype of tumor. Six patients underwent adjuvant radiation therapy after mastectomy for large lesions (range, 3-9.5 cm). Three of them received both chemotherapy and radiation therapy. No patients received intraoperative partial breast irradiation.

Description of Events and Prognostic Factors Analysis Ipsilateral breast tumor recurrence occurred in 15 patients (39.5%). Skin relapse occurred in 1 patient (2.7%). Seven women (18.4%) developed distant metastasis and 1 patient died (2.7%) from sarcoma as first event (Table 3). Most failures occurred within 2 years from diagnosis. Age at diagnosis, sex, size of primary tumor, nodal status, and histology were, on univariate analysis, not found to be of prognostic significance in local control or survival (Table 1).

Type of surgery, surgical margins, type of reconstruction, adjuvant chemotherapy, or radiation therapy also did not significantly influence local control and survival. The cumulative incidence of local recurrence at 5 years was 49.7% in patients affected by PS. There was some evidence that events occurred more frequently in patients with SS (85.7%, Gray test P ⫽ .06) (Figure 1A). The cumulative incidence of PS- and SS-related death was 45.8% and 85.7% at 5 years, respectively (Gray test P ⫽ .16) (Figure 1B). The cumulative incidence of sarcoma-related events at 5 years in patients who underwent mastectomy without reconstruction was 83.3%. Events did not occur more frequently in patients who underwent breast reconstruction (59.2%; Gray test P ⫽ .17) (Figure 2A). The cumulative incidence of sarcoma-related deaths at 5 years was 36.5% in patients who underwent reconstruction and 66.7% in patients with mastectomy alone (Gray test P ⫽ .25) (Figure 2B).

Discussion The therapeutic management of BS is still a matter of debate and controversy because of their rarity. In the past all soft tissue sarcomas of the breast except phyllodes were called ‘stromal sarcoma’ which today refers to a specific rare sarcoma arising from the intralobular stroma of the breast.15,19 The change in nomenclature and progress in medical care in the longterm reduced the reliability of information and also the strength of retrospective studies on BS. Also, the rarity of BS precludes prospective study and any results in the literature must be considered within the limits of retrospective analysis.5,20,21 Furthermore, many authors include in the analysis different histopathologic patterns such as phyllodes tumor which is biologically distinct from other BSs with a different prognosis and is best studied separately.15,22 With these limits, many prognostic factors have been studied. Tumor grade4,23,24 and size2,23-26 have been more consistently shown to be predictive of outcome. In our series, tumor size did not influence local control or survival. Curiously, in our population, histologic grade was high in the totality of cases so univariate analysis was not possible. The proportion of angiosarcoma subtypes reported in the literature varies from 10% to 42%27,28 and the prognosis of specific subtypes is known to be worse than that of other BSs28-32 with a 10-year survival ranging from 40%28,30 to 52%.28,29,33 The fact that in our study 91.9% of patients were affected by the angiosarcoma subtype and that the totality of cases were high grade explains the severe prognosis observed. The five-year sarcoma-related deaths in our study was 47.1%. Another important prognostic factor is the absence of residual disease, even though it is rare to find studies with a consistent portion of positive margin disease.28,31 We endeavored to compare a ‘close margins’ category to patients with ‘negative margins’ without finding any differences in prognosis. From the 1950s and onward, mastectomy was held as the gold standard22,23 but this option has been challenged over the years. Several studies show no differences in outcome in patients with breast conservative surgery with microscopically negative margins compared with mastectomy.4,22,24,27,28,34 In our series surgery does not seem to affect local failure rates and conservative surgery was

Clinical Breast Cancer December 2012

441

Outcome and Reconstructive Options in Sarcoma of the Breast Figure 1 (A) Cumulative Incidence of Primary and Secondary Sarcoma-Related Events. (B) Cumulative Incidence of Primary and Secondary Sarcoma-Related Deaths

A 1.0

B 1.0 Secondary

Gray test P-value: 0.06

Gray test P-value: 0.16 0.8

0.6 Primary 0.4

Cumulative Incidence

Cumulative Incidence

0.8

Secondary 0.6

0.4 Primary

0.2

0.2

0.0

0.0 0

1

2

3

4

0

5

1

2

Years

3

4

5

Years

Primary sarcoma; n = 14; 5 years: 49.7% Secondary sarcoma; n = 23; 5 years: 85.7%

Primary sarcoma; n = 14; 5 years: 25.0% Secondary sarcoma; n = 23; 5 years: 64.1%

Figure 2 (A) Cumulative Incidence of Sarcoma-Related Events by Reconstruction. (B) Cumulative Incidence of Sarcoma-Related Deaths by Reconstruction

B 1.0

A 1.0 Gray test P-value: 0.17

Gray test P-value: 0.25

No reconstruction 0.8 Reconstruction

0.6

0.4

No reconstruction 0.6

0.2

0.0

0.0 1

2

3

4

5

Years No reconstruction; n = 12; 5 years: 83.3% Reconstruction; n = 14; 5 years: 59.2%

proposed in 30% of cases. Furthermore, axillary metastasis occurred in 1 patient only, confirming that regional node involvement is uncommon during BS. When lymph node metastases are present, it could be important to consider the differential diagnosis of a metaplastic carcinoma or carcinosarcoma to better orient adjuvant treatments.

Clinical Breast Cancer December 2012

Reconstruction

0.4

0.2

0

442

Cumulative Incidence

Cumulative Incidence

0.8

0

1

2

3

4

5

Years No reconstruction; n = 12; 5 years: 66.7% Reconstruction; n = 14; 5 years: 36.5%

In our series all SSs were angiosarcoma and represented 62.2% of all BSs. This proportion of patients is in excess compared with that arising from other studies.28,35 In a series by Bousquet et al, the proportion of radiation-induced BSs was 42%; no difference in outcome was found in the 2 different groups.28 In our study there was some evidence that events occur more frequently in patients with SS.

Antonio Toesca et al The use of adjuvant chemotherapy in the treatment of BS is controversial. For all body soft tissue sarcomas, adjuvant therapy has not been proven to be reliably beneficial in the few randomized trials available.7 Several meta-analyses suggest a benefit for the addition of adjuvant chemotherapy for larger, high-grade soft tissue sarcoma of the extremities.7,36 Always considering soft tissue sarcomas in any location, the combination of doxorubicin and ifosfamide appears to be associated with benefits in terms of survival, however, with an association with significant toxicity.7,37 Concerning BSs, many studies report poor survival and local recurrence rate after adjuvant therapy showing no differences between groups treated with surgery alone and groups treated with chemotherapy after surgery.38,39,40 However, other studies reported a beneficial effect on the disease-free survival rate for high-grade sarcomas treated with chemotherapy after surgery with negative margins.7,25,32,41-43 Very few articles present data from neoadjuvant trials especially considering nonresectable cancer with very poor results.37,44 However, neoadjuvant treatment could reveal very important information about chemosensitivity allowing assessment of response to alternate agents after surgery. Development of novel treatments should be based on the increasing understanding of tumor biology. Excellent results with agents that target various molecular lesions and pathways have been obtained in different cancers. In gastrointestinal stromal tumor with c-kit inhibitor imatinib has been very effective. Inhibitors of the other tyrosine kinases are already in clinical trials in sarcoma, although no data are available on breast sarcoma.45 The vascular endothelial growth factor (VEGF) is important in angiogenesis and is expressed in soft tissue sarcomas and might correlate with prognosis. Sunitinib, sorafenib, and pazopanib have shown activity in initial clinical trials giving stabilization of disease.46 Bevacizumab, monoclonal antibody against VEGF, has activity against angiosarcoma with clinical benefit of stable disease.45,47 Inhibiting the pathway with monoclonal antibodies binding the receptor is a strategy undergoing investigation in all tissue sarcomas but solid preclinical and clinical data are needed. The role of radiation therapy is also unclear. A hyperfractionated and accelerated radiation dose is described as being successful in primary BS.7,42,48 In the treatment of SS, radiation therapy has less effect on local control.7,16,49,50 When a second course of radiation therapy in patients with secondary radiation-induced sarcoma is indicated, possible complications such as rib fracture, pneumonitis, and soft tissue necrosis can occur. Many advances have been made in reconstructive surgery for breast carcinoma, with an improvement in functional results and patient satisfaction. However, reconstructive surgery for BS has always been considered unsafe because a significant number of patients require extensive removal of tissue. In addition, many patients frequently develop sarcoma recurrence and management of a local relapse is always difficult in the presence of an implant or flap. Increasing knowledge of the clinicopathologic responses to therapy and the identification of appropriate candidates for reconstruction is very important in planning the surgery thoroughly and avoiding complications. In our series, approximately 54% of the patients had immediate reconstruction after mastectomy, in 1 case after nipple-sparing mastectomy to obtain the best esthetic results. Flap reconstruction was offered especially to patients with radiation-induced sarcoma.

The TRAM flap procedure was performed to increase tissue replacement. More frequently however, patients with SS do not undergo adjuvant radiation therapy so a silicon or saline implant reconstruction alone can be considered in order to achieve reasonable symmetry with the contralateral breast. Certainly, reconstruction failure with implant extrusion can occur in the presence of irradiated local tissue.51-54 Considering that in our series the cumulative incidence of sarcoma-related events and death was not affected by reconstruction and that complications occur rarely, reconstruction should be considered an appropriate option and the plastic surgeon should play an important role in the management of BS patients. Because most patients have a poor oncologic outcome, the timing of reconstruction should be immediate when possible and indications for plastic surgery should increase to preserve quality of life. Breast sarcomas are a rare malignancy requiring a multidisciplinary approach to optimize treatments and outcome and should be treated in a referral center.

Conclusion Secondary sarcomas were associated with a higher risk of events. No other factors were found to influence prognosis. Patients undergoing breast conservative surgery or reconstruction after mastectomy did not show a worse prognosis compared with patients undergoing mastectomy.

Clinical Practice Points ●

●

●

●

●

Sarcoma of the breast is a rare pathology representing ⬍ 1% of entire body sarcomas. Because of the rarity of the disease, the therapeutic management of BS is still a matter of debate and controversy. Rarity precludes prospective studies so retrospective analyses play an important role in a definition of clinical approaches. Surgery remains the mainstay of therapy. Several studies show no differences in outcome in patients with breast conservative surgery with microscopically negative margins compared with mastectomy. Axillary dissection is not necessary unless in the presence of clinical nodal involvement. The role of chemotherapy and radiation therapy has not been clearly defined even if a trend in improved survival seems present without statistical significance. Their indication after surgery is derived from extrapolation of data from large trials including all the soft tissue sarcomas irrespective of their primary site. Radiation therapy should be given as an adjuvant to surgery only for primary intermediate- to high-grade BS and a size larger than 5 cm. Data concerning adjuvant chemotherapy are more conflicting and a final demonstration of efficacy is lacking. The importance of this study is to confirm the significance of prognostic factors in management of adjuvant therapies and highlights that patients undergoing breast conservative surgery or reconstruction after mastectomy did not show a worse prognosis compared with patients undergoing mastectomy. Because most patients have a poor oncologic outcome, the timing of reconstruction should be immediate when possible, and indications for plastic surgery should increase to preserve quality of life.

Clinical Breast Cancer December 2012

443

Outcome and Reconstructive Options in Sarcoma of the Breast Acknowledgments Antonio Toesca and Gianluca Spitaleri contributed equally to this work. The authors thank Mr William Russell-Edu for English revision of the manuscript.

Disclosure All authors have no conflicts of interest.

References 1. Al-Benna S, Poggemann K, Steinau HU. Diagnosis and management of primary breast sarcoma. Breast Cancer Res Treat 2010; 122:619-26. 2. Pollard SG, Marks PV, Temple LN, et al. Breast sarcoma. A clinicopathologic review of 25 cases. Cancer 1990; 66:941-4. 3. Terrier P, Terrier-Lacombe MJ, Mouriesse H, et al. Primary breast sarcoma: a review of 33 cases with immunohistochemistry and prognostic factors. Breast Cancer Res Treat 1989; 13:39-48. 4. McGowan TS, Cummings BJ, O’Sullivan B, et al. An analysis of 78 breast sarcoma patients without distant metastases at presentation. Int J Radiat Oncol Biol Phys 2000; 46:383-90. 5. Confavreux C, Lurkin A, Mitton N, et al. Sarcomas and malignant phyllodes tumours of the breast–a retrospective study. Eur J Cancer 2006; 42:2715-21. 6. May DS, Stroup NE. The incidence of sarcomas of the breast among women in the United States, 1973-1986. Plast Reconstr Surg 1991; 87:193-4. 7. Sheth GR, Cranmer LD, Smith BD, et al. Radiation induced sarcoma of the breast: a systematic review. Oncologist 2012; 17:405-18. 8. Rubino C, Shamsaldin A, Lê MG, et al. Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment. Breast Cancer Res Treat 2005; 89: 277-88. 9. Young RJ, Brown NJ, Reed MW, et al. Angiosarcoma. Lancet Oncol 2010; 11:983-91. 10. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors, 5th Edition. Copyright 2007 Mosby, an imprint of Elsevier. 11. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema; a report of six cases in elephantiasis chirurgica. Cancer. 1948; 1:64-81. 12. Hollstein M, Marion MJ, Lehman T, et al. p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 1994; 15:1-3. 13. Yap J, Chuba PJ, Thomas R, et al. Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 2002; 52:1231-7. 14. Brady MS, Garfein CF, Petrek JA, et al. Post-treatment sarcoma in breast cancer patients. Ann Surg Oncol 1994; 1:66-72. 15. Jonathan C, Benjamin RS, Valero V. Primary soft tissue sarcoma of the breast. Curr Treat Options Oncol 2001; 1:169-76. 16. Casali PG, Jost L, Sleijfer S, et al. Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow up. Ann Oncol 2009; 20(Suppl 4): iv132-6. 17. Daigeler A, Kuhnen C, Moritz R, et al. Lymph node metastases in soft tissue sarcomas: a single center analysis of 1,597 patients. Langenbecks Arch Surg 2009; 394:321-9. 18. Esposito NN, Mohan D, Brufsky A, et al. Phyllodes tumor: a clinicopathologic and immunohistochemical study of 30 cases. Arch Pathol Lab Med 2006; 130:1516-20. 19. Callery CD, Rosen PP, Kinne DW. Sarcoma of the breast. A study of 32 patients with reappraisal of classification and therapy. Ann Surg 1985; 201:527-32. 20. Chelius M. Teleangiektasie. Heidelberger Klin Ann 1828; 499:517. 21. Lee B, Pack G. Giant intracanalicular myxoma: the socalled cystosarcoma phyllodes mammae of Johannes Muller. Am J Cancer 1931; 93:268. 22. Berg JW, Decrosse JJ, Fracchia AA, et al. Stromal sarcomas of the breast. A unified approach to connective tissue sarcomas other than cystosarcoma phyllodes. Cancer 1962; 15:418-24. 23. Lum YW, Jacobs L. Primary breast sarcoma. Surg Clin North Am 2008; 88:559-70. 24. Gutman H, Pollock RE, Ross MI, et al. Sarcoma of the breast: implications for extent of therapy. The M. D. Anderson experience. Surgery 1994; 116:505-9. 25. Barrow BJ, Janjan NA, Gutman H, et al. Role of radiotherapy in sarcoma of the breast–a retrospective review of the M.D. Anderson experience. Radiother Oncol 1999; 52:173-8. 26. Adem C, Reynolds C, Ingle JN, et al. Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review of the literature. Br J Cancer 2004; 91:237-41.

444

Clinical Breast Cancer December 2012

27. Zelek L, Llombart-Cussac A, Terrier P, et al. Prognostic factors in primary breast sarcomas: a series of patients with long-term follow-up. J Clin Oncol 2003; 21: 2583-8. 28. Bousquet G, Confavreux C, Magné N, et al. Outcome and prognostic factors in breast sarcoma: a multicenter study from the rare cancer network. Radiother Oncol 2007; 85:355-61. 29. Donnell RM, Rosen PP, Lieberman PH, et al. Angiosarcoma and other vascular tumors of the breast. Am J Surg Pathol 1981; 5:629-42. 30. Merino MJ, Carter D, Berman M. Angiosarcoma of the breast. Am J Surg Pathol 1983; 7:53-60. 31. Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996; 14:1679-89. 32. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma. The prognostic significance of tumor differentiation. Cancer 1988; 62:2145-51. 33. Penel N, Depadt G, Vilain MO, et al. Frequency of genetic diseases and cancer antecedents in 493 adults with visceral or soft tissue sarcoma [in French]. Bull Cancer 2003; 90:887-95. 34. Blanchard DK, Reynolds CA, Grant CS, et al. Primary nonphylloides breast sarcomas. Am J Surg 2003; 186:359-61. 35. Cha C, Antonescu CR, Quan ML, et al. Long-term results with resection of radiation-induced soft tissue sarcomas. Ann Surg 2004; 239:903-9. 36. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008; 113:573-81. 37. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13:1537-45. 38. Brady MS, Gaynor JJ, Brennan MF. Radiation-associated sarcoma of bone and soft tissue. Arch Surg 1992; 127:1379-85. 39. Kuten A, Sapir D, Cohen Y, et al. Postirradiation soft tissue sarcoma occurring in breast cancer patients: report of seven cases and results of combination chemotherapy. J Surg Oncol 1985; 28:168-71. 40. Thijssens KM, van Ginkel RJ, Suurmeijer AJ, et al. Radiation-induced sarcoma: a challenge for the surgeon. Ann Surg Oncol 2005; 12:237-45. 41. Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol 2010; 28: 2064-9. 42. Feigenberg SJ, Mendenhall NP, Reith JD, et al. Angiosarcoma after breast-conserving therapy: experience with hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 2002; 52:620-6. 43. Nakamura R, Nagashima T, Sakakibara M, et al. Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma. Breast Cancer 2007; 14:245-9. 44. Gortzak E, Azzarelli A, Buesa J, et al. A randomised phase II study on neo-adjuvant chemotherapy for ’high-risk’ adult soft-tissue sarcoma. Eur J Cancer 2001; 37:1096103. 45. Voutsadakis IA, Zaman K, Leyvraz S. Breast sarcomas: current and future perspectives. Breast 2011; 20:199-204. 46. Yudoh K, Kanamori M, Ohmori K, et al. Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas. Br J Cancer 2001; 84:1610-5. 47. Ganjoo KN. New developments in targeted therapy for soft tissue sarcoma. Curr Oncol Rep 2010; 12:261-5. 48. Palta M, Morris CG, Grobmyer SR, et al. Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy. Cancer 2010; 116:1872-8. 49. Schulz U, Gokel JM, Poleska W. Soft tissue sarcomas after radiation treatment for breast cancer. Three case studies and review of literature. Strahlenther Onkol 2000; 176:144-9. 50. Givens SS, Woo SY, Huang LY, et al. Non-metastatic Ewing’s sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy. Int J Oncol 1999; 14:1039-43. 51. Chang DW, Robb GL. Recent advances in reconstructive surgery for soft-tissue sarcomas. Curr Oncol Rep 2000; 2:495-501. 52. Crosby MA, Chike-Obi CJ, Baumann DP, et al. Reconstructive outcomes in patients with sarcoma of the breast. Plast Reconstr Surg 2010; 126:1805-14. 53. Evans GR, Schusterman MA, Kroll SS, et al. Reconstruction and the radiated breast: is there a role for implants? Plast Reconstr Surg 1995; 96:1111-5, discussion 1116-8. 54. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: A critical review of the literature. Plast Reconstr Surg 2009; 124:395-408.